Kors, J.A.

Prevalence of Symptomatic Heart Failure with Reduced and with Normal Ejection Fraction in an Elderly General Population-The CARLA Study (Article)

2013-03-15T00:00:00Z

Background/Objectives: Chronic heart failure (CHF) is one of the most important public health concerns in the industrialized world having increasing incidence and prevalence. Although there are several studies describing the prevalence of heart failure with reduced ejection fraction (HFREF) and heart failure with normal ejection fraction (HFNEF) in selected populations, there are few data regarding the prevalence and the determinants of symptomatic heart failure in the general population. Methods: Cross-sectional data of a population-based German sample (1,779 subjects aged 45-83 years) were analyzed to determine the prevalence and determinants of chronic SHF and HFNEF defined according to the European Society of Cardiology using symptoms, echocardiography and serum NT-proBNP. Prevalence was age-standardized to the German population as of December 31st, 2005. Results: The overall age-standardized prevalence of symptomatic CHF was 7.7% (95%CI 6.0-9.8) for men and 9.0% (95%CI 7.0-11.5) for women. The prevalence of CHF strongly increased with age from 3.0% among 45-54- year-old subjects to 22.0% among 75-83- year-old subjects. Symptomatic HFREF could be shown in 48% (n = 78), symptomatic HFNEF in 52% (n = 85) of subjects with CHF. The age-standardized prevalence of HFREF was 3.8 % (95%CI 2.4-5.8) for women and 4.6 % (95%CI 3.6-6.3) for men. The age-standardized prevalence of HFNEF for women and men was 5.1 % (95%CI 3.8-7.0) and 3.0 % (95%CI 2.1-4.5), respectively. Persons with CHF were more likely to have hypertension (PR = 3.4; 95%CI 1.6-7.3) or to have had a previous myocardial infarction (PR = 2.5, 95%CI 1.8-3.5). Conclusion: The prevalence of symptomatic CHF appears high in this population compared with other studies. While more women were affected by HFNEF than men, more male subjects suffered from HFREF. The high prevalence of symptomatic CHF seems likely to be mainly due to the high prevalence of cardiovascular risk factors in this population.

Electrocardiographic characteristics of patients with chronic obstructive pulmonary disease (Article)

2013-02-01T00:00:00Z

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease. Electrocardiography (ECG) carries information about cardiac disease and prognosis, but studies comparing ECG characteristics between patients with and without COPD are lacking. We related ECG characteristics of patients with COPD, to ECG characteristics of patients without COPD, and determined whether ECG abnormalities are related to COPD severity. A cross-sectional study was conducted within a cohort of 243 COPD patients, aged 65 years or older. All patients underwent extensive examinations, including resting 12-lead ECG and pulmonary function tests. The reference group (n = 293) was a sample from the general population, also aged 65 or older, without COPD. Abnormal ECGs were more prevalent in COPD patients (50%) than in patients without COPD (36%, p = 0.054). Conduction abnormalities were the most common ECG abnormality in COPD patients (28%) being significantly more prevalent than in patients without COPD (11%, p < 0.001). The mean heart rate was higher in COPD patients (72 bpm (SD 14)) compared to controls (65 bpm (SD 13), p < 0.001), and QTc prolongation was less frequent in COPD patients (9% versus 14%, p = 0.01). The prevalence of ECG abnormalities increased with severity of pulmonary obstruction. ECG abnormalities, especially conduction abnormalities are common in COPD patients, and the prevalence of ECG abnormalities increases with severity of COPD. This underlines the importance of an integrated-care approach for COPD patients, paying attention to early detection of unrecognized coexisting cardiac disorders.

The EU-ADR corpus: Annotated drugs, diseases, targets, and their relationships (Article)

2012-10-01T00:00:00Z

Corpora with specific entities and relationships annotated are essential to train and evaluate text-mining systems that are developed to extract specific structured information from a large corpus. In this paper we describe an approach where a named-entity recognition system produces a first annotation and annotators revise this annotation using a web-based interface. The agreement figures achieved show that the inter-annotator agreement is much better than the agreement with the system provided annotations. The corpus has been annotated for drugs, disorders, genes and their inter-relationships. For each of the drug-disorder, drug-target, and target-disorder relations three experts have annotated a set of 100 abstracts. These annotated relationships will be used to train and evaluate text-mining software to capture these relationships in texts.

Training text chunkers on a silver standard corpus: Can silver replace gold? (Article)

2012-01-30T00:00:00Z

Background: To train chunkers in recognizing noun phrases and verb phrases in biomedical text, an annotated corpus is required. The creation of gold standard corpora (GSCs), however, is expensive and time-consuming. GSCs therefore tend to be small and to focus on specific subdomains, which limits their usefulness. We investigated the use of a silver standard corpus (SSC) that is automatically generated by combining the outputs of multiple chunking systems. We explored two use scenarios: one in which chunkers are trained on an SSC in a new domain for which a GSC is not available, and one in which chunkers are trained on an available, although small GSC but supplemented with an SSC.Results: We have tested the two scenarios using three chunkers, Lingpipe, OpenNLP, and Yamcha, and two different corpora, GENIA and PennBioIE. For the first scenario, we showed that the systems trained for noun-phrase recognition on the SSC in one domain performed 2.7-3.1 percentage points better in terms of F-score than the systems trained on the GSC in another domain, and only 0.2-0.8 percentage points less than when they were trained on a GSC in the same domain as the SSC. When the outputs of the chunkers were combined, the combined system showed little improvement when using the SSC. For the second scenario, the systems trained on a GSC supplemented with an SSC performed considerably better than systems that were trained on the GSC alone, especially when the GSC was small. For example, training the chunkers on a GSC consisting of only 10 abstracts but supplemented with an SSC yielded similar performance as training them on a GSC of 100-250 abstracts. The combined system even performed better than any of the individual chunkers trained on a GSC of 500 abstracts.Conclusions: We conclude that an SSC can be a viable alternative for or a supplement to a GSC when training chunkers in a biomedical domain. A combined system only shows improvement if the SSC is used to supplement a GSC. Whether the approach is applicable to other systems in a natural-language processing pipeline has to be further investigated.

