Stijnen, Th.

Quantifying the benefit of early living-donor renal transplantation with a simulation model of the Dutch renal replacement therapy population (Article)

2012-01-01T00:00:00Z

Background.Early living-donor transplantation improves patient-and graft-survival compared with possible cadaveric renal transplantation (RTx), but the magnitude of the survival gain is unknown. For patients starting renal replacement therapy (RRT), we aimed to quantify the survival benefit of early living-donor transplantation compared with dialysis and possible cadaveric transplantation and to estimate the population benefit from increasing the early transplantation rate. Methods.We used a decision-analytic computer-simulation model, with a lifetime time horizon, simulating patients starting RRT, using data from the Dutch End-Stage Renal Disease Registry and published data. We compared the (quality adjusted) life expectancy (LE) of 'early living-donor RTx' and 'dialysis' (with possible cadaveric RTx if available). Results.LE and quality-adjusted LE benefits of the early living-donor RTx compared with the dialysis strategy for 40-year-old patients ranged from 7.5 to 9.9 life years (LYs) [6.7-8.8 quality-adjusted life years (QALYs)] depending on the primary renal disease. For 70-year-old patients, the benefit was 4.3-6.0 LYs (4.3-6.0 QALYs). Increasing the early transplantation rate from currently 5.8 to 22.2% (the highest in Europe) would increase average LE by 1.2 LYs and total LE for annual incident cases in the Netherlands by >1800 LYs. Conclusions.Efforts to increase early living-donor RTx could potentially substantially increase LE for patients starting RRT, especially in younger patients.

Selected medical students achieve better than lottery-admitted students during clerkships (Article)

2011-10-01T00:00:00Z

Medical Education 2011: 45: 1032-1040 Objectives A recent controlled study by our group showed that the dropout rate in the first 2years of study of medical students selected for entry by the assessment of a combination of non-cognitive and cognitive abilities was 2.6 times lower than that of a control group of students admitted by lottery. The aim of the present study was to compare the performance of these two groups in the clinical phase. Methods A prospective cohort study was performed to compare the performance of 389 medical students admitted by selection with that of 938 students admitted by weighted lottery between 2001 and 2004. Follow-up of these cohorts lasted 5.5-8.5years. The main outcome measures were the mean grade obtained on the first five discipline-specific clerkships by all cohorts and the mean grade achieved on all 10 clerkships by the cohorts of 2001 and 2002. Results Selected students obtained a significantly higher mean grade during their first five clerkships than lottery-admitted students (mean±standard error [SE] 7.95±0.03, 95% confidence interval [CI] 7.90-8.00 versus mean±SE 7.84±0.02, 95% CI 7.81-7.87; p<0.001). This difference reflected the fact that selected students achieved a grade of ≥8.0 1.5 times more often than lottery-admitted students. An analysis of all mean grades awarded on 10 clerkships revealed the same results. Moreover, the longer follow-up period over the clerkships showed that the relative risk for dropout was twice as low in the selected student group as in the lottery-admitted student group. Conclusions The selected group received significantly higher mean grades on their first five clerkships, which could not be attributed to factors other than the selection procedure. Although the risk for dropout before the clinical phase increased somewhat in both groups, the actual dropout rate proved to be twice as low in the selected group.

The combined analysis of uncertainty and patient heterogeneity in medical decision models (Article)

2011-07-01T00:00:00Z

The analysis of both patient heterogeneity and parameter uncertainty in decision models is increasingly recommended. In addition, the complexity of current medical decision models commonly requires simulating individual subjects, which introduces stochastic uncertainty. The combined analysis of uncertainty and heterogeneity often involves complex nested Monte Carlo simulations to obtain the model outcomes of interest. In this article, the authors distinguish eight model types, each dealing with a different combination of patient heterogeneity, parameter uncertainty, and stochastic uncertainty. The analyses that are required to obtain the model outcomes are expressed in equations, explained in stepwise algorithms, and demonstrated in examples. Patient heterogeneity is represented by frequency distributions and analyzed with Monte Carlo simulation. Parameter uncertainty is represented by probability distributions and analyzed with 2nd-order Monte Carlo simulation (aka probabilistic sensitivity analysis). Stochastic uncertainty is analyzed with 1st-order Monte Carlo simulation (i.e., trials or random walks). This article can be used as a reference for analyzing complex models with more than one type of uncertainty and patient heterogeneity.

Effect of oxandrolone on glucose metabolism in growth hormone-treated girls with turner syndrome (Article)

2011-02-01T00:00:00Z

Background: The weak androgen oxandrolone (Ox) may increase height but may also affect glucose metabolism in girls with Turner syndrome (TS). Methods: In a randomized, placebo-controlled, double-blind study, we assessed the effect of Ox at a dosage of either 0.06 or 0.03 mg/kg/day on glucose metabolism in 133 growth hormone (GH)-treated girls with TS. Patients were treated with GH (1.33 mg/m2/day) from baseline, combined with placebo (Pl) or Ox from the age of 8, and estrogens from the age of 12. Oral glucose tolerance tests (OGTT) were performed, and HbA1c levels were measured before, during, and after discontinuing Ox/Pl therapy. Results: Insulin sensitivity, assessed by the whole-body insulin sensitivity index (WBISI) decreased during GH+Ox/Pl (p = 0.003) without significant differences between the dosage groups. Values returned to pre-treatment levels after discontinuing GH+Ox/Pl. On GH+Ox, fasting glucose was less frequently impaired (Ox 0.03, p = 0.001; Ox 0.06, p = 0.02) and HbA1c levels decreased more (p = 0.03 and p = 0.001, respectively) than on GH+Pl. Conclusions: We conclude that in GH-treated girls with TS, Ox at a dosage of 0.03 or 0.06 mg/kg/day does not significantly affect insulin sensitivity. Insulin sensitivity decreases during GH therapy, to return to a pre-treatment level after discontinuing therapy.

Effectiveness of different modalities of psychotherapeutic treatment for patients with cluster C personality disorders: results of a large prospective multicentre study. (Article)

2011-01-01T00:00:00Z

Abstract BACKGROUND: No previous studies have compared the effectiveness of different modalities of psychotherapeutic treatment, as defined by different settings and durations, for patients with cluster C personality disorders. The aim of this multicentre study was to compare the effectiveness of 5 treatment modalities for patients with cluster C personality disorders in terms of psychiatric symptoms, psychosocial functioning, and quality of life. The following treatment modalities were compared: long-term outpatient (more than 6 months), short-term day hospital (up to 6 months), long-term day hospital, short-term inpatient, and long-term inpatient psychotherapy. METHODS: The study was conducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 371 patients with a DSM-IV-TR axis-II cluster C diagnosis. Patients were assigned to 5 different modalities of psychotherapeutic treatment, and effectiveness was assessed at 12 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychosocial functioning (Outcome Questionnaire-45), and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. RESULTS: Patients in all treatment groups had improved on all outcomes 12 months after baseline. Patients receiving short-term inpatient treatment showed more improvement than patients receiving other treatment modalities. CONCLUSIONS: Psychotherapeutic treatment, especially in the short-term inpatient modality, is an effective treatment for patients with cluster C personality disorders.

Effectiveness of outpatient, day hospital, and inpatient psychotherapeutic treatment for patients with cluster B personality disorders (Article)

2010-10-23T00:00:00Z

Abstract Background: For patients with cluster B personality disor- ders there is no consensus regarding the optimal treatment setting. The aim of this study was to compare the effective- ness of different psychotherapeutic settings for patients with cluster B personality disorders, i.e. outpatient, day hos- pital, and inpatient treatment. Methods: The study was con- ducted between March 2003 and June 2008 in 6 mental health care centres in the Netherlands, with a sample of 207 patients with a DSM-IV-TR axis II cluster B diagnosis. Patients were assigned to 3 different settings of psychotherapeutic treatment and effectiveness was assessed at 18 months after baseline. An intention-to-treat analysis was conducted for psychiatric symptoms (Brief Symptom Inventory), psychoso- cial functioning (Outcome Questionnaire-45), and quality of life (EQ-5D), using multilevel statistical modelling. As the study was non-randomised, the propensity score method was used to control for initial differences. Results: Patients in all 3 settings improved significantly in terms of psychiatric symptoms, social and interpersonal functioning, and quality of life 18 months after baseline. The inpatient group showed the largest improvements. The comparison of outpatient and inpatient treatment regarding psychiatric symptoms showed a marginally significant result (p = 0.057) in favour of inpatient treatment. Conclusions: Patients with cluster B personality disorders improved in all investigated treatment settings, with a trend towards larger improvements of psy- chiatric symptoms in the inpatient setting compared to the outpatient setting. Specialised inpatient treatment should be considered as a valuable treatment option for cluster B personality disorders, both in research and in clinical prac- tice.

The effect of oxandrolone on body proportions and body composition in growth hormone-treated girls with Turner syndrome (Article)

2010-08-01T00:00:00Z

Objective Untreated girls with Turner syndrome (TS) have short stature, relatively broad shoulders, a broad pelvis, short legs, a high fat mass and low muscle mass. Our objective was to assess the effect of the weak androgen oxandrolone (Ox) on body proportions and composition in growth hormone (GH)-treated girls with TS. DesignPatients 133 patients were included in a randomized, placebo-controlled, double-blind study. Methods Patients were treated with GH (1·33 mgm2per day) from baseline, combined with placebo (Pl) or Ox in a low (0·03 mgkg per day) or previously conventional (0·06 mgkg per day) dose from the age of eight, and oestrogens from the age of twelve. Sitting height, biacromial and biiliacal distances compared with height (i.e. shape values), BMI, waist circumference, sum of 4 skinfolds (sum4skin) and upper arm muscle area (UAMA) SD scores (SDS) were assessed half-yearly. Results Compared with GH + Pl, adult shape values on GH + Ox tended to be higher for sitting height (Ox 0·03, P = 0·2; Ox 0·06, P = 0·02) and biacromial distance (Ox 0·03, P = 0·2; Ox 0·06, P = 0·07) and lower for biiliacal distance (Ox 0·03, P = 0·004; Ox 0·06, P = 0·08). Sum4skin SDS tended to decrease more (Ox 0·03, P = 0·2; Ox 0·06, P = 0·005) while UAMA SDS increased more (Ox 0·03, P < 0·001; Ox 0·06, P < 0·001) than on GH + Pl. The increase in BMI and waist circumference SDS was comparable between the dosage groups. Conclusions In GH-treated girls with TS, Ox 0·06 increases sitting height and tends to increase biacromial distance and decrease biiliacal distance, while Ox 0·03 significantly decreases biiliacal distance compared with height. Furthermore, Ox 0·06 reduces subcutaneous fat mass, and both Ox dosages increase muscle mass.

Cardiac phenotype and angiotensin II levels in AT1a, AT 1b, and AT2 receptor single, double, and triple knockouts (Article)

2010-06-01T00:00:00Z

AimsOur aim was to determine the contribution of the three angiotensin (Ang) II receptor subtypes (AT1a, AT1b, AT2) to coronary responsiveness, cardiac histopathology, and tissue Ang II levels using mice deficient for one, two, or all three Ang II receptors.Methods and resultsHearts of knockout mice and their wild-type controls were collected for histochemistry or perfused according to Langendorff, and kidneys were removed to measure tissue Ang II. Ang II dose-dependently decreased coronary flow (CF) and left ventricular systolic pressure (LVSP), and these effects were absent in all genotypes deficient for AT1a, independently of AT1band AT2. The deletion of Ang II receptors had an effect neither on the morphology of medium-sized vessels in the heart nor on the development of fibrosis. However, the lack of both AT1subtypes was associated with atrophic changes in the myocardium, a reduced CF and a reduced LVSP. AT1adeletion alone, independently of the presence or absence of AT1band/or AT2, reduced renal Ang II by 50 despite a five-fold rise of plasma Ang II. AT1bdeletion, on top of AT1adeletion (but not alone), further decreased tissue Ang II, while increasing plasma Ang II. In mice deficient for all three Ang II receptors, renal Ang II was located only extracellularly. Conclusion The lack of both AT1subtypes led to a baseline reduction of CF and LVSP, and the effects of Ang II on CF and LVSP were found to be exclusively mediated via AT1a. The lack of AT1aor AT1bdoes not influence the development or maintenance of normal cardiac morphology, whereas deficiency for both receptors led to atrophic changes in the heart. Renal Ang II levels largely depend on AT1binding of extracellularly generated Ang II, and in the absence of all three Ang II receptors, renal Ang II is only located extracellularly.

Growth patterns during childhood and the relationship with acylation-stimulating protein (Article)

2010-06-01T00:00:00Z

Background/Objectives Acylation-stimulating protein (ASP) is an adipose tissue-derived hormone, which stimulates glucose and free fatty acid (FFA) uptake into adipocytes. Changes in ASP metabolism are associated with alterations in lipid metabolism. As postnatal catch-up growth has been associated with dyslipidaemia in later life, we investigated the association between ASP and birth size, adult size and different growth patterns during childhood. Methods The associations were investigated by multiple regression analyses in 285 young adults, aged 18-24. Subsequently, differences in ASP were analysed in four clinically relevant subgroups, young adults either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age with idiopathic short stature (ISS) or with normal stature (controls). Results Weight gain during childhood, particularly fat accumulation, was positively related to ASP levels in early adulthood, independent of birth size, age and gender. Foetal growth, reflected by birth size, was not related to ASP levels. Between the subgroups, no differences in ASP were found, but SGA-CU and ISS subjects had significantly higher levels of FFA. Conclusion Exaggerated weight gain during childhood, but not foetal growth, contributes to alterations in ASP metabolism, which may be associated with impaired FFA uptake and delayed triglycerides clearance. Therefore, exaggerated weight gain during childhood should be prevented.

Analysis of individual drug use as a time-varying determinant of exposure in prospective population-based cohort studies (Article)

2010-04-01T00:00:00Z

In pharmaco-epidemiology, the use of drugs is the determinant of interest when studying exposure-outcome associations. The increased availability of computerized information about drug use on an individual basis has greatly facilitated analyses of drug effects on a population-based scale. It seems likely that many negative findings in the early days of pharmaco-epidemiology can be explained by non-differential misclassification because of too simple (yes/no) exposure measures. In this paper, the authors discuss the importance of an adequate definition of drug exposure in pharmaco-epidemiological research and how this time-varying determinant can be analyzed in cohort studies. To reduce the risk of non-differential misclassification, a precise definition of exposure is mandatory and it is important to distinguish the complete follow-up period of a population into mutually exclusive episodes of non-use, past use and current use for each individual. By analyzing exposure to drugs as a time-dependent variable in a Cox regression model, cohort studies with complete coverage of all filled prescriptions can provide us with valid and precise risk estimates of drug-outcome associations. However, such estimates may be biased in the presence of time-dependent confounders which are themselves affected by prior exposure.

Value of information analyses of economic randomized controlled trials: The treatment of intermittent claudication (Article)

2010-03-01T00:00:00Z

Objective: The aim of this study is to design the optimal study comparing endovascular revascularization and supervised exercise training for patients with intermittent claudication and to demonstrate value of information (VOI) analysis of patient-level data from an economic randomized controlled trial to guide future research. Methods: We applied a net benefit framework to patient-level data on costs and quality-of-life of a previous randomized controlled trial. VOI analyses were performed using Monte Carlo simulation. We estimated the total expected value of perfect information (total EVPI), the total expected value of sample information (total EVSI), the partial expected value of perfect information (partial EVPI), and the partial expected value of sample information (partial EVSI). These VOI analyses identified the key parameters and the optimal sample size of future study designs. Sensitivity analyses were performed to explore the robustness of our assumptions about the population to benefit, the willingness-to-pay threshold, and the study costs. The VOI analyses are demonstrated in statistical software (R) and a spreadsheet (Excel) allowing other investigators to apply VOI analysis to their patient-level data. Results: The optimal study design for the treatment of intermittent claudication involves a randomized controlled trial collecting data on the quality-adjusted life expectancy and additional admission costs for 525 patients per treatment arm. The optimal sample size remained between 400 and 600 patients for a willingness-to-pay threshold between €30,000 and €100,000/quality-adjusted life-years, for even extreme assumptions about the study costs, and for a range of 3 to 7 years that future patients will benefit from the results of the proposed study. Conclusions: 1) The optimal study for patients with intermittent claudication collects data on two key parameters for 525 patients per trial arm; and 2) we have shown that value of information analysis provides an explicit framework to determine the optimal sample size and identify key parameters for the design of future clinical trials.

Overweight, Obesity, and Depression: a systematic review and meta-analysis of longitudinal studies (Article)

2010-03-01T00:00:00Z

Abstract CONTEXT: Association between obesity and depression has repeatedly been established. For treatment and prevention purposes, it is important to acquire more insight into their longitudinal interaction. OBJECTIVE: To conduct a systematic review and meta-analysis on the longitudinal relationship between depression, overweight, and obesity and to identify possible influencing factors. DATA SOURCES: Studies were found using PubMed, PsycINFO, and EMBASE databases and selected on several criteria. STUDY SELECTION: Studies examining the longitudinal bidirectional relation between depression and overweight (body mass index 25-29.99) or obesity (body mass index > or =30) were selected. DATA EXTRACTION: Unadjusted and adjusted odds ratios (ORs) were extracted or provided by the authors. DATA SYNTHESIS: Overall, unadjusted ORs were calculated and subgroup analyses were performed for the 15 included studies (N = 58 745) to estimate the effect of possible moderators (sex, age, depression severity). Obesity at baseline increased the risk of onset of depression at follow-up (unadjusted OR, 1.55; 95% confidence interval [CI], 1.22-1.98; P < .001). This association was more pronounced among Americans than among Europeans (P = .05) and for depressive disorder than for depressive symptoms (P = .05). Overweight increased the risk of onset of depression at follow-up (unadjusted OR, 1.27; 95% CI, 1.07-1.51; P < .01). This association was statistically significant among adults (aged 20-59 years and > or =60 years) but not among younger persons (aged <20 years). Baseline depression (symptoms and disorder) was not predictive of overweight over time. However, depression increased the odds for developing obesity (OR, 1.58; 95% CI, 1.33-1.87; P < .001). Subgroup analyses did not reveal specific moderators of the association. CONCLUSIONS: This meta-analysis confirms a reciprocal link between depression and obesity. Obesity was found to increase the risk of depression, most pronounced among Americans and for clinically diagnosed depression. In addition, depression was found to be predictive of developing obesity.

The effect of the weak androgen oxandrolone on psychological and behavioral characteristics in growth hormone-treated girls with Turner syndrome (Article)

2010-03-01T00:00:00Z

The weak androgen oxandrolone (Ox) increases height gain in growth-hormone (GH) treated girls with Turner syndrome (TS), but may also give rise to virilizing side effects. To assess the effect of Ox, at a conventional and low dosage, on behavior, aggression, romantic and sexual interest, mood, and gender role in GH-treated girls with TS, a randomized, placebo-controlled, double-blind study was conducted. 133 patients were treated with GH (1.33 mg/m2/d) from baseline, combined with placebo (Pl), Ox 0.03 mg/kg/d, or Ox 0.06 mg/kg/d from the age of eight, and with estrogens from the age of 12. The child behavior checklist (CBCL), Junior Dutch Personality Questionnaire (DPQ-J), State-subscale of the Spielberger's State-Trait Anger Scale, Romantic and Sexual Interest Questionnaire, Mood Questionnaire, and Gender Role Questionnaire were filled out before, during, and after discontinuing Ox/Pl. The changes during Ox/Pl therapy were not significantly different between the dosage groups. In untreated patients, the mean CBCL total (P = 0.002) and internalizing (P = 0.003) T scores, as well as the mean DPQ-J social inadequacy SD score (SDS) (P = 0.004) were higher than in reference girls, but decreased during GH + Ox/Pl therapy (P < 0.001, P = 0.05, P < 0.001, respectively). Whereas the mean total (P = 0.01) and internalizing (P < 0.001) T score remained relatively high, the mean social inadequacy SDS became comparable with reference values. We conclude that in GH-treated girls with TS, Ox 0.03 mg/kg/d or 0.06 mg/kg/d does not cause evident psychological virilizing side effects. Problem behavior, frequently present in untreated girls with TS, decreases during therapy, but total and internalizing problem behavior remain increased.

Uncertainty and patient heterogeneity in medical decision models (Article)

2010-03-01T00:00:00Z

Parameter uncertainty, patient heterogeneity, and stochastic uncertainty of outcomes are increasingly important concepts in medical decision models. The purpose of this study is to demonstrate the various methods to analyze uncertainty and patient heterogeneity in a decision model. The authors distinguish various purposes of medical decision modeling, serving various stakeholders. Differences and analogies between the analyses are pointed out, as well as practical issues. The analyses are demonstrated with an example comparing imaging tests for patients with chest pain. For complicated analyses step-by-step algorithms are provided. The focus is on Monte Carlo simulation and value of information analysis. Increasing model complexity is a major challenge for probabilistic sensitivity analysis and value of information analysis. The authors discuss nested analyses that are required in patient-level models, and in nonlinear models for analyses of partial value of information analysis.

The multiple propensity score as control for bias in the comparison of more than two treatment arms: An introduction from a case study in mental health (Article)

2010-02-01T00:00:00Z

Background and Objective: The propensity score method (PS) has proven to be an effective tool to reduce bias in nonrandomized studies, especially when the number of (potential) confounders is large and dimensionality problems arise. The PS method introduced by Rosenbaum and Rubin is described in detail for studies with 2 treatment options. Since in clinical practice we are often interested in the comparison of multiple interventions, there was a need to extend the PS method to multiple treatments. It has been shown that in theory a multiple PS method is possible. So far, its practical application is rare and a practical introduction lacking. Methods: A practical guideline to illustrate the use of the multiple PS method is provided with data from a mental health study. The multiple PS is estimated with a multinomial logistic regression analysis. The multiple PS is the probability of assignment to each treatment category. Subsequently, to estimate the treatment effects while controlling for initial differences, the multiple PSs, calculated for each treatment category, are included as extra predictors in the regression analysis. Results: With the multiple PS method, balance was achieved in all relevant pretreatment variables. The corrected estimated treatment effects were somewhat different from the results without control for initial differences. Conclusions: Our results indicate that the multiple PS method is a feasible method to adjust for observed pretreatment differences in nonrandomized studies where the number of pretreatment differences is large and multiple treatments are compared.

Associating explanatory variables with summary receiver operating characteristic curves in diagnostic meta-analysis (Article)

2009-12-01T00:00:00Z

Objective: To show how the bivariate random effects meta-analysis model can be used to study the relation between the explanatory variables and the performance of diagnostic tests as characterized by a summary receiver operating characteristic curve (SROCC). Study Design and Setting: The subject is discussed by means of a data example in which sensitivity and specificity are available for 149 studies on one of three tests for the diagnosis of coronary artery disease. The focus is on comparing SROCCs between different tests adjusted for potential confounders, but the methods can be applied much more generally. Results: Different types of SROCCs can be calculated. The influence of explanatory variables on an SROCC is an ensemble of sensitivity and specificity regression coefficients and covariance parameters. The regression coefficients of the SROCC are estimated and tested, and the percentage explained variability is determined. Under certain assumptions, the SROCCs of different covariate values do not cross. If these are fulfilled, it is much easier to describe the influence of explanatory variables. Conclusions can depend on the type of SROCC. Conclusion: The bivariate random effects meta-analysis model is an appropriate and convenient framework to investigate the effect of covariates on the performance of diagnostic tests as measured by SROCCs.

Multivariate random effects meta-analysis of diagnostic tests with multiple thresholds (Article)

2009-12-01T00:00:00Z

Background. Bivariate random effects meta-analysis of diagnostic tests is becoming a well established approach when studies present one two-by-two table or one pair of sensitivity and specificity. When studies present multiple thresholds for test positivity, usually meta-analysts reduce the data to a two-by-two table or take one threshold value at a time and apply the well developed meta-analytic approaches. However, this approach does not fully exploit the data. Methods. In this paper we generalize the bivariate random effects approach to the situation where test results are presented with k thresholds for test positivity, resulting in a 2 by (k+1) table per study. The model can be fitted with standard likelihood procedures in statistical packages such as SAS (Proc NLMIXED). We follow a multivariate random effects approach; i.e., we assume that each study estimates a study specific ROC curve that can be viewed as randomly sampled from the population of all ROC curves of such studies. In contrast to the bivariate case, where nothing can be said about the shape of study specific ROC curves without additional untestable assumptions, the multivariate model can be used to describe study specific ROC curves. The models are easily extended with study level covariates. Results. The method is illustrated using published meta-analysis data. The SAS NLMIXED syntax is given in the appendix. Conclusion. We conclude that the multivariate random effects meta-analysis approach is an appropriate and convenient framework to meta-analyse studies with multiple threshold without losing any information by dichotomizing the test results.

Influence of preterm birth and birth size on gonadal function in young men (Article)

2009-11-01T00:00:00Z

Background/Objectives: Preterm birth has been associated with reduced reproduction rates and being born small for gestational age (SGA) with reduced gonadal function. We hypothesized that alterations concerning gonadal function in young men are not due to preterm birth or being born SGA, but are due to other (environmental) factors. Methods: In 207 young men of the PROGRAM/PREMS cohort study, aged 18-24 yr, the influence of preterm birth, birth length, and birth weight on serum levels of anti-Mullerian hormone, inhibin B, testosterone, SHBG, non-SHBG-bound testosterone, LH, and FSH was analyzed with multiple regression modeling. In addition, markers of male gonadal function were analyzed in four subgroups: men born SGA with either short stature or catch-up growth, or men born appropriate for gestational age with idiopathic short stature or with normal stature (control). Results: Preterm birth and SGA did not affect gonadal function. After adjustment for age, birth size, adult height, fat mass, and socioeconomic status (SES), preterm birth even showed a positive relation with inhibin B. Higher SES was associated with higher inhibin B levels. Higher fat mass was associated with decreased testosterone and SHBG levels and maternal smoking with increased LH and non-SHBG-bound testosterone levels. After adjustment for confounders, there were no significant differences in gonadal function between the subgroups. Conclusion: Preterm birth and SGA did not affect gonadal function in young men. Factors that affected gonadal function were: lower SES, a higher fat mass, and maternal smoking during pregnancy. Copyright

Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004) (Article)

2009-10-01T00:00:00Z

Background: A population-based cohort of children aged 1-18 years with acute lymphoblastic leukaemia (ALL) was treated with a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). We aimed to confirm the results of the most effective DCOG ALL protocol for non-high-risk (NHR) patients to date (ALL-6), compare results with ALL-7 and ALL-8, and study prognostic factors in a non-randomised setting. Methods: From Jan 1, 1997, until Nov 1, 2004, patients with ALL were treated according to the ALL-9 protocol in eight Dutch academic centres with their affiliated peripheral hospitals. Patients were stratified into NHR and high risk (HR) groups. HR criteria were white-blood-cell count of 50 000 cells per μL or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement; patients who did not fulfil these criteria were deemed to be NHR. The NHR group was treated with a three-drug induction (dexamethasone, vincristine, and asparaginase) for 6 weeks, medium-dose methotrexate for 3 weeks, then maintenance therapy. HR patients received a four-drug induction (as for the NHR patients plus daunorubicin) for 6 weeks, high-dose methotrexate for 8 weeks, and two intensification courses before receiving maintenance therapy. Triple intrathecal medication was given 13 times in NHR patients, 15 times in HR patients (17 times for patients with initial CNS involvement). No patient received cranial irradiation. Maintenance therapy was given until 109 weeks for all patients and consisted of mercaptopurine and methotrexate for 5 weeks, alternated with dexamethasone and vincristine for 2 weeks. Kaplan-Meier analysis was done on an intention-to-treat basis with event-free survival as the primary endpoint. This trial is registered at trialregister.nl, number NTR460/SNWLK-ALL-9. Findings: 859 patients were recruited to the study. Complete remission was achieved in 592 (98·5%) of the 601 patients in the NHR group and 250 (96·9%) of the 258 in the HR group. Five patients in the NHR group and four in the HR group died during induction. Median follow-up for patients alive was 72·2 (range 4·8-132·7) months as of August, 2008. 5-year event-free survival was 81% (SE 1%) in all patients: 84% (2%) in NHR patients, and 72% (3%) in HR patients. Isolated CNS relapses occurred in 22 (2·6%) of 842 patients. In a multivariate analysis, DNA index was the strongest predictor of outcome (<1·16 vs ≥1·16; relative risk 0·42, 95% CI 0·22-0·78), followed by age (1-9 vs ≥10 years; 2·23, 1·60-3·11) and white-blood-cell count (<50 000 vs ≥50 000 cells per μL; 1·60, 1·13-2·26). Interpretation: The overall results of the dexamethasone-based DCOG ALL-9 protocol are better than those of our previous Berlin-Frankfurt-Münster-based protocols ALL-7 and ALL-8. The results for NHR patients were achieved with high cumulative doses of dexamethasone and vincristine, but without the use of anthracyclines, etoposide, cyclophosphamide, or cranial irradiation, therefore minimising the risk of side-effects. Funding: Dutch Health Insurers.

Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood (Article)

2009-06-03T00:00:00Z

Context: Growth during infancy appears to be an important determinant of cardiovascular disease and type 2 diabetes later in life. Objectives: To specify which period in the first year of life is related to determinants of cardiovascular disease and type 2 diabetes in early adulthood and to investigate the association between tempo of first-year weight gain (>0.67 SDs) and these determinants. Design, Setting, and Participants: Observational study using longitudinal data collected in the Programming Factors for Growth and Metabolism (PROGRAM) study of 217 healthy participants, aged 18 to 24 years, including a relatively large sample of participants born small for gestational age and participants with short stature, performed at a medical center in the Netherlands between August 2004 and September 2007. The association of cardiovascular disease and type 2 diabetes with tempo of weight gain was assessed in a subgroup of 87 participants. Main Outcome Measures: Associations between periods of first-year growth and tempo of weight gain and determinants of cardiovascular disease and type 2 diabetes in early adulthood. Results: Weight gain in the first 3 months of life was inversely associated with insulin sensitivity (β, -0.223; 95% confidence interval [CI], -0.386 to -0.060) and serum high-density lipoprotein cholesterol level (β, -0.053; 95% CI, -0.090 to -0.016) and positively associated with waist circumference (β, 1.437; 95% CI, 0.066 to 2.808), acute insulin response (β, 0.210; 95% CI, 0.024 to 0.395), ratio of total cholesterol to high-density lipoprotein cholesterol (β, 0.052; 95% CI, 0.010 to 0.094), and level of triglycerides (β, 0.066; 95% CI, 0.003 to 0.129) in early adulthood. Rapid weight gain during the first 3 months of life resulted in a higher percentage of body fat, more central adiposity, and reduced insulin sensitivity in early adulthood than when slower weight gain occurred during the entire first year. Conclusion: Rapid weight gain in the first 3 months of life is associated with several determinants of cardiovascular disease and type 2 diabetes in early adulthood.

Prematurity is not associated with reduced insulin sensitivity in adulthood (Article)

2009-05-01T00:00:00Z

Background: In 2005, 12.7% of all babies were born preterm, and the incidence is rising. Nowadays, due to improved survival, an increasing number of children born preterm reach young adulthood. A recent report suggested lower insulin sensitivity in children born preterm, which may put them at risk for the development of type 2 diabetes. It is, however, still unknown whether this reduced insulin sensitivity persists into adulthood. Methods: We determined insulin sensitivity and β-cell function with frequently sampled iv glucose tolerance tests in 305 young adults (aged 18-24 yr; 169 preterm and 136 term). Adult body composition was measured by dual energy x-ray absorptiometry. We investigated the effect of gestational age, size at birth, and adult body composition on insulin sensitivity. Results: In contrast to previous reports, we found no evidence that preterm birth has a deleterious effect on insulin sensitivity in young adulthood. Adult trunk fat and the use of oral contraceptives in women were the most important determinants of insulin insensitivity, independently of size at birth and duration of pregnancy. Conclusion: Contrary to our hypothesis, preterm birth was not associated with reduced insulin sensitivity in young adulthood. Copyright

Selection of medical students: A controlled experiment (Article)

2009-02-01T00:00:00Z

Objectives We aimed to discover, through a controlled experiment, whether cognitive and non-cognitive assessment would select higher-achieving applicants to medical school than selection by lottery. Methods We carried out a prospective cohort study to compare 389 medical students who had been admitted by selection and 938 students who had been admitted by weighted lottery, between 2001 and 2004. Main outcome measures were dropout rates, study rate (credits per year) and mean grade per first examination attempt per year. Study rates in the 4 pre-clinical years of medical school were used to categorise students' performance as average or optimal. Results Pre-admission variables did not differ between the two groups. The main outcome of the selection experiment was that relative risk for dropping out of medical school was 2.6 times lower for selected students than for lottery-admitted controls (95% confidence interval 1.59-4.17). Significant differences between the groups in the percentage of optimally performing students and grade point average for first examination attempts were found only in the 2001 cohort, when results favoured the selected group. The results of the selection process took into account both the assessment procedure involved and the number of students who withdrew voluntarily. Conclusions This is the first controlled study to show that assessing applicants' non-cognitive and cognitive abilities makes it possible to select students whose dropout rate will be lower than that of students admitted by lottery. The dropout rate in our overall cohort was 2.6 times lower in the selected group. © Blackwell Publishing Ltd 2009.