Comparing and combining chunkers of biomedical text (Article)

2011-04-01T00:00:00Z

Text chunking is an essential pre-processing step in information extraction systems. No comparative studies of chunking systems, including sentence splitting, tokenization and part-of-speech tagging, are available for the biomedical domain. We compared the usability (ease of integration, speed, trainability) and performance of six state-of-the-art chunkers for the biomedical domain, and combined the chunker results in order to improve chunking performance. We investigated six frequently used chunkers: GATE chunker, Genia Tagger, Lingpipe, MetaMap, OpenNLP, and Yamcha. All chunkers were integrated into the Unstructured Information Management Architecture framework. The GENIA Treebank corpus was used for training and testing. Performance was assessed for noun-phrase and verb-phrase chunking. For both noun-phrase chunking and verb-phrase chunking, OpenNLP performed best (F-scores 89.7% and 95.7%, respectively), but differences with Genia Tagger and Yamcha were small. With respect to usability, Lingpipe and OpenNLP scored best. When combining the results of the chunkers by a simple voting scheme, the F-score of the combined system improved by 3.1 percentage point for noun phrases and 0.6 percentage point for verb phrases as compared to the best single chunker. Changing the voting threshold offered a simple way to obtain a system with high precision (and moderate recall) or high recall (and moderate precision). This study is the first to compare the performance of the whole chunking pipeline, and to combine different existing chunking systems. Several chunkers showed good performance, but OpenNLP scored best both in performance and usability. The combination of chunker results by a simple voting scheme can further improve performance and allows for different precision-recall settings.

Cohort profile: The study of health in Pomerania (Article)

2011-04-01T00:00:00Z

Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction (Article)

2010-12-01T00:00:00Z

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10 -8). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

Association of health behaviour with heart rate variability: A population-based study (Article)

2010-11-25T00:00:00Z

Background: Reduced heart rate variability (HRV), a non-invasive marker of autonomic dysfunction, and an unhealthy lifestyle are associated with an increased morbidity and mortality of cardiovascular diseases (CVD). The autonomic dysfunction is a potential mediator of the association of behavioural risk factors with adverse health outcomes. We studied the association of HRV with behavioural risk factors in an elderly population.Methods: This analysis was based on the cross-sectional data of 1671 participants (age range, 45-83 years) of the prospective, population-based Cardiovascular Disease, Living and Ageing in Halle (CARLA) Study. Physical activity, smoking habits, alcohol consumption and dietary patterns were assessed in standardized interviews. Time and frequency domain measures of HRV were computed from 5-min segments of highly standardized 20-min electrocardiograms. Their association with behavioural risk factors was determined by linear and non-parametric regression modelling.Results: There were only weak and inconsistent associations of higher physical activity, moderate consumption of alcohol, and non-smoking with higher time and frequency domain HRV in both sexes, and no association with dietary pattern. Results changed only marginally by excluding subjects with CVD, diabetes mellitus and use of cardioactive medication.Conclusion: We hypothesized that HRV is associated with behavioural factors and therefore might be a mediator of the effect of behavioural risk factors on CVD, but this hypothesis was not confirmed by our results. These findings support the interpretation that there may be no true causal association of behavioural factors with HRV.

Automatic vs. manual curation of a multi-source chemical dictionary: The impact on text mining (Article)

2010-09-23T00:00:00Z

Background. Previously, we developed a combined dictionary dubbed Chemlist for the identification of small molecules and drugs in text based on a number of publicly available databases and tested it on an annotated corpus. To achieve an acceptable recall and precision we used a number of automatic and semi-automatic processing steps together with disambiguation rules. However, it remained to be investigated which impact an extensive manual curation of a multi-source chemical dictionary would have on chemical term identification in text. ChemSpider is a chemical database that has undergone extensive manual curation aimed at establishing valid chemical name-to-structure relationships. Results. We acquired the component of ChemSpider containing only manually curated names and synonyms. Rule-based term filtering, semi-automatic manual curation, and disambiguation rules were applied. We tested the dictionary from ChemSpider on an annotated corpus and compared the results with those for the Chemlist dictionary. The ChemSpider dictionary of ca. 80 k names was only a 1/3 to a 1/4 the size of Chemlist at around 300 k. The ChemSpider dictionary had a precision of 0.43 and a recall of 0.19 before the application of filtering and disambiguation and a precision of 0.87 and a recall of 0.19 after filtering and disambiguation. The Chemlist dictionary had a precision of 0.20 and a recall of 0.47 before the application of filtering and disambiguation and a precision of 0.67 and a recall of 0.40 after filtering and disambiguation. Conclusions. We conclude the following: (1) The ChemSpider dictionary achieved the best precision but the Chemlist dictionary had a higher recall and the best F-score; (2) Rule-based filtering and disambiguation is necessary to achieve a high precision for both the automatically generated and the manually curated dictionary. ChemSpider is available as a web service at http://www.chemspider. com/ and the Chemlist dictionary is freely available as an XML file in Simple Knowledge Organization System format on the web at http://www.biosemantics.org/ chemlist.

Unrecognised myocardial infarction and long-term risk of heart failure in the elderly: The Rotterdam study (Article)

2010-09-01T00:00:00Z

Objective: To examine the association between unrecognised myocardial infarction (MI) as detected by electrocardiography and the long-term risk of heart failure. Design: The Rotterdam Study is a prospective population-based cohort study of the general population of a suburb of the city of Rotterdam, The Netherlands. Participants: At baseline 2581 men and 3724 women aged ≥55 years were classified on the basis of electrocardiography, interview and clinical data into those with recognised MI, those with ECG-based unrecognised MI and those without MI. The participants were followed-up for incident heart failure, death or end of the study period on 12 October 2006. Results: During a median follow-up time of 13.2 years, 823 cases of heart failure occurred, of which 403 in men. Independently of cardiovascular risk factors, recognised and unrecognised MIs yielded HRs of developing heart failure in men of 2.6 (95% CI 2.0 to 3.3) and 2.1 (95% CI 1.5 to 2.9), respectively. In women, recognised MI was associated with heart failure (HR=2.8; 95% CI 1.9 to 4.1), whereas unrecognised MI was not significantly related to the risk of heart failure (HR=1.1; 95% CI 0.7 to 1.7). Conclusion: Unrecognised MI detected by electrocardiography yields a long-term risk of heart failure equivalent to recognised MI in men, but is not significantly related to heart failure in women. In the light of the high incidence of both unrecognised MI and heart failure in the elderly, it may be worthwhile for both doctors and patients to improve responsiveness to typical and atypical symptoms of MI.

Genome-wide association analysis identifies multiple loci related to resting heart rate (Article)

2010-07-16T00:00:00Z

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex-and body mass-adjusted RR interval (inverse heart rate) and ~2.5 million markers. Results with P < 5 × 10-8were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ~0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10-5increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

Erratum: Automatic vs. manual curation of a multi-source chemical dictionary: The impact on text mining (Journal of Cheminformatics (2010) 2 (3)) (Article)

2010-07-06T00:00:00Z

The spatial QRS-T angle in the Frank vectorcardiogram: accuracy of estimates derived from the 12-lead electrocardiogram (Article)

2010-07-01T00:00:00Z

Background and Purpose: The spatial QRS-T angle (SA), a predictor of sudden cardiac death, is a vectorcardiographic variable. Gold standard vertorcardiograms (VCGs) are recorded by using the Frank electrode positions. However, with the commonly available 12-lead ECG, VCGs must be synthesized by matrix multiplication (inverse Dower matrix/Kors matrix). Alternatively, Rautaharju proposed a method to calculate SA directly from the 12-lead ECG. Neither spatial angles computed by using the inverse Dower matrix (SA-D) nor by using the Kors matrix (SA-K) or by using Rautaharju's method (SA-R) have been validated with regard to the spatial angles as directly measured in the Frank VCG (SA-F). Our present study aimed to perform this essential validation. Methods: We analyzed SAs in 1220 simultaneously recorded 12-lead ECGs and VCGs, in all data, in SA-F-based tertiles, and after stratification according to pathology or sex. Results: Linear regression of SA-K, SA-D, and SA-R on SA-F yielded offsets of 0.01°, 20.3°, and 28.3° and slopes of 0.96, 0.86, and 0.79, respectively. The bias of SA-K with respect to SA-F (mean ± SD, -3.2° ± 13.9°) was significantly (P < .001) smaller than the bias of both SA-D and SA-R with respect to SA-F (8.0° ± 18.6° and 9.8° ± 24.6°, respectively); tertile analysis showed a much more homogeneous behavior of the bias in SA-K than of both the bias in SA-D and in SA-R. In pathologic ECGs, there was no significant bias in SA-K; bias in men and women did not differ. Conclusion: SA-K resembled SA-F best. In general, when there is no specific reason either to synthesize VCGs with the inverse Dower matrix or to calculate the spatial QRS-T angle with Rautaharju's method, it seems prudent to use the Kors matrix.

The potential yield of ECG screening of hypertensive patients: The Utrecht Health Project (Article)

2010-07-01T00:00:00Z

Objective: Several guidelines for hypertension and cardiovascular risk management recommend an ECG in hypertensive patients to improve risk prediction. We estimated the prevalence of clinically relevant ECG abnormalities and the number needed to screen (NNS) with a routine ECG to prevent the occurrence of one death in the next 10 years conditional on adequate treatment and follow-up. Methods: The study population consisted of 866 hypertensive participants recruited from the Utrecht Health Project (UHP), a dynamic population study in Utrecht. Baseline measurements included an ECG and the risk factors that enable a Systematic COronary Risk Evaluation (SCORE) risk estimation for each participant. ECGs were interpreted using Modular ECG Analysis System for computerized recognition of ECG abnormalities. NNS to prevent one death was computed by the reciprocal of the prevalence of the ECG abnormalities multiplied by number needed to treat to prevent one death when the ECG abnormality is managed according to the prevailing clinical guidelines. Results: The population consisted of 54.2% men with a mean age of 53.2 years (SD 11.5). The prevalence of ECG abnormalities was 17.6 [n = 95% confidence interval (CI) 15.0-20.1]. Prevalence of atrial fibrillation or prior myocardial infarction was 2.1% (95%CI 1.1-3.0) and of other ECG abnormalities related to increased cardiovascular disease risk 15.4% (95%CI 13.1-17.9). NNS to prevent one death from cardiovascular disease within 10 years was estimated at 260 (95%CI 220-308). Conclusion: Our findings support the existing recommendations to routinely record an ECG in unselected hypertensive patients as the prevalence of relevant abnormalities is considerable and NNS to prevent one death is lower than that in other widely accepted tests.

Finding a short and accurate decision rule in disjunctive normal form by exhaustive search (Article)

2010-07-01T00:00:00Z

Greedy approaches suffer from a restricted search space which could lead to suboptimal classifiers in terms of performance and classifier size. This study discusses exhaustive search as an alternative to greedy search for learning short and accurate decision rules. The Exhaustive Procedure for LOgic-Rule Extraction (EXPLORE) algorithm is presented, to induce decision rules in disjunctive normal form (DNF) in a systematic and efficient manner. We propose a method based on subsumption to reduce the number of values considered for instantiation in the literals, by taking into account the relational operator without loss of performance. Furthermore, we describe a branch-and-bound approach that makes optimal use of user-defined performance constraints. To improve the generalizability we use a validation set to determine the optimal length of the DNF rule. The performance and size of the DNF rules induced by EXPLORE are compared to those of eight well-known rule learners. Our results show that an exhaustive approach to rule learning in DNF results in significantly smaller classifiers than those of the other rule learners, while securing comparable or even better performance. Clearly, exhaustive search is computer-intensive and may not always be feasible. Nevertheless, based on this study, we believe that exhaustive search should be considered an alternative for greedy search in many problems.

Local Depolarization Abnormalities Are the Dominant Pathophysiologic Mechanism for Type 1 Electrocardiogram in Brugada Syndrome. A Study of Electrocardiograms, Vectorcardiograms, and Body Surface Potential Maps During Ajmaline Provocation (Article)

2010-02-23T00:00:00Z

Objectives: We sought to obtain new insights into the pathophysiologic basis of Brugada syndrome (BrS) by studying changes in various electrocardiographic depolarization and/or repolarization variables that occurred with the development of the signature type 1 BrS electrocardiogram (ECG) during ajmaline provocation testing. Background: BrS is associated with sudden cardiac death. Its pathophysiologic basis, although unresolved, is believed to reside in abnormal cardiac depolarization or abnormal repolarization. Methods: Ajmaline provocation was performed in 269 patients suspected of having BrS with simultaneous recording of ECGs, vectorcardiograms, and 62-lead body surface potential maps. Results: A type 1 ECG was elicited in 91 patients (BrS patients), 162 patients had a negative test result (controls), and 16 patients had an abnormal test result. Depolarization abnormalities were more prominent in BrS patients and were mapped to the right ventricle (RV) by longer right precordial filtered QRS complex durations (142 ± 23 ms vs. 125 ± 14 ms, p < 0.01) and right terminal conduction delay (60 ± 11 ms vs. 53 ± 9 ms, p < 0.01). Repolarization abnormalities remained concordant with depolarization abnormalities as indicated by steady low nondipolar content (12 ± 8% vs. 8 ± 4%, p = NS), lower spatial QRS-T integrals (33 ± 12 mV·ms vs. 40 ± 16 mV·ms, p < 0.05), similar spatial QRS-T angles (92 ± 39° vs. 87 ± 31°, p = NS), similar Tpeak-Tendinterval (143 ± 36 ms vs. 138 ± 25 ms, p = NS), and similar Tpeak-Tenddispersion (47 ± 37 ms vs. 45 ± 27 ms, p = NS). Conclusions: The type 1 BrS ECG is characterized predominantly by localized depolarization abnormalities, notably (terminal) conduction delay in the RV, as assessed with complementary noninvasive electrocardiographic techniques. We could not define a separate role for repolarization abnormalities but suggest that the typical signs of repolarization derangements seen on the ECG are secondary to these depolarization abnormalities.