Prevalence, incidence, and lifetime risk for the development of COPD in the elderly the rotterdam study (Article)

2009-02-01T00:00:00Z

Background: COPD is a major cause of chronic morbidity and mortality throughout the world. Although the prevalence of COPD is already well documented, there are only few studies regarding the incidence of COPD. Methods: In a prospective population-based cohort study among subjects aged ≥ 55 years, COPD was diagnosed with an algorithm based on the validation of hospital discharge letters, files from the general practitioner, and spirometry reports. Results: In this study cohort of 7,983 participants, 648 cases were identified with incident COPD after a median follow-up time of 11 years (interquartile range, 7.8 years). This resulted in an overall incidence rate (IR) of 9.2/1,000 person-years (PY) [95% confidence interval (CI), 8.5 to 10.0]. The IR of COPD was higher among men (14.4/1,000 PY; 95% CI, 13.0 to 16.0) than among women (6.2/1,000 PY; 95% CI, 5.5 to 7.0), and higher in smokers than in never-smokers (12.8/1,000 PY; 95% CI, 11.7 to 13.9 and 3.9/1,000 PY; 95% CI, 3.2 to 4.7, respectively). Remarkable was the high incidence in the youngest female age category of 55 to 59 years (7.4/1,000 PY; 95% CI, 4.1 to 12.6). For a 55-year-old man and woman still free of COPD at cohort entry, the risk for the development of COPD over the coming 40 years was 24% and 16%, respectively. Conclusion: The overall incidence of COPD in an elderly population is 9.2/1,000 PY, with a remarkably high incidence in the youngest women, suggesting a further shift toward the female sex in the gender distribution of COPD. During their further lives, one of four men and one of six women free of COPD at the age of 55 years will have COPD develop.

Influence of birth size on body composition in early adulthood: The programming factors for growth and metabolism (PROGRAM)-study (Article)

2009-02-01T00:00:00Z

Background/Objectives: Several studies have investigated the relationship of birth size with fat mass and lean body mass (LBM), but the findings differed greatly due to different ways of measuring FM and LBM, different study populations and age groups. We hypothesized that birth size has no influence on adult body composition, whereas weight gain during childhood has. Methods: In the programming factors for growth and metabolism (PROGRAM)-study, a cohort of 312 young adults, aged 18-24 years, FM and LBM were determined by dual energy X-ray absorptiometry (DXA). Subsequently, differences in FM and LBM were analysed in four subgroups, young adults either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age (AGA) with idiopathic short stature (ISS) or with normal stature (controls). Results: Age, gender, adult height SDS and adult weight SDS were significant positive determinants of FM and LBM, whereas weight gain during childhood was positively significant for FM and negatively for LBM. Birth weight SDS tended to be significant and birth length SDS was not. Weight gain during childhood was positively correlated with waist : hip ratio and trunk fat : total fat ratio. SGA-CU subjects had significantly higher FM and significantly lower LBM than controls. Conclusion: Weight gain during childhood is an important determinant of body composition in young adulthood, whereas birth size is less important. In clinical practice, too much weight gain in childhood should be prevented as it results in a relatively high fat mass, especially in children with catch-up growth in weight, like SGA-CU subjects.

The Use of Propensity Score Methods in Psychotherapy Research (Article)

2009-01-01T00:00:00Z

Abstract BACKGROUND: Randomized controlled trials are considered the best scientific proof of effectiveness. There is increasing concern, though, about their feasibility in psychotherapy research. We discuss a quasi-experimental study design for situations in which a randomized controlled trial is not feasible. Here, as an alternative strategy, the propensity score (PS) method is used to correct for selection bias. METHODS: We used data from a Dutch research project, SCEPTRE (Study on Cost-Effectiveness of Personality Disorder Treatment). The sample consisted of 749 psychotherapy patients with personality pathology. We tested whether the PS method was useful and applicable. We examined differences between 2 treatment groups (short vs. long treatment duration) in pretreatment characteristics before and after PS correction. This revealed the impact of the PS on outcome differences. RESULTS: The PS offered statistical control over observed pretreatment differences between patients in a non-randomized study. CONCLUSIONS: When a randomized controlled trial is not possible, this quasi-experimental design using the PS could be a feasible alternative. Its advantages and limitations are discussed. Implemented carefully, this method is promising for future effectiveness research.

Fat mass and apolipoprotein E genotype influence serum lipoprotein levels in early adulthood, whereas birth size does not (Article)

2008-11-01T00:00:00Z

Background/Objectives: An association between an unfavorable lipid profile and low birth weight has been reported, although this association remains controversial. We hypothesized that birth size does not have any influence on serum lipid levels but fat accumulation during childhood has. Methods: In the PROgramming factors for GRowth And Metabolism study, a cohort of 297 young adults, aged 18-24 yr, the influence of clinical parameters on total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, lipoprotein a, and apolipoprotein (apo) A-1 and apoB was analyzed with multiple regression modeling. In addition, differences in these lipid levels and ApoE genotype prevalence were analyzed in four subgroups: young adults either born small for gestational age with short stature or with catch-up growth, or born appropriate for gestational age with idiopathic short stature or with normal stature (controls). Results: Birth length SD score (SDS) and birth weight SDS were no significant determinants of the serum lipid levels, whereas gender, ApoE genotype, adult height SDS, adult weight SDS, and fat mass were. Comparison of the subgroups showed that small for gestational age with short stature subjects had a significantly higher apoB than controls. There were no other significant differences in lipid levels or ApoE genotype prevalence among the four subgroups. Conclusions: ApoE genotype is an important genetic determinant of lipid levels in young adulthood. Furthermore, fat accumulation during childhood significantly determines serum lipid levels, whereas birth size has no significant contribution. For public health practice, this means that parents and their children need to be informed about the risks of fat accumulation during childhood. Copyright

Cataract surgery and the risk of aging macula disorder: The Rotterdam study (Article)

2008-11-01T00:00:00Z

PURPOSE. To investigate still-controversial associations between prior cataract surgery and aging macula disorder (AMD) in a general population. METHODS. Baseline lens status and risk of incident AMD (iAMD) were examined in participants of the prospective population-based Rotterdam Study at risk for AMD (n = 6032). Slit lamp examination was used to determine lens status and stereoscopic color fundus photography to determine the presence of AMD. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated with generalized estimating equation (GEE) models. Stratified analyses were also performed for CFH Y402H genotype. RESULTS. After adjusting for age, sex, follow-up time, and the correlation between eyes, a history of cataract surgery was associated with incident dry late AMD (OR, 3.43; 95% CI, 1.82- 6.49). This association remained significant after additional adjustment for smoking status and AMD stage at baseline (OR, 3.44; 95% CI, 1.68-7.08). No statistically significant association was found between prior cataract surgery and the incidence of wet late AMD or early AMD. Homozygous CFH Y402H carriers had higher risks for all types of AMD compared to heterozygotes and noncarriers after cataract surgery, particularly for dry AMD. CONCLUSIONS. The findings imply that cataract surgery increases the risk of dry AMD, particularly in homozygous CFH Y402H carriers. The risk of AMD progression should be considered before recommending cataract surgery to patients with cataract and early AMD. Copyright

Small for gestational age children without early catch-up growth: Spontaneous growth and prediction of height at 8 years (Article)

2008-10-01T00:00:00Z

Background/Aim: About 10-15% of children born small for gestational age (SGA) have at the age of 2 years a height standard deviation score (HSDS 2y) still below -2. There is no model to predict which children will catch up in height after 2 years of age. The aim of this study was to determine the percentage of children with catch-up growth to a normal height after the age of 2 years and to develop a prediction model for growth after that age. Methods: In a cohort of 724 SGA children, the percentage of children with HSDS above -2 at 8 years of age was determined. In data of 97 children with HSDS 2y below -2, a prediction model was developed for growth between 2 and 8 years. Results: Thirty-nine percent of children with HSDS2y below -2 reached an HSDSabove -2 between 2 and 8 years (6% of the total group). Determinants of growth after age 2 years, all with a positive influence, were the difference between target height SDS and HSDS2y, change in height SDS during first 2 years of life, female gender and multiple birth. Conclusions: Catch-up growth to a normal height occurred in 91% of SGA children, in 6% between 2 and 8 years of age. The difference between target height SDS and HSDS2y was the most important determinant. The presented prediction model can identify children with low or high probability of catch-up growth after the age of 2 years. This may assist to determine which children require medical follow-up.

Meta-analysis of summary survival curve data (Article)

2008-09-30T00:00:00Z

The use of standard univariate fixed- and fandom-effects models in meta-analysis has become well known in the last 20 years. However, these models are unsuitable for meta-analysis of clinical trials that present multiple survival estimates (usually illustrated by a survival curve) during a follow-up period. Therefore, special methods are needed to combine the survival curve data from different trials in a meta-analysis. For this purpose, only fixed-effects models have been suggested in the literature. In this paper, we propose a multivariate random-effects model for joint analysis of survival proportions reported at multiple time points and in different studies, to be combined in a meta-analysis. The model could be seen as a generalization of the fixed-effects model of Dear (Biometrics 1994; 50:989-1002). We illustrate the method by using a simulated data example as well as using a clinical data example of meta-analysis with aggregated survival curve data. All analyses can be carried out with standard general linear MIXED model software.

Meta-analysis of diagnostic studies: A comparison of random intercept, normal-normal, and binomial-normal bivariate summary ROC approaches (Article)

2008-09-01T00:00:00Z

Background. The authors compared 3 recently introduced refinements of the Littenberg and Moses summary receiver operating characteristic (ROC) method for pooling studies of a diagnostic test: the random intercept (RI) linear meta-regression model, the approximate normal distribution (normal-normal [NN] model), and the binomial distribution (binomial-normal [BN] model). Methods. Using data from a published meta-analysis of magnetic resonance imaging of the menisci and cruciate ligaments, the authors varied the overall sensitivity and specificity, the between-studies variance, the within-study sample size, and the number of studies to evaluate the performances of the 3 methods in a simulation study. The parameters to be compared are the associated intercept, slope, and residual variance, using bias, mean squared error, and coverage probabilities. Results. The BN method always gave unbiased estimates of the intercept and slope parameter. The coverage probabilities were also reasonably acceptable, unless the number of studies was very small. In contrast, the RI and NN methods could produce large biases with poor coverage probabilities, especially when sample sizes of individual studies were small or when sensitivities or specificities were close to 1. Although this was rare in the simulations, the bivariate methods can suffer from nonconvergence mostly due to the correlation being close to ± 1. Conclusion. The binomial-normal model performed better than the other recently introduced methods for meta-analysis of data from studies of test performance.

Bivariate random effects meta-analysis of ROC curves (Article)

2008-09-01T00:00:00Z

Meta-analysis of receiver operating characteristic (ROC)-curve data is often done with fixed-effects models, which suffer many shortcomings. Some random-effects models have been proposed to execute a meta-analysis of ROC-curve data, but these models are not often used in practice. Straightforward modeling techniques for multivariate random-effects meta-analysis of ROC-curve data are needed. The 1st aim of this article is to present a practical method that addresses the drawbacks of the fixedeffects summary ROC (SROC) method of Littenberg and Moses. Sensitivities and specificities are analyzed simultaneously using a bivariate random-effects model. The 2nd aim is to show that other SROC curves can also be derived from the bivariate model through different characterizations of the estimated bivariate normal distribution. Thereby the authors show that the bivariate random-effects approach not only extends the SROC approach but also provides a unifying framework for other approaches. The authors bring the statistical meta-analysis of ROC-curve data back into a framework of relatively standard multivariate meta-analysis with random effects. The analyses were carried out using the software package SAS (Proc NLMIXED).

Influence of birth size and body composition on bone mineral density in early adulthood: The PROGRAM study (Article)

2008-09-01T00:00:00Z

Background/objectives: Low bone mineral density (BMD) may lead to osteoporosis and is associated with increased fracture risk. Associations between BMD and various factors have been reported. Our objective was to investigate whether birth size, lean body mass (LBM) and fat mass (FM) are determinants of BMD of the total body (BMDTB) and the lumbar spine (BMDLS). Methods: In the PROgramming factors for GRowth And Metabolism (PROGRAM) study of a cohort of 312 young adults aged 18-24 years, BMDTBand BMDLSwere determined by dual-energy X-ray absorptiometry (DXA). Subsequently, differences in BMDTBand BMDLSwere analysed in four subgroups: young adults born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age (AGA) with idiopathic short stature (ISS) or with normal stature (controls). Results: Adult weight, LBM, FM and weight gain during childhood were the main positive determinants for BMDTBin early adulthood, whereas birth size had no influence (adjusted R2= 0.50). Gender, adult weight, LBM, FM and weight gain were the significant determinants of BMDLS. In the subgroups, after correction for age, gender and adult body size, the ISS group had a significantly lower BMDTBthan controls but there was no difference in BMDLSbetween the subgroups. Conclusions: Prenatal growth has no significant influence on BMDTBand BMDLSin early adulthood. Gender and postnatal growth, particularly weight gain, are the main positive determinants. To achieve a normal BMD in adulthood, healthcare workers should aim for a normal weight gain in children.

Victimisation and suicide ideation in the TRAILS study: Specific vulnerabilities of victims (Article)

2008-08-01T00:00:00Z

Background: Scientific studies have provided some support for a link between being a victim of bullying and suicide ideation. We examine whether (1) parental psychopathology and (2) feelings of rejection (at home and at school) exacerbate vulnerability to suicide ideation in victims of bullying (pure victims and bully-victims). Method: Data were from a population-based cohort study of Dutch children (n = 1526, mean age = 12.29 years). Using peer nominations, three groups were established: (1) victim only; (2) bully-victims (children who are victims and who also bully others); (3) uninvolved. Self-report data on suicide ideation were obtained using two items from the Youth Self-Report (Achenbach, 1991). Parental internalising and externalising disorders were assessed, as were self-reported feelings of rejection at home and social well-being among classmates. Results: The association between victimisation and suicide ideation was moderated by parental internalising disorders (but not externalising disorders) and feelings of rejection at home. Victims (but not bully-victims) with parents with internalising disorders reported elevated levels of suicide ideation compared to children uninvolved in bullying. Victims feeling more rejected at home also reported more suicide ideation. There were no overall sex differences in suicide ideation. Surprisingly, bully-victims did not report higher levels of suicide ideation compared to children uninvolved in bullying. Conclusions: Parental internalising disorders and feelings of rejection at home confer a specific vulnerability for suicide ideation among victims of bullying.

A meta-regression analysis shows no impact of design characteristics on outcome in trials on tension-type headaches (Article)

2008-08-01T00:00:00Z

Objectives: In the conduct of a systematic review or meta-analysis, many possible sources of bias exist, such as bias caused by design characteristics. We studied the influence of the methodological study characteristics of randomized clinical trials (RCTs) on the outcome in a systematic review on conservative treatments in patients with tension-type headache (TTH). Study Design and Setting: Included were RCTs from a systematic review on TTH, which were a control group receiving a placebo or no treatment and presented data on recovery or headache severity, intensity, or frequency. Design characteristics were assessed using the Delphi list. Regression analysis is performed on separate design characteristics on size of treatment effect. Results: Out of the original data set of 146 trials, 61 trials fulfilled our selection criteria. The number of trials presenting only dichotomous data was larger than trials presenting only continuous data. All study characteristics show a nonsignificant relation with the effect estimate. Whether outcome is presented dichotomous or continuous appears to have a significant impact on treatment effect estimates. Conclusion: In this study, sample design characteristics do not show to have an impact on treatment effect estimates, but the way the treatment effect is measured has a significant impact.

Perceived and actual motor competence of children treated for cancer with vincristine containing chemotherapy (Article)

2008-08-01T00:00:00Z

Multicenter randomized controlled trial of the costs and effects of noninvasive diagnostic imaging in patients with peripheral arterial disease: The DIPAD trial (Article)

2008-05-01T00:00:00Z

OBJECTIVE. The purpose of our study was to compare the costs and effects of three noninvasive imaging tests as the initial imaging test in the diagnostic workup of patients with peripheral arterial disease. MATERIALS AND METHODS. Of 984 patients assessed for eligibility, 514 patients with peripheral arterial disease were randomized to MR angiography (MRA) or duplex sonography in three hospitals and to MRA or CT angiography (CTA) in one hospital. The outcome measures included the clinical utility, functional patient outcomes, quality of life, and actual diagnostic and therapeutic costs related to the initial imaging test during 6 months of follow-up. RESULTS. With adjustment for potentially predictive baseline variables, the learning curve, and hospital setting, a significantly higher confidence and less additional imaging were found for MRA and CTA compared with duplex sonography. No statistically significant differences were found in improvement in functional patient outcomes and quality of life among the groups. The total costs were significantly higher for MRA and duplex sonography than for CTA. CONCLUSION. The results suggest that both CTA and MRA are clinically more useful than duplex sonography and that CTA leads to cost savings compared with both MRA and duplex sonography in the initial imaging evaluation of peripheral arterial disease.

Estimating decreased risks for Huntington disease without a test (Article)

2008-04-01T00:00:00Z

The majority of individuals at risk for Huntington disease (HD) is afraid to learn more precisely about their genetic status, as is suggested by the low uptake of the predictive test for HD. Subsequently, the future expectancies of individuals at risk are often based on rough risk estimates such as 50% (child of an affected individual) or 25% (grandchild). Individuals at risk can be offered a better risk estimate based on their current age, length of the disease causing CAG-repeat in the HD gene in close relatives, information on the age at onset, or test results of children. Regression modelling and Cox regression determined relations between ages at onset and CAG repeat length in a sample of 755 tested individuals. A model for calculating the adjusted residual risk status was constructed and implemented in a spreadsheet that can be used in genetic counselling. This model and accompanying spreadsheet broadens the information repertoire for genetic counsellors by providing an optimal estimation of the residual risk status.

Meta-analyses of chronic disease trials with competing causes of death may yield biased odds ratios (Article)

2008-04-01T00:00:00Z

Objective: To study the odds ratio (OR) as measure of treatment effect in the context of mutually exclusive causes of death. Study Design and Setting: As example we consider meta-analyses of randomized trials of implantable cardioverter defibrillator implantation (ICD). We compare the pooled OR to the pooled cause-specific hazard ratio (HR) for each of the mutually exclusive outcomes "sudden cardiac death" (SCD) and "death other than SCD.". Results: The pooled OR and cause-specific HR for the reduction of SCD are similar (0.43 and 0.44, respectively) for nine included trials. However, the OR erroneously presumes a potential trend toward an adverse effect of the ICD on "death other than arrhythmia" (OR 1.11 [0.84-1.45]), whereas such an effect is small with the cause-specific HR (HR 1.03 [0.79-1.32]). In general, it is shown that a spurious association of treatment with "other death" may be seen when a substantial number of death from the cause of interest is postponed. Conclusion: The OR should be used with caution to study effects of treatment on mutually exclusive causes of death. Practically this concern applies primarily to meta-analysis where the use of the cause-specific HR, whenever available, is recommended.

Decrease in peripheral muscle strength and ankle dorsiflexion as long-term side effects of treatment for childhood cancer (Article)

2008-04-01T00:00:00Z

Background. This study investigated muscle strength, passive ankle dorsiflexion, and their association with motor performance in children after treatment for acute lymphoblastic leukemia, Wilms tumor, B-non-Hodgkin lymphoma, and malignant mesenchymal tumors. Procedure. Muscle strength was assessed with a hand-held dynamometer and ankle dorsiflexion with a goniometer in 92 and 64 survivors, respectively. Motor performance was measured with the Movement Assessment Battery for Children (movement-ABC). Age at testing: 6.1-12.9 years. Mean time since completing treatment: 3.3 years. Results were compared to 155 healthy controls. Results. Muscle strength of the survivors was reduced in ankle dorsiflexors on both sides (P < 0.001), wrist dorsiflexors on the non-dominant side (P < 0.001), and pinch grip on the non-dominant (P = 0.001) and dominant side (P = 0.01). Passive ankle dorsiflexion of the survivors was significantly less on both sides (P < 0.01). Movement-ABC percentile score was affected by pinch grip strength on the non-dominant (P < 0.004), and dominant side (P = 0.024) but not by strength of other muscle groups or by passive ankle dorsiflexion. Conclusion. Peripheral muscle strength and ankle dorsiflexion are reduced in the long-term in children treated for cancer with chemotherapy. However, neither decreased muscle strength nor reduced ankle dorsiflexion could completely explain reduced scores on the movement-ABC.

Value of information analysis used to determine the necessity of additional research: MR imaging in acute knee trauma as an example (Article)

2008-02-01T00:00:00Z

Purpose: To help guide future outcomes research regarding the use of magnetic resonance (MR) imaging in patients with acute knee trauma in an emergency department setting, with use of prospective data from a randomized clinical trial and value of information analysis. Materials and Methods: A total of 189 patients (123 male, 66 female; mean age, 33.4 years) were randomly assigned to undergo radiography alone (n = 93) or radiography and MR imaging (n = 96). Institutional review board approval and informed consent (parental consent for minors) were obtained. During 6 months of follow-up, data on quality of life and 39 cost parameters were collected. Value-of-information analysis was used to estimate the expected benefit of future research to eliminate the decision uncertainty that remained after trial completion. In addition, the parameters that were responsible for most of the decision uncertainty were identified, the expected benefits of various study designs were evaluated, and the optimal sample size was estimated. Results: Only three parameters were responsible for most of the decision uncertainty: number of quality-adjusted life-years, cost of an overnight hospital stay, and friction costs. A study in which data on these three parameters are gathered would have an optimal sample size of 3500 patients per arm and would be expected to result in a societal benefit of €5.6 million or 70 quality-adjusted life-years. Conclusion: The optimal study design for use of MR imaging to evaluate acute knee trauma involves a trial in which there are 3500 patients per trial arm, and data on the number of quality-adjusted life-years, cost of an overnight hospital stay, and friction costs are collected.

Fat mass accumulation during childhood determines insulin sensitivity in early adulthood (Article)

2008-02-01T00:00:00Z

Background/Objectives: Low birth weight and postnatal catch-up growth have been associated with an increased risk for diabetes mellitus type II (DMII). We evaluated the contribution of birth and adult size, body composition, and waist-to-hip ratio to DMII risk factors in young adulthood. Methods: In a group of 136 young adults, aged 18-24 yr, insulin sensitivity and disposition index were determined by frequent sampling iv glucose tolerance test. The association of clinical parameters with these variables was analyzed with multiple regression modeling. In addition, differences in insulin sensitivity and disposition index, a measure for β-cell function, were analyzed in four subgroups, young adults either born small for gestational age SGA with short stature (n = 25) or SGA with catch-up growth (n = 23) or born appropriate for gestational age with idiopathic short stature (n = 23) or with normal stature (controls) (n = 26). Results: Fat mass was the only significant predictor of insulin sensitivity, whereas birth length and birth weight were not significant. After correction for age, gender, and adult body size, insulin sensitivity was significantly lower in subjects born SGA with catch-up growth compared with controls. None of the variables had a significant influence on disposition index, and there was no significant difference in disposition index between the subgroups. Conclusions: Our data show that a higher body fat mass at 21 yr is associated with reduced insulin sensitivity, independent of birth size. These findings have important implications for public health practice. Copyright

Prediction model for adult height of small for gestational age children at the start of growth hormone treatment (Article)

2008-02-01T00:00:00Z

Context: GH treatment is approved for short children born small for gestational age (SGA). The optimal dose is not yet established. Objective: Our objective was to develop a model for prediction of height at the onset of puberty and of adult height (AH). Design and Setting: Two GH studies were performed in short SGA children. Patients/Intervention: A total of 150 SGA children with height SD scores (SDS) less than -2, age 3 yr or older, no signs of catch-up growth, available height at the onset of puberty, and at least 1 yr of GH treatment before the onset of puberty were studied. In one study, patients were randomly assigned to either 0.033 or 0.067 mg/kg·d; in the other study all received 0.033 mg/kg·d. In 71 children, AH was reached. Main Outcome Measures: Height SDS at the onset of puberty and AH SDS were calculated. Results: Determinants positively related to height SDS at the onset of puberty were: height SDS at the start; target height SDS; and GH dose, whereas age at the start and female gender were negatively related. Positively related to AHSDS were: height SDS and chronological age - bone age at the start; target height SDS; and GH dose, whereas serum IGF binding protein (IGFBP)-3 SDS at the start was negatively related. There was a significant interaction between GH dose and IGFBP-3 SDS, indicating a smaller GH dose effect for higher levels of IGFBP-3. The final model explained 57% of the variance in height SDS at the onset of puberty and 41% of AH SDS. Conclusions: The prediction model for height SDS at the onset of puberty and AH SDS of short SGA children treated with GH provides useful information about the expected long-term growth. Because GH dosage is one of the determinants, the model aids in determining the optimal GH dose for each child. Copyright

Rapid identification and antimicrobial susceptibility testing reduce antibiotic use and accelerate pathogen-directed antibiotic use (Article)

2008-02-01T00:00:00Z

Introduction: Rapid bacterial identification and susceptibility tests can lead to earlier microbiological diagnosis and pathogen-directed, appropriate therapy. We studied whether accelerated diagnostics affected antibiotic use and patient outcomes. Patients and methods: A prospective randomized clinical trial was performed over a 2-year period. Inpatients were selected on the basis of a positive culture from normally sterile body fluids and randomly assigned to either a rapid intervention arm or the control arm. The intervention arm used the Vitek 2 automated identification and susceptibility testing device, combined with direct inoculation of blood cultures. In the control arm, the Vitek 1 system inoculated from subcultures was used. Follow-up was 4 weeks after randomization. Results: A total of 1498 patients were randomized: 746 in the intervention arm and 752 in the control arm. For susceptibility testing, the rapid arm was 22 h faster than the control arm, and for identification, it was 13 h faster (P < 0.0001). In the rapid arm, antibiotic use was 6 defined daily doses lower per patient than in the control arm (P = 0.012). Whereas antibiotics were switched more in the rapid group on the day of randomization (P = 0.006), in the control group they were switched more on day two (P = 0.02). Mortality rates did not differ significantly between the two groups (17.6% versus 15.2%). Conclusions: While rapid bacterial identification and susceptibility testing led to earlier changes and a significant reduction in antibiotic use, they did not reduce mortality.

The binomial distribution of meta-analysis was preferred to model within-study variability (Article)

2008-01-01T00:00:00Z

Objective: When studies report proportions such as sensitivity or specificity, it is customary to meta-analyze them using the DerSimonian and Laird random effects model. This method approximates the within-study variability of the proportion by a normal distribution, which may lead to bias for several reasons. Alternatively an exact likelihood approach based on the binomial within-study distribution can be used. This method can easily be performed in standard statistical packages. We investigate the performance of the standard method and the alternative approach. Study Design and Setting: We compare the two approaches through a simulation study, in terms of bias, mean-squared error, and coverage probabilities. We varied the size of the overall sensitivity or specificity, the between-studies variance, the within-study sample sizes, and the number of studies. The methods are illustrated using a published meta-analysis data set. Results: The exact likelihood approach performs always better than the approximate approach and gives unbiased estimates. The coverage probability, in particular for the profile likelihood, is also reasonably acceptable. In contrast, the approximate approach gives huge bias with very poor coverage probability in many cases. Conclusion: The exact likelihood approach is the method of preference and should be used whenever feasible.

Semi-parametric modelling of the distribution of the baseline risks in meta-analysis (Article)

2007-12-30T00:00:00Z

In meta-analysis of clinical trials, often meta-regression analyses are performed to explain the heterogeneity in treatment effects that usually exist between trials. A popular explanatory variable is the risk observed in the control group, the baseline risk. The relationship between the treatment effect and the baseline risk is investigated by fitting a linear model that allows randomness on the true baseline risk by assuming a normal distribution with unknown mean and variance. However, the normality assumption could be too strong to adequately describe the underlying distribution. Therefore, we developed a new semi-parametric method that relaxes the normality assumption to a more flexible and general distribution. We applied a penalized Gaussian mixture distribution to represent the baseline risk distribution. Furthermore, a bivariate hierarchical model is formulated in order to take into account the correlation between the baseline and treatment effect. To fit the proposed model, a penalized likelihood function is maximized by an Expectation Maximization (EM) algorithm. We illustrate our method on a number of simulated data sets and on a published meta-analysis data set. Copyright

Sodium and potassium intake and risk of cardiovascular events and all-cause mortality: The Rotterdam Study (Article)

2007-11-01T00:00:00Z

Background: Dietary electrolytes influence blood pressure, but their effect on clinical outcomes remains to be established. We examined sodium and potassium intake in relation to cardiovascular disease (CVD) and mortality in an unselected older population. Methods: A case-cohort analysis was performed in the Rotterdam Study among subjects aged 55 years and over, who were followed for 5 years. Baseline urinary samples were analyzed for sodium and potassium in 795 subjects who died, 206 with an incident myocardial infarction and 181 subjects with an incident stroke, and in 1,448 randomly selected subjects. For potassium, dietary data were additionally obtained by food-frequency questionnaire for 78% of the cohort. Results: There was no consistent association of urinary sodium, potassium, or sodium/potassium ratio with CVD and all-cause mortality over the range of intakes observed in this population. Dietary potassium estimated by food frequency questionnaire, however, was associated with a lower risk of all-cause mortality in subjects initially free of CVD and hypertension (RR = 0.71 per standard deviation increase; 95% confidence interval: 0.51-1.00). We observed a significant positive association between urinary sodium/potassium ratio and all-cause mortality, but only in overweight subjects who were initially free of CVD and hypertension (RR = 1.19 (1.02-1.39) per unit). Conclusion: The effect of sodium and potassium intake on CVD morbidity and mortality in Western societies remains to be established.

No adverse effect of vincristine on handwriting in children after completion of therapy (Article)

2007-11-01T00:00:00Z

Background. Long-term writing difficulties in children after treatment with vincristine for acute lymphoblastic leukemia, Wilms tumor, B non-Hodgkin lymphoma, and malignant mesenchymal tumors, were investigated. Procedure. Handwriting of 33 survivors and 33 controls matched for age, sex, and grade, was assessed with the BHK-scale. The examiner was blinded for whether a child was a case or a control. Results. No significant difference in writing speed was found. Mean difference in number of letters produced during 5 min was 6.4 (±67.1, range -103 to +169). No significant difference was found in quality of writing scores; mean difference in points was 1.5 (±7.7, range -19 to +22). Cumulative vincristine dose, age at diagnosis or time since completion of treatment did not affect writing speed or quality. Conclusion. Chemotherapy, including vincristine, does not lead to long-term problems in speed or quality of writing in children treated for cancer.

Risk of type 2 diabetes attributable to C-reactive protein and other risk factors (Article)

2007-10-01T00:00:00Z

OBJECTIVE - To calculate the population-attributable risk (PAR) of C-reactive protein (CRP) and other risk factors for type 2 diabetes. RESEARCH DESIGN AND METHODS - The Rotterdam Study is a population-based, prospective follow-up study among 7,983 participants aged ≥55 years. Risk factors including serum CRP were determined at baseline. Participants with diabetes at baseline were excluded, and the cohort was followed for a mean of 10.8 years. The hazard ratio (HR) and PAR for diabetes were computed for all studied risk factors. RESULTS - Serum CRP > 1 mg/l (HR 1.67, PAR 0.33), BMI >25 kg/m2(HR 2.51, PAR 0.51), waist circumference >102 for men and >88 cm for women (HR 1.36, PAR 0.14), current smoking (HR 1.16, PAR 0.03), age >65 years (HR 1.35, PAR 0.15), and family history of diabetes (HR 1.87, PAR 0.16) were related to diabetes and contributed to the risk of the disease. Serum CRP was a greater contributor to the risk of diabetes in women than in men (PAR values of 0.37 vs. 0.28, respectively). Age and current smoking PARs were not statistically significantly contributing to the risk of diabetes in women. Combined PAR was 0.80 (95% CI 0.74-0.85) for all six studied risk factors and 0.71 (0.64-0.78) for modifiable risk factors (serum CRP, BMI, waist circumference, and current smoking). CONCLUSIONS - High CRP is one of the major contributors to the risk of type 2 diabetes. The contribution of modifiable risk factors to the risk of diabetes is considerable.

Validity of the Framingham point scores in the elderly: Results from the Rotterdam study (Article)

2007-07-01T00:00:00Z

Background: The National Cholesterol Education Program recommends assessing 10-year risk of coronary heart disease (CHD) in individuals free of established CHD with the Framingham Point Scores (FPS). Individuals with a risk >20% are classified as high risk and are candidates for preventive intervention. We aimed to validate the FPS in a European population of elderly subjects. Methods: Subjects free of established CHD at baseline were selected from the Rotterdam study, a population-based cohort of subjects 55 years or older in the Netherlands. We studied calibration, discrimination (c-index), and the accuracy of high-risk classifications. Events consisted of fatal CHD and nonfatal myocardial infarction. Results: Among 6795 subjects, 463 died because of CHD and 336 had nonfatal myocardial infarction. Predicted 10-year risk of CHD was on average well calibrated for women (9.9% observed vs 10.1% predicted) but showed substantial overestimation in men (14.3% observed vs 19.8% predicted), particularly with increasing age. This resulted in substantial number of false-positive classifications (specificity 70%) in men. In women, discrimination of the FPS was better than that in men (c-index 0.73 vs 0.63, respectively). However, because of the low baseline risk of CHD and limited discriminatory power, only 33% of all CHD events occurred in women classified as high risk. Conclusions: The FPS need recalibration for elderly men with better incorporation of the effect of age. In elderly women, FPS perform reasonably well. However, maintaining the rational of the high-risk threshold requires better performing models for a population with low incidence of CHD.