Trends in incidence, severity, and outcome of hospitalized myocardial infarction (Article)

2010-02-01T00:00:00Z

Background-In 2000, the definition of myocardial infarction (MI) changed to rely on troponin rather than creatine kinase (CK) and its MB fraction (CK-MB). The implications of this change on trends in MI incidence and outcome are not defined. Methods and Results-This was a community study of 2816 patients hospitalized with incident MI from 1987 to 2006 in Olmsted County, Minnesota, with prospective measurements of troponin and CK-MB from August 2000 forward. Outcomes were MI incidence, severity, and survival. After troponin was introduced, 278 (25%) of 1127 incident MIs met only troponin-based criteria. When cases meeting only troponin criteria were included, incidence did not change between 1987 and 2006. When restricted to cases defined by CK/CK-MB, the incidence of MI declined by 20%. The incidence of non-ST-segment elevation MI increased markedly by relying on troponin, whereas that of ST-segment elevation MI declined regardless of troponin. The age-and sex-adjusted hazard ratio of death within 30 days for an infarction occurring in 2006 (compared with 1987) was 0.44 (95% confidence interval, 0.30 to 0.64). Among 30-day survivors, survival did not improve, but causes of death shifted from cardiovascular to noncardiovascular (P=0.001). Trends in long-term survival among 30-day survivors were similar regardless of troponin. Conclusions-Over the last 2 decades, a substantial change in the epidemiology of MI occurred that was only partially mediated by the introduction of troponin. Non-ST-segment elevation MIs now constitute the majority of MIs. Although the 30-day case fatality improved markedly, long-term survival did not change, and the cause of death shifted from cardiovascular to noncardiovascular.

Serum glucose and insulin are associated with QTc and RR intervals in nondiabetic elderly (Article)

2010-02-01T00:00:00Z

Aims: To study whether nondiabetic persons with impaired fasting serum glucose and hyperinsulinemia have QTc/QT interval prolongation and RR interval shortening in the electrocardiogram (ECG), and whether these were associated with an increased risk of sudden cardiac death. Methods: This study consisted of two analyses. First, a cross-sectional analysis was used as part of the population-based Rotterdam Study including 1050 men and 1520 women (≥55 years) without diabetes mellitus. Participants in round 3 of the Rotterdam Study for whom an ECG and fasting serum glucose and fasting insulin measurements were available were eligible for the study. Participants using digoxin or QTc-prolonging drugs and participants with left ventricular hypertrophy and left and right bundle branch block were excluded. The endpoints of the study were the lengths of the QTc, QT, and RR intervals. The associations were examined by means of linear regression analysis. Secondly, in all 6020 participants of the Rotterdam Study with an ECG, the associations between the QTc, QT, and RR intervals and sudden cardiac death were examined by means of Cox regression analysis. Results: Overall, there was a significant association between impaired fasting serum glucose and the QTc interval with an increase of 2.6 ms (95% confidence interval (CI): 0.3; 5.0) in those with fasting glucose >6 mmol/l. Hyperinsulinemia was also associated with QTc prolongation (3.0 ms (0.8; 5.3)) in those with fasting insulin ≥100 pmol/l. Impaired fasting glucose (IFG) and hyperinsulinemia were significantly associated with a decrease of the RR interval (-33.7 ms (-48.8;-18.6) and -44.4 ms (-58.7; -30.0) respectively). Participants in the fourth quartile of the QTc and QT intervals had a significantly increased risk of sudden cardiac death compared to participants in the first quartile (hazard ratio (HR) 2.87 (95% CI: 2.02-4.06); HR 3.05 (1.99-4.67) respectively). Furthermore, there was a significant inverse association between the fourth quartile of the RR interval compared to the first quartile and the risk of sudden cardiac death (HR 0.49 (0.34-0.80)). Conclusion: In this population-based study, we demonstrated that IFG and hyperinsulinemia are associated with a significantly increased QTc interval and with significant shortening of the RR interval, the latter probably due to an increased sympathetic activity. In addition, we demonstrated that both a prolonged QTc interval and a shortened RR interval are associated with an increased risk of sudden cardiac death.

Genome-wide association study of PR interval (Article)

2010-02-01T00:00:00Z

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

GeneE: gene and protein query expansion with disambiguation. (Article)

2010-01-01T00:00:00Z

SUMMARY: When referring to genes, authors often use synonyms instead of the official gene symbols. In order to accurately retrieve as many relevant documents as possible, we have developed GeneE, a web application that expands a gene query to include all known synonyms, and adds disambiguation information for ambiguous terms, before forwarding the query to either PubMed, Google or Jane. The query expansion algorithm is also available as a web service. AVAILABILITY: http://biosemantics.org/geneE

The association of serum testosterone levels and ventricular repolarization (Article)

2010-01-01T00:00:00Z

It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, our aim was to study whether serum levels of testosterone are associated with QTc, QT and RR interval variation. Setting: two independent population-based cohort studies. Participants: 445 male participants (≥ 55 years) from the Rotterdam study cohort and 1,428 male participants from the study of health in Pomerania (SHIP) with an electrocardiogram who were randomly sampled for assessment of serum testosterone at baseline, after exclusion of participants with testosterone altering drugs, QTc prolonging drugs or dig(it)oxin, left ventricular hypertrophy and left and right bundle branch block. Endpoints: length of the QTc, QT and RR intervals. Analysis: linear regression model, adjusted for the two individual studies and a pooled analysis of both studies. The pooled analysis of the Rotterdam study and SHIP showed that the QTc interval gradually decreased among the tertiles (P value for trend 0.024). The third tertile of serum testosterone was associated with a lower QTc interval compared to the first tertile [-3.4 ms (-6.5; -0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT interval compared to the first tertile [-0.7 ms (-3.1; 1.8)]. The RR interval gradually increased among the tertiles (P value for trend 0.002) and the third tertile of serum testosterone showed an increased RR interval compared to the first tertile [33.5 ms (12.2; 54.8)]. In the pooled analysis of two population-based studies, serum testosterone levels were not associated with the QT interval, which could be due to a lack of power. Lower QTc intervals in men with higher serum testosterone levels could be due to the association of serum testosterone with prolongation of the RR interval.