Should new reference values on the AIMS test need to be established for Dutch children? - Reply [4] (Article)

2007-07-01T00:00:00Z

Generic and disease-specific health related quality of life of liver patients with various aetiologies: A survey (Article)

2007-04-01T00:00:00Z

Most studies on health related quality of life (HRQoL) of chronic liver patients were done in small clinical populations or restricted to one aetiology or disease stage. There is still a need for a study in a large liver patient population with various aetiologies and disease stages, approaching a population-based study. We evaluated the impact of liver disease aetiology on generic HRQoL, disease-specific HRQoL and fatigue and we compared HRQoL and fatigue between aetiological groups and healthy Dutch controls. Members of the Dutch liver patient association completed the Liver Disease Symptom Index, Short Form-36, and Multidimensional Fatigue Index-20. We compared the HRQoL between patients with viral hepatitis, autoimmune hepatitis, cholestatic diseases, hemochromatosis and other liver diseases by linear, ordinal and logistic regression, corrected for disease stage and other significant factors. Viral hepatitis patients showed a worse mental health than other aetiological groups. Hemochromatosis patients demonstrated 17% more bodily pain than viral hepatitis patients and the strongest decrease in role emotional health with increasing age. Aetiological groups showed a worse generic HRQoL and more fatigue than controls. In conclusion, viral hepatitis and hemochromatosis patients have a more impaired HRQoL than patients of other liver disease aetiological groups.

A new method to determine mean adult height from incomplete follow-up data (Article)

2007-03-01T00:00:00Z

Background/Aim: In long-term growth studies with adult height (AH) as outcome, reporting is often required while data are incomplete because some participants have not yet reached AH whereas others might be lost to follow-up. Current practice is to analyze only participants who did reach AH, which can easily give biased results. We introduce a new method into the area of growth research. Methods: We used the data of patients from a registration database and a growth study. The new method uses growth data in time intervals. The percentage of children still growing and the mean growth at each interval are used to determine mean AH. Results: With the new method, estimated mean AHs had smaller bias and standard error than with commonly used methods. The method is not hampered by a correlation between AH and age at reaching AH, unlike methods merely using patients who have reached AH. Conclusion: In contrast to commonly used methods, the new method provides valid results on mean AH when complete actual measurements of AH are not (yet) available, provided that drop-out, if any, is not related to (disappointing) growth. As it also uses observed data of children with incomplete follow-up, the method employs the data more effectively. Copyright

Prediction of adult height in growth-hormone-treated children with growth hormone deficiency (Article)

2007-03-01T00:00:00Z

Context: Several studies have searched for factors that significantly influence adult height (AH) of children with GH deficiency (GHD) who have been treated with biosynthetic GH, but a prediction model for AH has not yet been presented. Objective: Our objective was to develop models for prediction of AH, using information available at the start of GH treatment or after 1 yr of treatment. Design and Setting: For this retrospective study, data were collected from the National Registry of Growth Hormone Treatment in Children, which contained data of Dutch children treated with GH. Patients/Intervention: Patients included males born before 1985 and females born before 1987 with either diagnosis of GHD (syndromes, tumors, and other diseases were excluded) or a maximal GH response during provocation tests of less than 11 ng/ml, treated with biosynthetic GH for at least 1 yr. To be able to use the complete group of 342 children for the development of the models, multiple imputation was used for missing values. Main Outcome Measure: We assessed AH SD scores (SDS). Results: Each prediction model contained both target height SDS and current height SDS. The change in height SDS during the first year proved an important predictor for AH. In all models, addition of GH dose was not significant. The percent explained variance, after correction for overfitting, ranged from 37% (prepubertal children, prediction at start) to 60% (pubertal children, prediction after 1 yr). Conclusion: The presented prediction models give accurate predictions of AH for children with GHD at start and after 1 yr of GH treatment. They are useful tools in the treatment of these children. Copyright

Genetic variation, C-reactive protein levels, and incidence of diabetes (Article)

2007-03-01T00:00:00Z

C-reactive protein (CRP) has been shown to be associated with type 2 diabetes, but whether CRP has a causal role is not yet clear. We examined the association in the Rotterdam Study, a population-based prospective cohort study. The association of baseline serum CRP and incident diabetes during follow-up was investigated, and a meta-analysis was conducted on the BMI-adjusted relation of CRP and diabetes. Furthermore, the association of CRP haplotypes with serum CRP and risk of diabetes was assessed. The age-and sex-adjusted hazard ratio for diabetes was 1.41 (95% CI 1.29-1.54) per 1 SD increase in natural logarithm of CRP, and it was 1.88, 2.16, and 2.83 for the second, third, and fourth quartiles of CRP, respectively, compared with the first quartile. The risk estimates attenuated but remained statistically significant after additional adjustment for obesity indexes, which agreed with the results of the meta-analysis. The most common genetic haplotype was associated with a significantly lower CRP level compared with the three other haplotypes. The risk of diabetes was significantly higher in the haplotype with the highest serum CRP level compared with the most common haplotype (OR 1.45, 95% CI 1.08-1.96). These findings support the hypothesis that serum CRP enhances the development of diabetes.

Limitations of acceptability curves for presenting uncertainty in cost-effectiveness analysis (Article)

2007-03-01T00:00:00Z

Clinical journals increasingly illustrate uncertainty about the cost and effect of health care interventions using cost-effectiveness acceptability curves (CEACs). CEACs present the probability that each competing alternative is optimal for a range of values of the cost-effectiveness threshold. The objective of this article is to demonstrate the limitations of CEACs for presenting uncertainty in cost-effectiveness analyses. These limitations arise because the CEAC is unable to distinguish dramatically different joint distributions of incremental cost and effect. A CEAC is not sensitive to any change of the incremental joint distribution in the upper left and lower right quadrants of the cost-effectiveness plane; neither is it sensitive to radial shift of the incremental joint distribution in the upper right and lower left quadrants. As a result, CEACs are ambiguous to risk-averse policy makers, inhibit integration with risk attitude, hamper synthesis with other evidence or opinions, and are unhelpful to assess the need for more research. Moreover, CEACs may mislead policy makers and can incorrectly suggest medical importance. Both for guiding immediate decisions and for prioritizing future research, these considerable drawbacks of CEACs should make us rethink their use in communicating uncertainty. As opposed to CEACs, confidence and credible intervals do not conflate magnitude and precision of the net benefit of health care interventions. Therefore, they allow (in)formal synthesis of study results with risk attitude and other evidence or opinions. Presenting the value of information in addition to these intervals allows policy makers to evaluate the need for more empirical research.

New reference values for the Alberta Infant Motor Scale need to be established (Article)

2007-03-01T00:00:00Z

Aim: The Alberta Infant Motor Scale (AIMS) is an infant developmental test, which can be used to evaluate motor performance from birth to independent walking. Between 1990 and 1992 Piper and Darrah determined reference values in a cohort in Canada. To our knowledge no study has been carried out to determine whether the Canadian data are representative for other countries. In the present study we aimed to establish whether the AIMS test needs new reference values for Dutch children. Methods: Motor performance of 100 Dutch children, aged 0-12 months, was measured using the AIMS test. Results: The mean percentile score of the Dutch children was 28.8 (±22.9, range 1-85). The percentile scores of the group were significantly lower than scores of the Canadian norm population (p < 0.001), whereby 75% of the Dutch children scored below the 50th percentile. These lower scores were not be explained by sex, racial differences or congenital disorders and were seen in all age groups. Conclusion: We conclude that new reference values on the AIMS test for the age group of 0-12 months need to be established for Dutch children. It is recommended that the need for new normative data is also determined in all other European countries.

Concurrent loss of chromosome arm 1p and chromosome 3 predicts a decreased disease-free survival in uveal melanoma patients. (Article)

2005-12-01T00:00:00Z

PURPOSE: Uveal melanoma is a highly malignant disease with a mortality rate of 50% at 10 to 15 years. Previous studies have shown that chromosomal changes are associated with decreased survival of the patient. However, in these studies the small number of tumors analyzed did not allow robust statistical analysis. In the present study, the independent numerical changes in chromosomes 1, 3, 6, and 8 on disease-free survival (DFS) was assessed in a large series of patients with uveal melanoma. METHODS: One hundred twenty tumors from patients with uveal melanoma were analyzed for numerical changes in chromosomes 1, 3, 6, and 8, with cytogenetic analysis, fluorescent in situ hybridization, and/or comparative genomic hybridization. Data were correlated with disease outcome in univariate and multivariate analyses, by Kaplan-Meier and Cox regression analyses. RESULTS: At a mean follow-up time of 45 months, 42 patients had died or had metastatic disease. In the univariate analysis, loss of chromosome 3, gain of 8q, largest tumor diameter, or the presence of epithelioid cells was associated with a decreased DFS. In the multivariate analysis, the effect of monosomy 3 on survival was largely modified by changes in 1p36. Regarding all chromosomal changes, only the concurrent loss of the short arm of chromosome 1 and all of chromosome 3 was an independent prognostic parameter for disease-free survival (P < 0.001). CONCLUSIONS: In uveal melanoma, concurrent loss of the short arm of chromosome 1 and all of chromosome 3 is an independent predictor of decreased DFS.

Imaging peripheral arterial disease: a randomized controlled trial comparing contrast-enhanced MR angiography and multi-detector row CT angiography. (Article)

2005-09-01T00:00:00Z

PURPOSE: To prospectively evaluate clinical utility, patient outcomes, and costs of contrast material-enhanced magnetic resonance (MR) angiography compared with multi-detector row computed tomographic (CT) angiography for initial imaging in the diagnostic work-up of patients with peripheral arterial disease. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Patients referred for diagnostic imaging work-up to evaluate the feasibility of a revascularization procedure were randomly assigned to undergo either MR angiography or CT angiography. Clinical utility was assessed with therapeutic confidence (scale of 0-10) at initial imaging and with the need for additional imaging. Patient outcomes included ankle-brachial index, maximum walking distance, change in clinical status, and health-related quality of life. Actual diagnostic and therapeutic costs were calculated from the hospital perspective. Differences between group means were calculated with unpaired t tests and 95% confidence intervals. RESULTS: A total of 157 consecutive patients with peripheral arterial disease were prospectively randomized to undergo MR angiography (51 men, 27 women; mean age, 63 years) or CT angiography (50 men, 29 women; mean age, 64 years). For one of the 78 patients in the MR group, no data were available. Mean confidence for MR angiography (7.7) was slightly lower than that for CT angiography (8.0, P = .8). During 6 months of follow-up, 13 patients in the MR group compared with 10 patients in the CT group underwent additional vascular imaging (P = .5). Although not statistically significant, there was a consistent trend of less improvement in the MR group across all patient outcomes. The average cost for diagnostic imaging was 359 ($438) higher in the MR group than in the CT group (95% confidence interval: 209, 511 [$255, $623]; P < .001). Therapeutic costs were higher in the MR group, but the difference was not significant. CONCLUSION: The results suggest that CT angiography has some advantages over MR angiography in the initial evaluation of peripheral arterial disease.

Intravenous contrast material administration at helical 16-detector row CT coronary angiography: effect of iodine concentration on vascular attenuation. (Article)

2005-08-01T00:00:00Z

The institutional review board approved this study, and all patients gave written informed consent. One hundred twenty-five patients scheduled to undergo retrospectively electrocardiographically gated 16-detector row computed tomographic coronary angiography were prospectively randomized into the following five groups with respect to the intravenous administration of a 140-mL bolus of contrast material at 4 mL/sec: group 1 (iohexol [300 mg of iodine per milliliter]), group 2 (iodixanol [320 mg I/mL]), group 3 (iohexol [350 mg I/mL]), group 4 (iomeprol [350 mg I/mL]), and group 5 (iomeprol [400 mg I/mL]). Attenuation was measured in the descending aorta and coronary arteries. One-way analysis of variance was used to compare groups. Mean attenuation values in the descending aorta were significantly (P < .05) lower in group 1 and higher in group 5 compared with the mean values in the other three groups. The same pattern was observed in the coronary arteries. Contrast materials with higher iodine concentrations yield significantly higher attenuation in the descending aorta and coronary arteries.

Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. (Article)

2005-02-08T00:00:00Z

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been proposed as an inflammatory marker of cardiovascular disease. In the present study, we investigated whether Lp-PLA2 is an independent predictor of coronary heart disease and ischemic stroke. METHODS AND RESULTS: The Rotterdam Study is a population-based follow-up study in 7983 subjects > or =55 years of age. We performed a case-cohort study, including 308 coronary heart disease cases, 110 ischemic stroke cases, and a random sample of 1820 subjects. We used Cox proportional-hazard models with modification of the standard errors based on robust variance estimates to compute hazard ratios adjusted for age, sex, body mass index, systolic blood pressure, non-HDL cholesterol, HDL cholesterol, diabetes, smoking, alcohol consumption, cholesterol-lowering medication, white blood cell count, and C-reactive protein. Compared with the first quartile of Lp-PLA2 activity, multivariate-adjusted hazard ratios for coronary heart disease for the second, third, and fourth quartiles were 1.39 (95% CI, 0.92 to 2.10), 1.99 (95% CI, 1.32 to 3.00), and 1.97 (95% CI, 1.28 to 3.02), respectively (P for trend=0.01). Corresponding multivariate-adjusted hazard ratios for ischemic stroke were 1.08 (95% CI, 0.55 to 2.11), 1.58 (95% CI, 0.82 to 3.04), and 1.97 (95% CI, 1.03 to 3.79) (P for trend=0.03). The relation between Lp-PLA2 and coronary heart disease was present in both subjects with non-HDL cholesterol levels below the median and those with non-HDL cholesterol levels above the median. CONCLUSIONS: This study shows that Lp-PLA2 activity is an independent predictor of coronary heart disease and ischemic stroke in the general population.

Genetic risk estimation by healthcare professionals (Article)

2005-01-01T00:00:00Z

OBJECTIVES: To assess whether healthcare professionals correctly incorporate the relevance of a favourable test outcome in a close relative when determining the level of risk for individuals at risk for Huntington's disease. DESIGN AND SETTING: Survey of clinical geneticists and genetic counsellors from 12 centres of clinical genetics (United Kingdom, 6; The Netherlands, 4; Italy, 1; Australia, 1) in May-June 2002. Participants were asked to assess risk of specific individuals in 10 pedigrees, three of which required use of Bayes' theorem. PARTICIPANTS: 71 clinical geneticists and 41 other healthcare professionals involved in genetic counselling. MAIN OUTCOME MEASURES: Proportion of respondents correctly assessing risk in the three target pedigrees; proportion of respondents who were confident of their estimate. RESULTS: 50%-64% of respondents (for the three targets separately) did not include the favourable test information and incorrectly estimated the risks as being about equal to the prior risks; 77%-91% of these respondents were "sure" or "completely sure" that their estimations were correct. Twenty of the 112 respondents correctly estimated the risks for all three target pedigrees. CONCLUSIONS: Clinical geneticists and genetic counsellors frequently use prior risks in situations where Bayes' theorem should be applied, leading to overestimations of the risk for an individual.

Annual revaccination against influenza and mortality risk in community-dwelling elderly persons. (Article)

2004-11-03T00:00:00Z

CONTEXT: Although large-scale observational studies have demonstrated the effectiveness of influenza vaccination, no large studies have systematically addressed the clinical benefit of annual revaccinations. OBJECTIVE: To investigate the effect of annual influenza revaccination on mortality in community-dwelling elderly persons. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study using the computerized Integrated Primary Care Information (IPCI) database in the Netherlands including community-dwelling individuals aged 65 years or older from 1996 through 2002. For each year, we computed the individual cumulative exposure to influenza vaccination since study start. MAIN OUTCOME MEASURE: Association between the number of consecutive influenza vaccinations and all-cause mortality vs no vaccination after adjusting for age, sex, chronic respiratory and cardiovascular disease, hypertension, diabetes mellitus, renal failure, and cancer. RESULTS: The study population included 26,071 individuals, of whom 3485 died during follow-up. Overall, a first vaccination was associated with a nonsignificant annual reduction of mortality risk of 10% (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.78-1.03) while revaccination was associated with a reduced mortality risk of 24% (HR, 0.76; 95% CI, 0.70-0.83). Compared with a first vaccination, revaccination was associated with a reduced annual mortality risk of 15% (HR, 0.85; 95% CI, 0.75-0.96). During the epidemic periods this reduction was 28% (HR, 0.72; 95% CI, 0.53-0.96). Similar estimates were obtained for persons with and without chronic comorbidity and those aged 70 years or older at baseline. Overall, influenza vaccination is estimated to prevent 1 death for every 302 vaccinees at a vaccination coverage that varied between 64% and 74%. CONCLUSION: Annual influenza vaccination is associated with a reduction in all-cause mortality risk in a population of community-dwelling elderly persons, particularly in older individuals.

Peripheral arterial disease: therapeutic confidence of CT versus digital subtraction angiography and effects on additional imaging recommendations. (Article)

2004-11-01T00:00:00Z

PURPOSE: To compare multi-detector row computed tomographic (CT) angiography and digital subtraction angiography (DSA) prior to revascularization in patients with symptomatic peripheral arterial disease for the purpose of assessing recommendations for additional imaging and physician confidence ratings for chosen therapy. MATERIALS AND METHODS: In a randomized controlled trial, 73 patients were assigned to CT angiography, and 72 were assigned to DSA. Physician confidence in the treatment decision was measured as a continuous outcome on a scale of 0-10 (uncertain to certain) and as a dichotomous outcome (further imaging recommended, yes or no). Mean confidence scores and additional imaging recommendations were compared between CT and DSA groups in an intention-to-diagnose-and-treat analysis. To detect trends in confidence, confidence scores were plotted over time, and multiple linear regression analysis was performed. To detect trends in additional imaging recommendations, logistic regression analysis was used. Data from eligible nonrandomized patients were analyzed separately. RESULTS: No statistically significant difference in baseline characteristics between randomized groups was found. CT had a lower confidence score than did DSA (7.2 vs 8.2, P < .001). Further imaging was recommended more often after CT (25 of 71 patients, 35%) than after DSA (nine of 66 patients, 14%; P = .003). Analysis of trends demonstrated increasing (but not statistically significant) confidence in CT and stable confidence in DSA. No significant difference was found in baseline characteristics between randomized and nonrandomized patients. Among nonrandomized patients, no significant difference in mean confidence score (8.2 vs 8.3, P = .26) was found between CT (n = 24) and DSA (n = 26). CONCLUSION: With CT angiography, physician confidence decreases with an associated increase in additional imaging prior to revascularization in patients with symptomatic peripheral arterial disease. Given that CT is less invasive than DSA, results suggest that CT may replace DSA in selected cases.

Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. (Article)

2004-05-01T00:00:00Z

BACKGROUND: Increased levels of inflammatory proteins have been found in the brains and plasma samples of patients with dementia. Whether the levels of inflammatory proteins in plasma samples are elevated before clinical onset of dementia is unclear. OBJECTIVE: To determine whether high levels of inflammatory proteins in plasma samples are associated with an increased risk of dementia. DESIGN AND SETTING: A case-cohort study within the Rotterdam Study, a population-based prospective cohort study in the Netherlands. PARTICIPANTS: The source population comprises 6713 subjects who, at baseline (1990-1993), were free of dementia and underwent venipuncture. From these, we selected both a random subcohort of 727 subjects and 188 cases who had developed dementia at follow-up. MAIN OUTCOME MEASURES: The associations between plasma levels of alpha1-antichymotrypsin, C-reactive protein, interleukin 6, the soluble forms of intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 and the risk of dementia were examined using the Cox proportional hazards regression models. RESULTS: High levels of alpha1-antichymotrypsin, interleukin 6, and, to a lesser extent, C-reactive protein were associated with an increased risk of dementia; rate ratios per standard deviation increase were 1.49 (95% confidence interval, 1.23-1.81), 1.28 (95% confidence interval, 1.06-1.55), and 1.12 (95% confidence interval, 0.99-1.25), respectively. Similar associations were observed for Alzheimer disease, whereas rate ratios of vascular dementia were higher for alpha1-antichymotrypsin and C-reactive protein. Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia. CONCLUSION: Plasma levels of inflammatory proteins are increased before clinical onset of dementia, Alzheimer disease, and vascular dementia.

Relationship between atherosclerosis and late-life depression: the Rotterdam Study. (Article)

2004-04-01T00:00:00Z

CONTEXT: Depression in late life has been associated with vascular abnormalities. Several studies have demonstrated that persons with brain infarcts are more likely to have depressive disorders. Furthermore, depression is related to the subsequent development of ischemic heart disease. OBJECTIVE: To investigate the relationship between atherosclerosis at different locations and depression in the general population. DESIGN: Cross-sectional population-based study. SETTING: The Rotterdam Study, a population-based cohort study. PARTICIPANTS: In 4019 men and women 60 years and older, we assessed atherosclerosis at different locations, including common carotid intima-media thickness, plaques in the carotid arteries, the ankle-brachial blood pressure index, and aortic atherosclerosis. An overall measure of extracoronary atherosclerosis was obtained in 3747 persons by computing the principal component of these extracoronary atherosclerosis measures. In a subgroup of 1986 persons, we additionally measured coronary calcifications. MAIN OUTCOME MEASURE: All subjects were screened for depressive symptoms. Screen-positive subjects had a psychiatric interview to diagnose depressive disorder. RESULTS: More severe extracoronary atherosclerosis was associated with a higher prevalence of depressive disorders. For every 1-standard deviation increase, the prevalence increased by 30%. Furthermore, we found a strong relationship of severe coronary and aortic calcifications with depressive disorders (odds ratio, 3.89; 95% confidence interval, 1.55-9.77; and odds ratio, 2.00; 95% confidence interval, 1.02-3.96, respectively). CONCLUSIONS: Atherosclerosis and depression are associated in the elderly. This finding is compatible with the vascular depression hypothesis. However, the cross-sectional nature of the study does not allow causal inferences. In particular, earlier depressive episodes may have contributed to the development of atherosclerosis.

Generic and disease-specific health related quality of life in non-cirrhotic, cirrhotic and transplanted liver patients: a cross-sectional study. (Article)

2003-11-17T00:00:00Z

BACKGROUND: Studies on Health Related Quality of Life (HRQoL) of chronic liver patients were performed in clinical populations. These studies included various disease stages but small variations in aetiology and no transplanted patients. We performed a large HRQoL study in non-cirrhotic, cirrhotic and transplanted liver patients with sufficient variety in aetiology. We compared the generic HRQoL and fatigue between liver patients and healthy controls and compared the disease-specific and generic HRQoL and fatigue between non-cirrhotic, cirrhotic and transplanted liver patients, corrected for aetiology. METHODS: Members of the Dutch liver patient association received the Short Form-36, the Liver Disease Symptom Index and the Multidimensional Fatigue Index-20. Based on reported clinical characteristics we classified respondents (n = 1175) as non-cirrhotic, compensated cirrhotic, decompensated cirrhotic or transplants. We used linear, ordinal and logistic regression to compare the HRQoL between groups. RESULTS: All liver patients showed a significantly worse generic HRQoL and fatigue than healthy controls. Decompensated cirrhotic patients showed a significantly worse disease-specific and generic HRQoL and fatigue than non-cirrhotic patients, while HRQoL differences between non-cirrhotic and compensated cirrhotic patients were predominantly insignificant. Transplanted patients showed a better generic HRQoL, less fatigue and lower probabilities of severe symptoms than non-cirrhotic patients, but almost equal probabilities of symptom hindrance. CONCLUSIONS: HRQoL in chronic liver patients depends on disease stage and transplant history. Non-cirrhotic and compensated cirrhotic patients have a similar HRQoL. Decompensated patients show the worst HRQoL, while transplanted patients show a significantly better HRQoL than cirrhotic and non-cirrhotic patients.

A unified approach to modelling linkage to quantitative and qualitative traits (Article)

2003-09-01T00:00:00Z

For quantitative traits with a genetic component, random effects approaches are used to test for linkage at observed marker loci. We propose to use these approaches also for binary outcomes observed in sib pairs derived from a population-based cohort study. In addition to a random effect modelling correlation due to polygenic effect, a random effect is included to model the correlation between siblings due to sharing alleles identical by descent (IBD) at the observed marker locus. A two-step analysis is proposed. Firstly, score statistics are computed to test whether correlation is present in the data. Secondly, random effects models are fitted, yielding heritability estimates. To illustrate the methods, data on the contribution of the COL2A1 gene to various binary and quantitative outcomes including the presence of Heberden's nodes and bone mineral density (BMD) are analysed. For most of the traits studied, the score statistics were significant, indicating the presence of genetic effects. For BMD and for Heberden's nodes, the variance explained by the marker locus was 44% (P = 0.0008) and 15% (P = 0.38) respectively. We conclude that the score statistics can be used as a preliminary data analysis. In more sophisticated analysis, heritabilities can be estimated by fitting random effects models.

Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens (Article)

2003-01-01T00:00:00Z

Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age. Girls were randomly assigned to group A (4 IU/m(2).d; approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter 6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6 IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized 17beta-estradiol was given orally. After a mean duration of GH treatment of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or -0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, -1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than -2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated. In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV.

Validation and calibration of the Kabi Pharmacia International Growth Study prediction model for children with idiopathic growth hormone deficiency (Article)

2003-01-01T00:00:00Z

In 1999 a model was published for prediction of growth in children with idiopathic GH deficiency (IGHD) during GH therapy, derived using data from the Kabi Pharmacia International Growth Study (KIGS) database (Pharmacia \\|[amp ]\\| Upjohn, Inc., International Growth Database). We validated and calibrated this KIGS model for growth in the first year of GH therapy using data from 136 Dutch children with IGHD. Observed vs. predicted outcomes were plotted, and the fitted regression line was significantly different from the line of identity (P = 0.03). It appeared that the predictions were too extreme: relatively low predictions were too low, relatively high predictions were too high. This is a well known phenomenon in the context of prediction models, called overoptimism. For valid application to other data the KIGS predictions should be calibrated. Calibrated predictions are obtained using Y(cal) = Y(orig) + (2.153 - 0.192 x Y(orig)), where Y(cal) is the calibrated prediction, and Y(orig) is the KIGS prediction. The calibrated prediction will be higher than the original KIGS prediction when the original prediction is less than 11.2 cm/yr and will be lower otherwise. The variability of the prediction errors of the calibrated predictions was positively related to the value of the prediction (P < 0.001), described by the equation SD(pred err) = -1.017 + 0.286 x Y(cal). Our calibrated model will give better predictions for children with IGHD fulfilling the same criteria.

Thiazide diuretics and the risk for hip fracture (Article)

2003-01-01T00:00:00Z

BACKGROUND: Since most hip fractures are related to osteoporosis, treating accelerated bone loss can be an important strategy to prevent hip fractures. Thiazides have been associated with reduced age-related bone loss by decreasing urinary calcium excretion. OBJECTIVE: To examine the association between dose and duration of thiazide diuretic use and the risk for hip fracture and to study the consequences of discontinuing use. DESIGN: Prospective population-based cohort study. SETTING: The Rotterdam Study. PARTICIPANTS: 7891 individuals 55 years of age and older. MEASUREMENTS: Hip fractures were reported by the general practitioners and verified by trained research assistants. Details of all dispensed drugs were available on a day-to-day basis. Exposure to thiazides was divided into 7 mutually exclusive categories: never use, current use for 1 to 42 days, current use for 43 to 365 days, current use for more than 365 days, discontinuation of use since 1 to 60 days, discontinuation of use since 61 to 120 days, and discontinuation of use since more than 120 days. RESULTS: 281 hip fractures occurred. Relative to nonuse, current use of thiazides for more than 365 days was statistically significantly associated with a lower risk for hip fracture (hazard ratio, 0.46 [95% CI, 0.21 to 0.96]). There was no clear dose dependency. This lower risk disappeared approximately 4 months after thiazide use was discontinued. CONCLUSIONS: Thiazide diuretics protect against hip fracture, but this protective effect disappears within 4 months after use is discontinued.

Effect of discontinuation of long-term growth hormone treatment on carbohydrate metabolism and risk factors for cardiovascular disease in girls with Turner syndrome (Article)

2002-01-01T00:00:00Z

GH treatment increases insulin levels in girls with Turner syndrome (TS), who are already predisposed to develop diabetes mellitus and other risk factors for developing cardiovascular disease. Therefore, in the present study, we investigated carbohydrate metabolism and several other risk factors that may predict development of cardiovascular disease in girls with TS after discontinuation of long-term GH treatment. Fifty-six girls, participating in a randomized dose-response study, were examined before, during, and 6 months after discontinuing long-term GH treatment with doses of 4 IU/m(2).d ( approximately 0.045 mg/kg.d), 6 IU/m(2).d, or 8 IU/m(2).d. After a minimum of 4 yr of GH treatment, low-dose micronized 17beta-estradiol was given orally. Mean (SD) age at 6 months after discontinuation of GH treatment was 15.8 (0.9) yr. Mean duration of GH treatment was 8.8 (1.7) yr. Six months after discontinuation of GH treatment, fasting glucose levels decreased and returned to pretreatment levels. The area under the curve for glucose decreased to levels even lower than pretreatment level (P < 0.001). Fasting insulin levels and the area under the curve for insulin decreased to levels just above pretreatment level (P < 0.001 for both), although being not significantly different from the control group. No dose-dependent differences among GH dosage groups were found. At 6 months after discontinuation, impaired glucose tolerance was present in 1 of 53 girls (2%), and none of the girls developed diabetes mellitus type 1 or 2. Compared with pretreatment, the body mass index SD-score had increased (P < 0.001), and the systolic and diastolic blood pressure SD-score had decreased significantly at 6 months after discontinuation of GH treatment (P < 0.001 for both) although remaining above zero (P < 0.001, P < 0.05, and P < 0.005, respectively). Compared with pretreatment, total cholesterol (TC) did not change after discontinuation of GH treatment, whereas the atherogenic index [AI = TC/high-density lipoprotein cholesterol (TC/HDL-c)] and low-density lipoprotein cholesterol (LDL-c) had decreased; and both HDL-c and triglyceride levels increased (P < 0.001 for AI, LDL-c, and HDL-c; P < 0.05 for triglyceride). Compared with the control group, AI, serum TC, and LDL-c levels were significantly lower (P < 0.001 for all), whereas HDL-c levels were significantly higher (P < 0.05). In conclusion, after discontinuation of long-term GH treatment in girls with TS, the GH-induced insulin resistance disappeared, blood pressure decreased but remained higher than in the normal population, and lipid levels and the AI changed to more cardio-protective values.

Doxazosin and hydrochlorothiazide equally affect arterial wall thickness in hypertensive males with hypercholesterolaemia (the DAPHNE study) Doxazosin Atherosclerosis Progression Study in Hypertensives in the Netherlands (Article)

2002-01-01T00:00:00Z

BACKGROUND: Observational studies suggest a synergistic effect of hypertension and hyperlipidaemia on the progression of atherosclerosis. The alpha-blocker doxazosin has favourable effects on plasma lipids, insulin resistance and blood pressure, while the diuretic hydrochlorothiazide (HCTZ) principally affects blood pressure and increases insulin resistance. METHODS: A randomised double-blind study over 36 months was performed to compare the effects of doxazosin and HCTZ on fasting lipids and on progression of peripheral atherosclerosis. Eighty males (45 to 70 years) with peripheral atherosclerotic disease and increased cholesterol levels (5.2-8.0 mmol/l) were treated for essential hypertension with either doxazosin (n = 41) or HCTZ (n = 39). Main outcome measures were arterial intima-media thickness (IMT) of the carotid and femoral arteries and fasting lipid parameters. RESULTS: In the doxazosin-treated group, significant changes were observed in the concentration of triglycerides (-13.7%, p < 0.01), HDLc (+25.7%, p < 0.05) and IDLc (-30.1%, P < 0.05). In the HCTZ-treated group no significant changes in plasma lipid levels were observed. On follow-up visits systolic blood pressure in the doxazosin-treated group was 6 mm higher than in the HCTZ group. Nevertheless, the groups treated with doxazosin or HCTZ showed no differential effect on IMT after three years of treatment (p = 0.8). A significant reduction of the IMT of combined carotid and femoral arterial walls was shown in both treatment groups (p < 0.005). CONCLUSIONS: Hypertension treatment with doxazosin or HCTZ resulted in a comparable change in arterial IMT after three years, in spite of differences in effect on plasma lipids. The study emphasises the importance of blood pressure control in patients with peripheral vascular disease and hypercholesterolaemia.