Abnormal spatial QRS-T angle predicts mortality in patients undergoing dobutamine stress echocardiography for suspected coronary artery disease (Article)

2010-01-01T00:00:00Z

Objective: To investigate the association between (cardiac) mortality and spatial QRS-T angle in patients undergoing dobutamine - atropine stress echocardiography (DSE) for evaluation of known or suspected coronary disease. Methods: Between 1990 and 2003, 2347 patients underwent DSE for evaluation of coronary disease at the Erasmus Medical Center. Echocardiographic images were analyzed offline using a 16-segment, 5-point scoring model for regional function. Twelve-lead resting ECGs were analyzed and patients were grouped in three categories according to their spatial QRS-T angle: normal (0-105°), borderline (105-135°), and abnormal (135-180°). Results: Mean age was 61±13 years, 66% were male, 32% had hypertension, 26% had hypercholesterolemia, 28% were smokers, and 12% were diabetic. During a mean follow-up of 7±3.4 years, 26.5% (623) of the patients died; 15.3% (359) died due to a cardiac cause. Abnormal QRS-T angle (135-180°) was present in 21% of the patients.Abnormal QRS-T angle was a predictor of cardiac death [hazard ratio: 3.2 (2.6-4.1)] and all-cause mortality [hazard ratio: 2.2 (1.8-2.6)]. After multivariate analysis abnormal and borderline QRS-T angle, peak wall motion score, age, male sex, history of diabetes, history of heart failure, smoking, and hypertension were independent predictors of (cardiac) death. Conclusion: Abnormal QRS-T angle is an independent predictor of (cardiac) death in patients undergoing DSE. Abnormal QRS-T angle should be considered as a risk factor in stable patients evaluated for coronary disease.

Data mining on electronic health record databases for signal detection in pharmacovigilance: Which events to monitor? (Article)

2009-12-28T00:00:00Z

Purpose: Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post-marketing drug safety surveillance. The EU-ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high-priority events. Methods: Scientific literature, medical textbooks, and websites of regulatory agencies were reviewed to create a preliminary list of events that are deemed important in pharmacovigilance. Two teams of pharmacovigilance experts independently rated each event on five criteria: 'trigger for drug withdrawal', 'trigger for black box warning', 'leading to emergency department visit or hospital admission', 'probability of event to be drug-related', and 'likelihood of death'. In case of disagreement, a consensus score was obtained. Ordinal scales between 0 and 3 were used for rating the criteria, and an overall score was computed to rank the events. Results: An initial list comprising 23 adverse events was identified. After rating all the events and calculation of overall scores, a ranked list was established. The top-ranking events were: cutaneous bullous eruptions, acute renal failure, anaphylactic shock, acute myocardial infarction, and rhabdomyolysis. Conclusions: A ranked list of 23 adverse drug events judged as important in pharmacovigilance was created to permit focused data mining. The list will need to be updated periodically as knowledge on drug safety evolves and newissues in drug safety arise. Copyright

Novel protein-protein interactions inferred from literature context (Article)

2009-11-18T00:00:00Z

We have developed a method that predicts Protein-Protein Interactions (PPIs) based on the similarity of the context in which proteins appear in literature. This method outperforms previously developed PPI prediction algorithms that rely on the conjunction of two protein names in MEDLINE abstracts. We show significant increases in coverage (76% versus 32%) and sensitivity (66% versus 41% at a specificity of 95%) for the prediction of PPIs currently archived in 6 PPI databases. A retrospective analysis shows that PPIs can efficiently be predicted before they enter PPI databases and before their interaction is explicitly described in the literature. The practical value of the method for discovery of novel PPIs is illustrated by the experimental confirmation of the inferred physical interaction between CAPN3 and PARVB, which was based on frequent co-occurrence of both proteins with concepts like Z-disc, dysferlin, and alpha-actinin. The relationships between proteins predicted by our method are broader than PPIs, and include proteins in the same complex or pathway. Dependent on the type of relationships deemed useful, the precision of our method can be as high as 90%. The full set of predicted interactions is available in a downloadable matrix and through the webtool Nermal, which lists the most likely interaction partners for a given protein. Our framework can be used for prioritizing potential interaction partners, hitherto undiscovered, for follow-up studies and to aid the generation of accurate protein interaction maps.

A dictionary to identify small molecules and drugs in free text (Article)

2009-11-15T00:00:00Z

Motivation: From the scientific community, a lot of effort has been spent on the correct identification of gene and protein names in text, while less effort has been spent on the correct identification of chemical names. Dictionary-based term identification has the power to recognize the diverse representation of chemical information in the literature and map the chemicals to their database identifiers. Results: We developed a dictionary for the identification of small molecules and drugs in text, combining information from UMLS, MeSH, ChEBI, DrugBank, KEGG, HMDB and ChemIDplus. Rule-based term filtering, manual check of highly frequent terms and disambiguation rules were applied. We tested the combined dictionary and the dictionaries derived from the individual resources on an annotated corpus, and conclude the following: (i) each of the different processing steps increase precision with a minor loss of recall; (ii) the overall performance of the combined dictionary is acceptable (precision 0.67, recall 0.40 (0.80 for trivial names); (iii) the combined dictionary performed better than the dictionary in the chemical recognizer OSCAR3; (iv) the performance of a dictionary based on ChemIDplus alone is comparable to the performance of the combined dictionary.

Genee: Gene and protein query expansion with disambiguation (Article)

2009-10-16T00:00:00Z

When referring to genes, authors often use synonyms instead of the official gene symbols. In order to accurately retrieve as many relevant documents as possible, we have developed GeneE, a web application that expands a gene query to include all known synonyms, and adds disambiguation information for ambiguous terms, before forwarding the query to either PubMed, Google or Jane. The query expansion algorithm is also available as a web service.