Three-dimensional US assessment of hepatic volume, head circumference, and abdominal circumference in healthy and growth-restricted fetuses (Article)

2002-01-01T00:00:00Z

PURPOSE: To establish reproducibility and normal values for fetal hepatic volume and its significance in identification of fetal growth restriction relative to head and upper abdominal circumferences according to a cross-sectional study design. MATERIALS AND METHODS: Pregnant women (n = 135) underwent ultrasonography. The coefficient of variation (CV) for hepatic volume scans obtained at 0 and 20 minutes and hepatic area tracings, performed twice for each scan, was determined (n = 20; range, 23-36 weeks). Normal data for hepatic volume and head and upper abdominal circumferences were obtained (n = 85; range, 20-36 weeks) and related to data from growth-restricted fetuses (birth weight < P5 centile; n = 24; range, 22-36 weeks). RESULTS: CV was 2.9% for volume scans and 1.6% for area tracings. In 85 uncomplicated cases, mean fetal hepatic volume (P50 centile) was 9.7 mL +/- 4.4 (SD) at 20 weeks and 96.4 mL +/- 8.2 at 36 weeks of gestation. In 24 growth-restricted fetuses, hepatic volume, head circumference, and upper abdominal circumference expressed as percentages of the normal P50 centile were 45%, 90%, and 82%, respectively. Mean difference in hepatic volume between fetal growth restriction and normal fetal development, as expressed with the z score, -4.32 +/- 1.4, was significantly different (P <.05) from that for head circumference, -3.04 +/- 1.3, but not from that for upper abdominal circumference, -4.7 +/- 1.2. Fetal hepatic measurement was obtained in 109 pregnancies. CONCLUSION: Acceptable reproducibility exists for hepatic volume determinations. In fetal growth restriction, reduction is more pronounced for hepatic volume than for head or upper abdominal circumference; hepatic volume is a better discriminator than head circumference but not upper abdominal circumference.

The value of plasma markers for the clinical behaviour of phaeochromocytomas (Article)

2002-01-01T00:00:00Z

OBJECTIVE: Phaeochromocytomas (PCCs) are widely known for their clinical unpredictability. This study intends to define predictive plasma markers for their variable postoperative behaviour. Furthermore, the diagnostic accuracy of these plasma tests was determined. DESIGN AND METHODS: A retrospective correlative study was performed in a series of 83 operated and four autopsied patients in order to correlate preoperative catecholamine (CAT) levels of 103 PCCs with their clinical behaviour. In a subset of cases, chromogranin-A (Chr-A) and enzymes/precursors of the CAT biosynthesis were studied for their predictive value. RESULTS: Basal CAT levels were elevated in 81/87 instances (sensitivity: 93%). Four of six cases with normal measurements showed only medullary hyperplasia. Larger PCCs, particularly those showing necrosis, capsular and vascular invasion, secreted higher CAT levels. Bilateral, hereditary tumours were less productive than their unilateral counterparts. Extra-adrenal PCCs secreted significantly lower levels of epinephrine (EPI) than intra-adrenal tumours. Fourteen patients developed metastases. According to Kaplan-Meier estimations, patients with higher levels of dopamine, norepinephrine (NE) and aromatic l-amino acid decarboxylase as well as lower ratios of EPI/EPI+NE, had significantly shorter metastases-free intervals. Existence of preoperative hypertension, left ventricular hypertrophy and measured blood pressures showed significant positive relationships with CAT levels, but not with Chr-A. CONCLUSIONS: These data showed that plasma CAT measurement is a sensitive method in the diagnostic work-up of PCCs. Those tumours producing normal levels are commonly small and asymptomatic. Furthermore, certain secretion patterns are indicative of the presence of metastases as well as the size and site of sporadic and syndrome-related PCCs.

Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease (Article)

2001-01-01T00:00:00Z

BACKGROUND: Previous studies have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may help to prevent Alzheimer's disease. The results, however, are inconsistent. METHODS: We studied the association between the use of NSAIDs and Alzheimer's disease and vascular dementia in a prospective, population-based cohort study of 6989 subjects 55 years of age or older who were free of dementia at base line, in 1991. To detect new cases of dementia, follow-up screening was performed in 1993 and 1994 and again in 1997 through 1999. The risk of Alzheimer's disease was estimated in relation to the use of NSAIDs as documented in pharmacy records. We defined four mutually exclusive categories of use: nonuse, short-term use (1 month or less of cumulative use), intermediate-term use (more than 1 but less than 24 months of cumulative use), and long-term use (24 months or more of cumulative use). Adjustments were made by Cox regression analysis for age, sex, education, smoking status, and the use or nonuse of salicylates, histamine Hz-receptor antagonists, antihypertensive agents, and hypoglycemic agents. RESULTS: During an average follow-up period of 6.8 years, dementia developed in 394 subjects, of whom 293 had Alzheimer's disease, 56 vascular dementia, and 45 other types of dementia. The relative risk of Alzheimer's disease was 0.95 (95 percent confidence interval, 0.70 to 1.29) in subjects with short-term use of NSAIDs, 0.83 (95 percent confidence interval, 0.62 to 1.11) in those with intermediate-term use, and 0.20 (95 percent confidence interval, 0.05 to 0.83) in those with long-term use. The risk did not vary according to age. The use of NSAIDs was not associated with a reduction in the risk of vascular dementia. CONCLUSIONS: The long-term use of NSAIDs may protect against Alzheimer's disease but not against vascular dementia.

[(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas (Article)

2001-01-01T00:00:00Z

Selecting the appropriate approach for resection and follow-up of pheochromocytomas (PCCs) is highly dependent upon reliable localization and exclusion of multifocal, bilateral, or metastatic disease. Metaiodobenzylguanidine (MIBG) scintigraphy was developed for functional localization of catecholamine-secreting tissues. Somatostatin receptor imaging (SRI) has a high sensitivity for localizing head and neck paragangliomas, but studies of intraabdominal PCCs are rare. In this study we review our experience of [(123)I]MIBG and SRI, performed since 1983 and 1989, respectively, in the work-up of primary and recurrent PCCs. Scintigraphic results were correlated with catecholamine secretion, size and site, malignancy, associated tumor syndromes, and morphological features. [(123)I]MIBG scans were performed in a total of 75 patients, in 70 cases before resection of primary PCCs and in 5 cases because of recurrent disease. Ninety-one PCCs were resected. The overall detection rates were 83.3% and 89.8% for PCCs larger than 1.0 cm. Multifocal disease was detected in 4 patients with [(123)I]MIBG. [(123)I]MIBG uptake correlated with greater size of PCC (r = 0.33; P = 0.008) and greater concentration of plasma epinephrine (r = 0.32; P = 0.006). [(123)I]MIBG-negative PCCs (n = 14) had significantly (P = 0.01) smaller diameters than [(123I)]MIBG-positive tumors. Furthermore, [(123)I]MIBG uptake was significantly higher in unilateral (P = 0.02), benign (P = 0.02), sporadic (P = 0.02), intraadrenal (P = 0.02), and capsular invasive (P = 0.03) PCCs than in bilateral, malignant, MEN2A/2B-related, extraadrenal, and noninvasive PCCs, respectively. The detection rate of SRI was only 25% (8 of 32) for primary benign PCCs. In 14 patients metastases occurred, which were effectively visualized with [(123)I]MIBG in 8 of 14 cases. SRI was able to detect metastases in 7 of 8 cases, including 3 [(123)I]MIBG-negative metastatic cases. In addition, [(123)I]MIBG and SRI detected 2 recurrences. In conclusion, [(123)I]MIBG uptake is correlated with the size, epinephrine production, and site of PCCs. Its role in bilateral and MEN2A/2B-related PCCs seems limited. In cases of recurrent elevation of catecholamines, localization of metastases and/or recurrence should be attempted with [(123)I]MIBG scintigraphy. In suspicious metastatic PCCs, SRI might be considered to supplement [(123)I]MIBG scintigraphy.

Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner's syndrome participating in a randomized dose-response study (Article)

2001-01-01T00:00:00Z

To assess bone mineral density (BMD) in girls with Turner's syndrome before and during long-term treatment with GH, longitudinal measurements using phalangeal radiographic absorptiometry were performed in 68 girls with Turner's syndrome. These previously untreated girls, age 2-11 y, participating in a randomized, dose-response trial, were randomly assigned to one of three GH dosage groups: group A, 4 IU/m(2)/d ( approximately 0.045 mg/kg/d); group B, first year 4 IU/m(2)/d, thereafter 6 IU/m(2)/d ( approximately 0.0675 mg/kg/d); or group C, first year 4 IU/m(2)/d, second year 6 IU/m(2)/d, thereafter 8 IU/m(2)/d ( approximately 0.090 mg/kg/d). In the first 4 y of GH treatment, no estrogens for pubertal induction were prescribed to the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg body weight/d, orally) when they had reached the age of 12 y. BMD results were adjusted for bone age and sex, and expressed as SD scores using reference values of healthy Dutch girls. At baseline, almost every individual BMD value of bone consisting predominantly of cortical bone, as well as that of bone consisting predominantly of trabecular bone, was within the normal range of healthy girls and the SD scores were not significantly different from zero [mean (SE) 0.38 (0.22) and -0.04 (0.13)]. During 7 y of GH treatment, BMD SD scores showed a significant increase to values significantly higher than zero [mean (SE) 0.87 (0.15) and 0.95 (0.14)]. The increment in BMD SD score of bone consisting predominantly of cortical bone was significantly higher in group C compared with that of the other two GH dosage groups. The pretreatment bone age was significantly negatively related to the increment in BMD SD score. We found no significant influence of spontaneous puberty or the use of low-dose estrogens in the last 3 y of the study period on the increment in BMD SD score during 7 y of GH treatment. In conclusion, most untreated young girls with Turner's syndrome have a normal volumetric BMD. During 7 y of GH treatment with 4, 6, or 8 IU/m(2)/d, the BMD SD score increased significantly.

Incidence and progression rates of age-related maculopathy: the Rotterdam Study (Article)

2001-01-01T00:00:00Z

PURPOSE: To describe the incidence rate of age-related macular degeneration (AMD) and the progression rates of early stages of age-related maculopathy (ARM), and to study the hierarchy of fundus features that determine progression. METHODS: A group of 4953 subjects aged 55 years and older living in Rotterdam, The Netherlands, was studied at baseline and at 2-year follow-up to determine the incidence of neovascular and atrophic AMD. A subgroup of 1244 subjects was studied for progression of early stages of ARM. Fundus transparencies were graded for features of ARM using the International Classification System. ARM was stratified in four exclusive stages, according to type of drusen and presence of pigmentary irregularities. RESULTS: The overall 2-year cumulative incidence of AMD was 0.2%, increasing to 1.8% in subjects of 85 years and older. Of those in the early stages, one fourth showed progression to a more severe stage. The most important predictors for progression were more than 10% of macular area covered by drusen (odds ratio [OR] 5.7, 95% confidence interval [CI] 2.9-11.3), presence of depigmentation (OR 4.0, 95% CI 2.5-6.4), and hyperpigmentation (OR 3.4, 95% CI 2.1-5.4). CONCLUSIONS: The incidence of AMD appears to be lower in The Netherlands than in the United States. Progression of early ARM stages occurs in a distinct pattern at a stable rate, with a large area of drusen and presence of pigmentary changes as the most important predictors.

Balloon dilation and stent implantation for treatment of femoropopliteal arterial disease: meta-analysis (Article)

2001-01-01T00:00:00Z

PURPOSE: To perform a meta-analysis of long-term results of balloon dilation and stent implantation in the treatment of femoropopliteal arterial disease. MATERIALS AND METHODS: The English-language literature was searched for studies published between 1993 and 2000. Inclusion criteria for articles were presentation of long-term primary patency rates, standard errors (explicitly reported or derivable), and baseline characteristics of the study population. Two reviewers independently extracted data, and discrepancies were resolved by consensus. Primary patency rates were combined by using a technique that allows adjustment for differences across study populations. Analyses were adjusted for lesion type and clinical indication. RESULTS: Nineteen studies met the inclusion criteria, representing 923 balloon dilations and 473 stent implantations. Combined 3-year patency rates after balloon dilation were 61% (standard error, 2.2%) for stenoses and claudication, 48% (standard error, 3.3%) for occlusions and claudication, 43% (standard error, 4.1%) for stenoses and critical ischemia, and 30% (standard error, 3.7%) for occlusions and critical ischemia. The 3-year patency rates after stent implantation were 63%-66% (standard error, 4.1%) and were independent of clinical indication and lesion type. Funnel plots demonstrated an asymmetric distribution of the data points associated with stent studies. CONCLUSION: Balloon dilation and stent implantation for claudication and stenosis yield similar long-term patency rates. For more severe femoropopliteal disease, the results of stent implantation seem more favorable. Publication bias could not be ruled out.

Ontwikkelingen in de biostatistiek (Inaugural Lecture)

2000-09-01T00:00:00Z

Randomized clinical trial of adenosine 5'-triphosphate in patients with advanced non-small-cell lung cancer (Article)

2000-01-01T00:00:00Z

BACKGROUND: Extracellular adenosine 5'-triphosphate (ATP) is involved in the regulation of a variety of biologic processes, including neurotransmission, muscle contraction, and liver glucose metabolism, via purinergic receptors. In nonrandomized studies involving patients with different tumor types including non-small-cell lung cancer (NSCLC), ATP infusion appeared to inhibit loss of weight and deterioration of quality of life (QOL) and performance status. We conducted a randomized clinical trial to evaluate the effects of ATP in patients with advanced NSCLC (stage IIIB or IV). METHODS: Fifty-eight patients were randomly assigned to receive either 10 intravenous 30-hour ATP infusions, with the infusions given at 2- to 4-week intervals, or no ATP. Outcome parameters were assessed every 4 weeks until 28 weeks. Between-group differences were tested for statistical significance by use of repeated-measures analysis, and reported P values are two-sided. RESULTS: Twenty-eight patients were allocated to receive ATP treatment and 30 received no ATP. Mean weight changes per 4-week period were -1.0 kg (95% confidence interval [CI] = -1.5 to -0.5) in the control group and 0.2 kg (95% CI = -0.2 to +0.6) in the ATP group (P =.002). Serum albumin concentration declined by -1.2 g/L (95% CI= -2.0 to -0.4) per 4 weeks in the control group but remained stable (0.0 g/L; 95% CI = -0.3 to +0.3) in the ATP group (P =.006). Elbow flexor muscle strength declined by -5.5% (95% CI = -9.6% to -1. 4%) per 4 weeks in the control group but remained stable (0.0%; 95% CI= -1.4% to +1.4%) in the ATP group (P =.01). A similar pattern was observed for knee extensor muscles (P =.02). The effects of ATP on body weight, muscle strength, and albumin concentration were especially marked in cachectic patients (P =.0002, P =.0001, and P =. 0001, respectively, for ATP versus no ATP). QOL score changes per 4-week period in the ATP group showed overall less deterioration than in the control group-physical scores (-0.2% versus -2.4%; P =. 0002); functional scores (+0.4% versus -5.5%; P =.02); psychologic scores (-0.7% versus -2.4%; P =.11); overall QOL score (+0.1% versus -3.5%; P =.0001). CONCLUSIONS: This randomized trial demonstrates that ATP has beneficial effects on weight, muscle strength, and QOL in patients with advanced NSCLC.

Carbohydrate metabolism during long-term growth hormone (GH) treatment and after discontinuation of GH treatment in girls with Turner syndrome participating in a randomized dose-response study. Dutch Advisory Group on Growth Hormone (Article)

2000-01-01T00:00:00Z

To assess possible side-effects of GH treatment with supraphysiological doses on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during long term GH treatment and after discontinuation of GH treatment, the results of oral glucose tolerance tests and hemoglobin A1c measurements were analyzed in 68 girls with TS participating in a randomized dose-response trial. These previously untreated girls, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2 x day (-0.045 mg/kg x day); group B, first year ,4 IU/m2 day; thereafter, 6 IU/m2 x day (approximately 0.0675 mg/kg x day); group C, first year, 4 IU/m2 x day; second year, 6 IU/m2 x day; thereafter, 8 IU/m2 x day (approximately 0.090 mg/kg x day). After the first 4 yr, girls 12 yr of age or older started with 5 microg/kg BW-day 17beta-estradiol for induction of puberty. To assess the effects of long term high dose GH treatment on CH metabolism, the 7-yr data from the oral glucose tolerance tests in 9 girls of group C were evaluated (group C1). To determine whether the changes in CH metabolism during GH treatment would persist after discontinuation of GH treatment, the data for 28 girls who had reached adult height (group A, n = 9; group B, n = 10; group C, n = 9) were evaluated at baseline, after 4 yr of GH treatment, and 6 months after discontinuation of GH. Seven-year data for group C1 showed that glucose levels did not significantly change during GH treatment, whereas fasting insulin levels as well as glucose-induced insulin levels increased significantly. The data for the 28 girls who were treated with GH for a mean (SD) period of 85.3 (13.3) months demonstrated that the GH-induced higher insulin levels decreased to values close to or equal to pretreatment values after discontinuation of GH treatment. Changes in CH variables were not significantly related to the GH dose. Hemoglobin A1c levels never showed an abnormal value. The prevalence of impaired glucose tolerance was low, and none of the girls developed diabetes mellitus. In conclusion, long term GH treatment with dosages up to 8 IU/m2 x day in girls with TS has no adverse effects on glucose levels, but induced higher levels of insulin, indicating relative insulin resistance. The increased insulin levels during long term GH treatment decreased after discontinuation of GH treatment to values close to or equal to pretreatment values. Although the reversibility of the effects of long term GH is reassuring, the consequence of long term hyperinsulinism is still unknown.