Lifetime endogenous estrogen exposure and electrocardiographic frontal T axis changes in postmenopausal women (Article)

2009-08-20T00:00:00Z

Objective: The protective effect of endogenous estrogens in cardiovascular disease may in part originate from effects of circulating estrogens on the electrophysiological properties of the myocardium. The aim of this study was to investigate the relation between reproductive factors and the electrocardiographic frontal T axis in postmenopausal women. Design: Cohort study. Setting: The study was conducted at the University Medical Center Utrecht. Patients: In total, 998 postmenopausal women were included. Main outcomes: Information of women's reproductive life was obtained by a questionnaire. Electrocardiographic frontal T axes were categorized as normal (25-65°) or abnormal (-180° to 24° and 66-180°). Logistic regression analysis was used to assess the relationship between reproductive factors and the frontal T axis. Moreover, the effect of the lifetime cumulative number of menstrual cycles, a composite measure of all reproductive factors, on the frontal T axis was investigated. Results: The mean age was 66.0 (±5.6) years and 15.3% had T-axes abnormalities. Later menopausal age decreased the risk on frontal T-axis abnormalities; the multivariable adjusted odds ratio was 0.97 (95% CI: 0.94-0.99) per year increasing menopause. For the lifetime cumulative number of menstrual cycles the age-adjusted odds ratio was 0.84 (95% CI: 0.75-0.99) per 100 menstrual cycles increase. Conclusions: Later age at menopause and increasing lifetime cumulative number of menstrual cycles decreased the risk on frontal T-axis changes. This supports the view that estrogens may protect against ventricular repolarization disturbances.

Is self-reported moderate drinking in the cardiovascular benefit range associated with alcoholic behavior? a population based study (Article)

2009-07-01T00:00:00Z

This article aims at identifying a threshold number of drinks per day beyond which there is a high risk of developing alcoholic behavior that would enable physicians to more confidently support the use of alcohol for cardiovascular risk prevention. In a randomly selected, population-based sample of 2,042 adults 45 years or older, we graded alcohol drinking behavior using the Self-Administered Alcoholism Screening Test, quantified alcohol amount by questionnaire, and assessed the prevalence of cardiovascular disease (coronary, peripheral, or cerebrovascular disease) by medical record review. Although optimal alcohol use (≤2 drinks/day) was associated with reduced odds of cardiovascular disease, 43% of alcoholics and 82% of problem drinkers reported alcohol use in the optimal range as well. The association of alcohol use in the optimal range with alcohol-related behavioral problems supports the reluctance in physicians from recommending alcohol use for cardiovascular benefit, not withstanding the underreporting of alcohol use by alcoholics.

Common variants at ten loci influence QT interval duration in the QTGEN Study (Article)

2009-04-01T00:00:00Z

QT interval duration, reflecting myocardial repolarization on the electrocardiogram, is a heritable risk factor for sudden cardiac death and drug-induced arrhythmias. We conducted a meta-analysis of three genome-wide association studies in 13,685 individuals of European ancestry from the Framingham Heart Study, the Rotterdam Study and the Cardiovascular Health Study, as part of the QTGEN consortium. We observed associations at P < 5 × 108with variants in NOS1AP, KCNQ1, KCNE1, KCNH2 and SCN5A, known to be involved in myocardial repolarization and mendelian long-QT syndromes. Associations were found at five newly identified loci, including 16q21 near NDRG4 and GINS3, 6q22 near PLN, 1p36 near RNF207, 16p13 near LITAF and 17q12 near LIG3 and RFFL. Collectively, the 14 independent variants at these 10 loci explain 5.4-6.5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias.

Calcium channel blockers, NOS1AP, and heart-rate-corrected QT prolongation (Article)

2009-04-01T00:00:00Z

Objectives To study whether NOS1AP single nucleotide polymorphisms (SNPs), rs10494366 T>G and rs10918594 C>G, modify the heart-rate-corrected QT (QTc) prolonging effect of calcium channel blockers. Background Common variation in the NOS1AP gene has been associated with QT interval variation in several large population samples. NOS1 is presumed to influence intracellular calcium. Methods The prospective population-based Rotterdam Study includes 16 603 ECGs from 7565 participants (≥ 55 years), after exclusion of patients with left ventricular hypertrophy, left and right bundle branch block, as well as carriers of pacemakers. The endpoint was the length of the QTc interval in calcium channel blocker users and non-users with the minor alleles compared with the major alleles (wild type). We used a repeated-measurement analysis, adjusted for all known confounders. Results Use of verapamil was associated with a significant QTc interval prolongation [6.0 ms 95% confidence interval (CI) 1.7; 10.2] compared with non-users. Furthermore, users of verapamil with the rs10494366 GG genotype showed significantly more QTc prolongation than users with the TT genotype [25.4 ms (95% CI: 5.9-44.9)] (P value for multiplicative interaction 0.0038). Users of isradipine with the GG genotype showed more QTc prolongation than users with the TT genotype [19.8 ms (95% CI: 1.9-37.7)]; however, SNP rs10494366 did not modify the effect on QTc interval on a multiplicative scale (P= 0.3563). SNP rs10918594 showed similar results. Conclusion In conclusion, we showed that the minor alleles of both NOS1AP SNPs significantly potentiate the QTc prolonging effect of verapamil. Pharmacogenetics and Genomics 19:260-266

Combination of electrocardiographic and echocardiographic information identifies individuals prone to a progressive increase in left ventricular mass over 5 years (Article)

2009-04-01T00:00:00Z

Objective We assessed whether the relationship between electrocardiographic and echocardiographic information on left ventricular hypertrophy predicts the development of left ventricular mass over 5 years. Methods Linear regression analyses between various electrocardiographic indices of left ventricular hypertrophy and left ventricular mass (echocardiography) indexed to height2.7(LVMIht) was performed in 1488 individuals in each gender subgroup (45-79 years, 841 female, exclusion of intraventricular conduction defects) from the population-based, longitudinal 'Study of Health in Pomerania'. A parameter expressing the difference between observed ECG indices of left ventricular hypertrophy and ECG indices predicted on the basis of echocardiographic readings was calculated in each individual at the baseline visit. Results In individuals with complete echocardiographic data at baseline and 5-year-follow-up (n = 1031, exclusion of aortic valve disease), LVMIhtat 5-year-follow-up was significantly correlated with the parameter derived from the Cornell product (P< 0.001), the Cornell voltage (P< 0.001), the Gubner-Ungerleider-product (P<0.001), the Gubner-Ungerleider-voltage (P<0.001), Lewis voltage (P<0.001) and aVL voltage (P<0.001), but not with Sokolow-Lyon-index-derived parameters. LVMIhtat baseline did not significantly correlate with any of these ECG-derived parameters. In female individuals with Cornell products higher than expected based on echocardiographic readings, left ventricular mass increased from 162.3 ± 2.6 g to 180.5 ± 2.8 g (males: 213.1 ± 3.7 g to 236.3 ± 4.2 g), whereas left ventricular mass increased only from 161.8 ± 2.5 g to 173.5 ± 2.8 g (males: 209.7 ± 3.7g to 215.8 ± 3.7 g) in individuals with lower than expected Cornell products (P< 0.001). Conclusion The relationship of electrocardiographic and echocardiographic information on left ventricular mass may identify individuals at risk for developing progressive increase in left ventricular mass.

Cardiovascular diseases, risk factors and short-term heart rate variability in an elderly general population: The CARLA study 2002-2006 (Article)

2009-03-01T00:00:00Z

Background: A reduced heart rate variability (HRV) is associated with worse prognosis, increased incidence of cardiovascular disease (CVD) and mortality. There are conflicting results and a lack of population-based data regarding the association of HRV with CVD risk factors and its potential role as independent cause or mediator of CVD risk. Methods: Cross-sectional data of a population-based cohort including 1,779 women and men aged 45-83 years were used to analyse associations of time and frequency domain measures of HRV (derived from 5-min ECG segments) with age, behavioural and biomedical risk factors and disease in the whole sample and in a "healthy" subgroup. Results: Age was inversely associated with all measures of HRV (mean standard deviation of normal intervals across 10-year age-groups 32.1, 26.9, 27.1 and 24.8 ms in women, 29.3, 25.9, 23.8 and 25.7 ms in men). There was no association of physical activity, current smoking or alcohol with HRV. In age-adjusted models, triglycerides, glucose, waist-to-hip ratio and diabetes were inversely associated with HRV in men and women, and low/high density cholesterol and hypertension in men only (up to 43% difference across risk factor quartiles). Multivariable adjustment and restriction to the "healthy" subgroup attenuated the associations. Conclusions: We found only weak and inconsistent associations of HRV with cardiovascular risk factors. However, these results as well as those from previous studies are still compatible with the hypothesis that short-term HRV may be a marker of ill health or a mediator of the effect of selected biomedical risk factors on CVD.

IK1 modulates the U-wave: insights in a 100-year-old enigma (Article)

2009-03-01T00:00:00Z

Mapping the domain of medical informatics (Article)

2009-02-09T00:00:00Z

Objectives: The domain of medical informatics (MI) is not well defined. It covers a wide range of research topics. Our objective is to characterize the field of MI by means of the scientific literature in this domain. Methods: We used titles and abstracts from MEDLINE records of papers published between July 1993 and July 2008, and extracted uni-, bi- and trigrams as features. Starting with the ISI category of medical informatics, we applied a semi-automated procedure to identify the set of journals and proceedings pertaining to MI. A clustering algorithm was subsequently applied to the articles from this set of publications. Results: MI literature can be divided into three subdomains: 1) the organization, application, and evaluation of health information systems, 2) medical knowledge representation, and 3) signal and data analysis. Over the last fifteen years, the field has remained relatively stable, although most journals have shifted their focus somewhat. Conclusions: We identified the scientific literature pertaining to the field of MI, and the main areas of research. We were able to show trends in the field, and the positioning of different journals within this field.

Psychotropic drugs associated with corrected QT interval prolongation (Article)

2009-02-01T00:00:00Z

AIMS:: To study whether listed putative corrected QT (QTc)-prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances and to evaluate whether this is a class effect or an individual drug effect, we conducted a prospective population-based cohort study. METHODS:: This study was conducted as part of the Rotterdam Study and included 3377 men and 4845 women (ĝ‰¥55 years) who had triennial electrocardiograms (ECGs). The primary end points of the study were the length of the QTc interval at each ECG, the difference in QTc interval between consecutive ECGs within one person, and the risk of an abnormally prolonged QTc interval. Drug use at the index date was obtained from automated dispensing records. The associations were examined by means of a repeated measurement analysis, adjusted for age, sex, diabetes mellitus, hypertension, myocardial infarction, heart failure, and use of class 1 QTc-prolonging drugs. RESULTS:: Of the 8222 participants, 813 participants (9.9%) developed QTc prolongation during follow-up and 492 participants (74.4% women) used psychotropic drugs at the time of an ECG. Starting tricyclic antidepressants increased the QTc interval significantly with 6.9 milliseconds (95% confidence interval [CI], 3.1-10.7 milliseconds) between consecutive ECGs in comparison with consecutive ECGs of participants not using tricyclic antidepressants, in particular starting amitriptyline (8.5 milliseconds; 95% CI, 2.8-14.2 milliseconds), maprotiline (13.9 milliseconds; 95% CI, 3.6-24.3 milliseconds), and nortriptyline (35.3 milliseconds; 95% CI, 8.0-62.6 milliseconds). Starting lithium also increased the QTc interval significantly (18.6 milliseconds; 95% CI, 4.8-32.4 milliseconds). CONCLUSIONS:: In this population-based prospective cohort study, we confirmed the importance of antidepressants and antipsychotics as potential contributors to QTc prolongation. Especially, starting tricyclic antidepressant drugs (as a class) is associated with a significant intraindividual increase in the QTc interval in comparison to the change in nonusers. The tricyclic antidepressants seem to prolong the QTc interval as a class effect.

Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration (Article)

2009-01-05T00:00:00Z

QT-interval prolongation is an electrophysiologic phenomenon associated with sudden cardiac death. The QT-interval in the general population is ∼35% heritable. In genome-wide association studies, a common variant (rs10494366T > G) within the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was identified and consistently associated with QT-interval duration. Yet, the causal variant remains unclear. Therefore, we performed fine mapping of the association of the NOS1AP locus with QT-interval within the Rotterdam Study, a population-based, prospective cohort study of individuals of ≥55 years of age. First, we tested the association of single-nucleotide polymorphisms (SNPs) in or within ±100 kb of the NOS1AP gene with QT-interval duration, using sex-specific unstandardized residuals after regression on age and RR-interval, in 385 individuals using the combined set of SNPs present in the Affymetrix 500k and Illumina 550k chip arrays. Subsequently, we examined correspondence of the association signals in 4606 individuals using the Illumina 550k array. A C-to-T SNP at chromosome 1 position 160300514 (rs12143842, T-allele frequency = 24%) was associated with a QT-interval duration increase of 4.4 ms per additional T-allele (P = 4.4 × 10-28). For comparison, the most strongly associated variant to date, rs10494366T > G, was associated with a 3.5 ms increase (P = 1.6 × 10-23) per additional G-allele. None of the inferred haplotypes showed a stronger effect than the individual rs12143842C > T SNP. In conclusion, we found rs12143842 6 kb upstream distance of NOS1AP to be more strongly associated to QT-interval duration than rs10494366T > G. Functional analysis of this marker is warranted.