Apolipoprotein E genotype and the progression of Alzheimer's disease: the Rotterdam Study (Article)

1999-05-26T00:00:00Z

The APOE*4 allele of the apolipoprotein E gene increases the risk of Alzheimer's disease (AD), but whether it also affects the course of the disease is controversial. However, all studies on this issue until now have been based on patients at various stages of disease. In the present population-based study, 97 patients were included at a similar stage, i.e., before the onset of symptoms, and followed for up to 5 years. We found that the APOE*4 allele is not a strong determinant of survival in AD. As change in cognitive function and severity of dementia are similar for AD patients with and without APOE*4, our study suggests that progression of AD is not related to the APOE*4 allele.

Final height in girls with Turner's syndrome treated with once or twice daily growth hormone injections. Dutch Advisory Group on Growth Hormone (Article)

1999-01-01T00:00:00Z

OBJECTIVES: To study final height in girls with Turner's syndrome treated with once or twice daily injections of growth hormone (GH) in combination with low dose ethinyl oestradiol. DESIGN: Until final height was reached, the effect of fractionated subcutaneous injections given twice daily was compared with once daily injections of a total GH dose of 6 IU/m2/day. Twice daily injections were given as one third in the morning and two thirds at bedtime. All girls concurrently received low dose oestradiol (0.05 microgram ethinyl oestradiol/kg/day, increased to 0.10 microgram/kg/day after 2.25 years). PATIENTS: Nineteen girls with Turner's syndrome aged > or = 11 years (mean (SD) 13.6 (1.7) years). MEASUREMENTS: To determine final height gain, we assessed the difference between the attained final height and the final height predictions at the start of treatment. These final height predictions were calculated using the Bayley-Pinneau (BP) prediction method, the modified projected adult height (mPAH), the modified index of potential height (mIPHRUS), and the Turner's specific prediction method (PTSRUS). RESULTS: The gain in final height (mean (SD)) was not significantly different between the once daily and the twice daily regimens (7.6 (2.3) v 5.1 (3.2) cm). All girls exceeded their adult height prediction (range, 1.6-12.3 cm). Thirteen of the 19 girls had a final height gain > 5.0 cm. Mean (SD) attained final height was 155.5 (5.4) cm. A "younger bone age" at baseline and a higher increase in height standard deviation score for chronological age (Dutch-Swedish-Danish references) in the first year of GH treatment predicted a higher final height gain after GH treatment. CONCLUSIONS: Division of the total daily GH dose (6 IU/m2/day) into two thirds in the evening and one third in the morning is not advantageous over the once daily GH regimen with respect to final height gain. Treatment with a GH dose of 6 IU/m2/day in combination with low dose oestrogens can result in a significant increase in adult height in girls with Turner's syndrome, even if they start GH treatment at a relatively late age.

Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial (Article)

1999-01-01T00:00:00Z

Short stature and ovarian failure are the main features in Turner syndrome (TS). To optimize GH and estrogen treatment, we studied 68 previously untreated girls with TS, age 2-11 yr, who were randomly assigned to one of three GH dosage groups: group A, 4 IU/m2 day (approximately 0.045 mg/kg x day); group B, first yr 4, thereafter 6 IU/m2 x day (approximately 0.0675 mg/kg/day); group C, first yr 4, second yr 6, thereafter 8 IU/m2 x day (approximately 0.090 mg/kg x day). In the first 4 yr of GH treatment, no estrogens for pubertal induction were given to the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg bw x day, orally) when they had reached the age of 12 yr. Subjects were followed up until attainment of adult height or until cessation of treatment because of satisfaction with the height achieved. Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood. After 7 yr, 85% of the girls had reached a height within the normal range for healthy Dutch girls. The 7-yr increment in height SD-score was significantly higher in groups B and C than in group A. In addition, we evaluated the data of 32 of the 68 girls who had completed the trial after a mean duration of treatment of 7.3 yr (range, 5.0 - 8.75). Mean (SD) height was 158.8 cm (7.1), 161.0 cm (6.8), and 162.3 cm (6.1) in groups A, B, and C, respectively. The mean (SD) difference between predicted adult height before treatment and achieved height was 12.5 cm (2.1), 14.5 cm (4.0), and 16.0 cm (4.1) for groups A, B, and C, respectively, being significantly different between group A and group C. GH treatment was well tolerated in all three GH dosage groups. In conclusion, GH treatment starting in relatively young girls with TS results in normalization of height during childhood, as well as of adult height, in most of the individuals. With this GH and estrogen treatment regimen, most girls with TS can grow and develop much more in conformity with their healthy peers.

Body proportions during long-term growth hormone treatment in girls with Turner syndrome participating in a randomized dose-response trial (Article)

1999-01-01T00:00:00Z

To assess body proportions in girls with Turner syndrome (TS) during long term GH treatment, height, sitting height (SH), hand (Hand) and foot (Foot) lengths, and biacromial (Biac) and biiliacal (Biil) diameters were measured in 68 girls with TS participating in a GH dose-response trial. These previously untreated girls with TS, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2 x day; group B, first year 4 and thereafter 6 IU/m2 x day; group C, first year 4, second year 6, and thereafter 8 IU/m2 x day. Seven-year data were evaluated to assess the effect of GH treatment on body proportions during childhood. In addition, data from all girls who had reached adult height were evaluated to determine the effect on the adult body proportions. All results were adjusted for age and sex and expressed as SD scores using reference values of healthy Dutch girls. To describe the proportions of SH, Hand, Foot, Biac, and Biil to height, these values were adjusted for the SD score of height and were expressed as shape values, using the formula, e.g. for SH: shape SH = (SH SD score - height SD score)/square root(2 - 2 x correlation coefficient between SH and height in the reference population). Furthermore, SD scores using references of untreated girls with TS were calculated for height and SH. Values less than -2 or more than +2 were considered outside the normal range. At baseline, the shape values of all measurements were significantly higher than zero, but most mean shape values were still within the normal range. Seven-year data of 64 girls and adult height data of 32 girls showed that an increase in height was accompanied by an even higher increase in Foot, resulting in mean SD scores above zero and shape values of +2 and higher. The increase in the shape value of Foot was significantly higher in groups B and C compared to that in group A after 7 yr of GH treatment, but there were no significant differences between the GH dosage groups in the girls who had reached adult height. The shape values of SH had decreased to values closer to zero after reaching adult height, especially in group A. A similar pattern in the relationship of SH to height was seen using references of girls with TS. No significant changes in the other proportions were found after reaching adult height. In conclusion, on the average, untreated girls with TS have relatively large trunk, hands, and feet, and broad shoulders and pelvis compared to height. The increase in height after long term GH treatment is accompanied by an even higher increase in Foot and a moderate improvement of the disproportion between height and SH. Recently published reference data from untreated adults with TS and the results of a different patient group receiving a comparable GH dosage suggest that the disproportionate growth of feet has to be considered a part of the natural development in TS, but might be influenced by higher GH dosages. The development of large feet can play a role in the decision of the girl to discontinue GH treatment in the last phase of growth.

A goodness-of-fit test for Cox's proportional hazards model based on martingale residuals (Article)

1998-12-01T00:00:00Z

A goodness-of-fit test for Cox's proportional hazards model is proposed on the basis of martingale residuals. The test is derived as the score test for the presence of an extra random effect in the exponential part of the hazard function. Assumptions about the distribution of the random effects are not made; only the correlation matrix must be specified. This can be done on the basis of an existing division of individuals into groups, such as families, or on the basis of the distance between observed covariates. The variance of the test statistic is derived using a counting process approach. Corrections for the estimation of parameters are available. The test is demonstrated in a simulated data set as well as in a real data set on ovarian cancer.

Energy utilization and growth in breast-fed and formula-fed infants measured prospectively during the first year of life (Article)

1998-01-01T00:00:00Z

This study is the first to report approximations of energy requirements for male and female breast-fed and formula-fed infants based on individual estimates of total daily energy expenditure (TDEE) and energy deposition derived from total body fat (TBF) and fat-free mass (FFM) gain as determined by total-body electrical conductivity. In 46 healthy, full-term infants the effect of > or = 4 mo of exclusive breast-feeding compared with formula feeding on macronutrient and energy intake, TDEE, energy deposition, and growth were investigated prospectively. Metabolizable energy intake (MEI) was assessed from macronutrient intake by test weighing (MEI-TW) and from the sum of TDEE and energy deposition (MEI-Pred). At 1-2, 2-4, 4-8, and 8-12 mo of age MEI-Pred averaged 431 +/- 38, 393 +/- 33, 372 +/- 33, and 355 +/- 21 kJ x kg(-1) x d(-1) for boys, and 401 +/- 59, 376 +/- 25, 334 +/- 33, and 326 +/- 17 kJ x kg(-1) x d(-1) for girls. No significant difference between breast-fed and formula-fed infants was found with respect to weight, length, head circumference, TBF, FFM, and TDEE at all ages, or for gain in length, weight, TBF, and FFM. MEI-TW was significantly different between feeding groups at 1-4 mo of age (formula-fed being greater than breast-fed, P < 0.005). This feeding effect, however, was not significant for MEI-Pred (MJ/d). MEI-TW differed from MEI-Pred only in breast-fed infants at 1-4 mo (P < 0.05 at 2-4 mo). The data from this study indicate that energy requirements in infants are lower than the recommendations in guidelines currently in use.

Serum inhibin B as a marker of spermatogenesis (Article)

1998-01-01T00:00:00Z

Inhibin B is produced by Sertoli cells, provides negative feedback on FSH secretion, and may prove to be an important marker for the functioning of seminiferous tubules. The purpose of the present study was to examine the relationship between the spermatogenic function of the testis of subfertile men and the plasma concentrations of inhibin B and FSH. These parameters were estimated in a group of 218 subfertile men. Serum inhibin B levels were closely correlated with the serum FSH levels (r = -0.78, P < 0.001), confirming the role of inhibin B as feedback signal for FSH production. The spermatogenic function of the testis was evaluated by determining testicular volume and total sperm count. Inhibin B levels were significantly correlated with the total sperm count and testicular volume (r = 0.54 and r = 0.63, respectively; P < 0.001). Testicular biopsies were obtained in 22 of these men. Inhibin B was significantly correlated with the biopsy score (r = 0.76, P < 0.001). Receiver operating characteristic analysis revealed a diagnostic accuracy of 95% for differentiating competent from impaired spermatogenesis for inhibin B, whereas for FSH, a value of 80% was found. We conclude that inhibin B is the best available endocrine marker of spermatogenesis in subfertile men.

Dead space and slope indices from the expiratory carbon dioxide tension-volume curve (Article)

1997-08-01T00:00:00Z

The slope of phase 3 and three noninvasively determined dead space estimates derived from the expiratory carbon dioxide tension (PCO2) versus volume curve, including the Bohr dead space (VD,Bohr), the Fowler dead space (VD,Fowler) and pre-interface expirate (PIE), were investigated in 28 healthy control subjects, 12 asthma and 29 emphysema patients (20 severely obstructed and nine moderately obstructed) with the aim to establish diagnostic value. Because breath volume and frequency are closely related to CO2 elimination, the recording procedures included varying breath volumes in all subjects during self-chosen/natural breathing frequency, and fixed frequencies of 10, 15 and 20 breaths x min(-1) with varying breath volumes only in the healthy controls. From the relationships of the variables with tidal volume (VT), the values at 1 L were estimated to compare the groups. The slopes of phase 3 and VD,Bohr at 1 L VT showed the most significant difference between controls and patients with asthma or emphysema, compared to the other two dead space estimates, and were related to the degree of airways obstruction. Discrimination between no-emphysema (asthma and controls) and emphysema patients was possible on the basis of a plot of intercept and slope of the relationship between VD,Bohr and VT. A combination of both the slope of phase 3 and VD,Bohr of a breath of 1 L was equally discriminating. The influence of fixed frequencies in the controls did not change the results. The conclusion is that Bohr dead space in relation to tidal volume seems to have diagnostic properties separating patients with asthma from patients with emphysema with the same degree of airways obstruction. Equally discriminating was a combination of both phase 3 and Bohr dead space of a breath of 1 L. The different pathophysiological mechanisms in asthma and emphysema leading to airways obstruction are probably responsible for these results.

Late Lumen Loss After Coronary Angioplasty Is Associated With the Activation Status of Circulating Phagocytes Before Treatment (Article)

1995-01-01T00:00:00Z

Background The purpose of this pilot study was to identify biological risk factors for restenosis after percutaneous transluminal coronary angioplasty (PTCA) to predict the long-term outcome of PTCA before treatment. Methods and Results To investigate whether blood granulocytes and monocytes could determine luminal renarrowing after PTCA, several characteristics of these phagocytes were assessed before angioplasty in 32 patients who underwent PTCA of one coronary artery and who had repeat angiograms at 6-month follow-up. The plasma levels of interleukin (IL)-1ß, tumor necrosis factor-, IL-6, fibrinogen, C-reactive protein, and lipoprotein(a) before angioplasty were assessed as well. We found that the expression of the membrane antigens CD64, CD66, and CD67 by granulocytes was inversely associated with the luminal renarrowing normalized for vessel size (relative loss) at 6 months after PTCA, while the production of IL-1ß by stimulated monocytes was positively associated with the relative loss. Next, these univariate predictors were corrected for the established clinical risk factors of dilation of the left anterior descending coronary artery and current smoking, which were statistically significant classic predictors in our patient group. Only the expression of CD67 did not predict late lumen loss independent of these established clinical risk factors. Multiple linear regression analysis showed that luminal renarrowing could be predicted reliably (R2=.65; P<.0001) in this patient group on the basis of the vessel dilated and only two biological risk factors that reflect the activation status of blood phagocytes, ie, the expression of CD66 by granulocytes and the production of IL-1ß by stimulated monocytes. Conclusions The results of the present study indicate that activated blood granulocytes prevent luminal renarrowing after PTCA, while activated blood monocytes promote late lumen loss. To validate this new finding, further study in an independent patient group is required.

Does phase 2 of the expiratory PCO2 versus volume curve have diagnostic value in emphysema patients? (Article)

1995-01-01T00:00:00Z

It has been postulated that serial inhomogeneity of ventilation in the peripheral airways in emphysema is represented by the shape of expiratory carbon dioxide tension versus volume curve. We examined the diagnostic value of this test in patients with various degrees of emphysema. The volumes between 25-50% (V25-50) and 25-75% (V25-75) of the expiratory carbon dioxide tension versus volume curve were determined in 29 emphysematous patients (20 severely obstructed and 9 moderately obstructed), 12 asthma patients in exacerbation of symptoms, and 28 healthy controls. Discriminant analysis was used to examine whether these diagnostic groups could be separated. With regard to phase 2 of the expiratory CO2 versus volume curve (mixture of anatomic deadspace and alveolar air), a plot of intercept versus slope of the relationships of (V25-50) and (V25-75) versus inspiratory volume (VI) from functional residual capacity (FRC), obtained during natural breathing frequency, proved to be most discriminating in the separation between healthy controls and severely obstructed emphysema patients. Separating healthy controls and severely obstructed emphysema patients on the basis of the discriminant line for V25-50, 9 of the 12 asthma patients in exacerbation were classified as normal, and only 5 of the 9 moderately obstructed emphysema patients as emphysematous. For V25-75 involvement of phase 3 of the curve (alveolar plateau) in asthma patients in exacerbation caused a marked overlap with the severely obstructed emphysema patients. In the healthy controls, a fixed breathing frequency of 20 breaths.min-1 led to an increase of both volumes.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk factors for Alzheimer's disease: Overview of the EURODEM collaborative re-analysis of case-control studies (Article)

1991-01-01T00:00:00Z

Studies of risk factors for Alzheimer's disease have been hampered by low statistical power. The data from 11 case-control studies were pooled and re-analysed to evaluate the evidence for the association of Alzheimer's disease with family history of dementia and related disorders, parental age, medical history, and environmental factors. This paper gives a brief description of the participating studies and discusses the strategy that has been followed in the collaborative analysis.