Methodology of QT-interval measurement in the modular ECG analysis system (MEANS) (Article)

2009-01-01T00:00:00Z

Background: QT prolongation as can be induced by drugs, signals the risk of life-threatening arrhythmias. The methodology of QT measurement in the modular ECG analysis system (MEANS) is described. Methods: In the simultaneously recorded leads of the standard 12-lead electrocardiogram (ECG), the QRS complexes are detected by a spatial velocity function. They are typed as dominant or nondominant, and a representative complex per lead is obtained by averaging over the dominant complexes. QRS onset and T end are determined by a template technique, and QT is measured. MEANS performance was evaluated on the 125 ECGs of the common standards for quantitative electrocardiography (CSE) multilead database, of which the waveform boundaries have been released. Results: MEANS detected correctly all 1445 complexes of the CSE library, with one false-positive detection due to a sudden baseline jump. All dominant complexes were correctly typed. The average of the differences between MEANS and reference was less than 2 ms (=1 sample) for both QRS onset and T end, and 2.1 ms for QT duration. The standard deviation of the differences was 3.8, 8.4, and 10.4 ms, respectively. Conclusions: A standard deviation of 10.4 ms for QT measurement seems large when related to the regulatory requirement that a prolongation as small as 5 ms should be detected. However, QT variabilities as encountered in different individuals will be larger than when measured in one individual during pharmacological intervention. Finally, if the U wave is part of the total repolarization, then T and U form a continuum and the end of T becomes questionable.

Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in β-blocker users (Article)

2009-01-01T00:00:00Z

Several β-blockers are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6*4 is the main polymorphism leading to decreased enzyme activity. The clinical significance of impaired elimination of β-blockers is controversial, and most studies suffer from inclusion of small numbers of poor metabolizers (PMs) of CYP2D6. In this study, the association between CYP2D6*4 and blood pressure or heart rate was examined in 1,533 users of β-blockers in the Rotterdam Study, a population-based cohort study. In CYP2D6 *4/*4 PMs, the adjusted heart rate in metoprolol users was 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (P < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio = 3.86; 95% confidence interval 1.68-8.86; P = 0.0014). The diastolic blood pressure in PMs was 5.4 mm Hg lower in users of β-blockers metabolized by CYP2D6 (P = 0.017) and 4.8 mm Hg lower in metoprolol users (P = 0.045) compared with EMs. PMs are at increased risk of bradycardia.

Cigarette smoking and risk of atrial fibrillation: The Rotterdam Study (Article)

2008-12-01T00:00:00Z

Background: Cigarette smoking is an important risk factor for cardiovascular disease, but it is unknown whether it also contributes to the risk of atrial fibrillation. Methods and results: The study is part of the Rotterdam Study, a population-based cohort study among subjects aged ≥55 years. The association between cigarette smoking and the risk of atrial fibrillation was examined in 5,668 subjects without atrial fibrillation at baseline. During a median follow-up of 7.2 years, 371 cases of atrial fibrillation were identified. Relative risks (RR) were calculated with 95% CIs using the Cox proportional hazards model, adjusted for age, gender, body mass index, hypertension, systolic blood pressure, serum cholesterol level, diabetes mellitus, left ventricular hypertrophy on the electrocardiogram, prevalent and incident myocardial infarction, prevalent heart failure, and the use of pulmonary medication. After multivariate adjustment, current smokers and former smokers had increased risks of atrial fibrillation as compared to never smokers (RR 1.51, 95% CI 1.07-2.12; and RR 1.49, 95% CI 1.14-1.97, respectively). No differences were found between men and women. Conclusions: The results of this prospective, population-based study show that current and former smoking of cigarettes are associated with increased risk of atrial fibrillation.

The meaning of the Tp-Te interval and its diagnostic value (Article)

2008-11-01T00:00:00Z

Background: The interval between T peak (Tp) and T end (Te) has been proposed as a measure of transmural dispersion of repolarization, but experimental and clinical studies to validate Tp-Te have given conflicting results. We have investigated the meaning of Tp-Te and its diagnostic potential. Methods: We used a digital model of the left ventricular wall to simulate the effect of varying action potential durations on the timing of Tp and Te. Furthermore, we used the vectorcardiogram to explain the relationships between Tp locations in the precordial electrocardiogram leads. Results: Prolongation or ischemic shortening of action potentials in our model did not result in substantial Tp shifts. The phase relationships revealed by the vectorcardiogram showed that Tp-Te in the precordial leads is a derivative of T loop morphology. Conclusion: Tp-Te is the resultant of the global distribution of the repolarization process and is a surrogate diagnostic parameter.

Left ventricular function and heart failure in myocardial infarction: Impact of the new definition in the community (Article)

2008-11-01T00:00:00Z

Objectives: The aim of this study is to evaluate ventricular function and the occurrence of heart failure (HF) among persons with myocardial infarction (MI) meeting only troponin criteria compared to persons meeting creatine kinase and its MB fraction (CK-MB) criteria. Background: The 2000 American College of Cardiology/European Society of Cardiology MI definition enabled identification of MIs meeting only troponin-based criteria. Data on ventricular function and HF among these are lacking. Methods: Between November 2002 and May 2006, we prospectively identified 835 persons with MI in the community using standardized criteria including cardiac pain, electrocardiogram, and biomarkers. Troponin and CK-MB were prospectively measured in all; each patient was classified according to the criteria met. Results: We performed echocardiograms (median of 1 day post-MI) in 482 patients (age 68 ± 15 years; 45% women); 363 patients met CK-MB criteria, whereas 119 met only troponin criteria. The latter had lower wall motion score index (1.3 ± 0.4 vs 1.5 ± 0.5 for CK-MB; P < .01). Diastolic dysfunction was similar in both groups. After 1 year of follow up, 142 patients developed post-MI HF. Patients meeting only troponin criteria had a lower risk of HF after adjustment for age, sex, comorbidity (hazard ratio 0.56, 95% confidence interval 0.37-0.85, P < .01), which persisted after further adjustments for systolic or diastolic function. Conclusions: In the community, the prospective application of the new MI definition identifies patients meeting only troponin criteria with better systolic function than cases meeting CK-MB criteria. Such MIs have a lower risk of subsequent HF. These findings are important for risk stratification in clinical practice.

Electrocardiographic criteria for left ventricular hypertrophy in children (Article)

2008-09-01T00:00:00Z

Previous studies to determine the sensitivity of the electrocardiogram (ECG) for left ventricular hypertrophy (LVH) in children had their imperfections: they were not done on an unselected hospital population, several criteria used in adults were not applied to children, and obsolete limits of normal for the ECG parameters were used. Furthermore, left ventricular mass (LVM) was taken as the reference standard for LVH, with no regard for other clinical evidence. The study population consisted of 832 children from whom a 12-lead ECG and an M-mode echocardiogram were taken on the same day. The validity of the ECG criteria was judged on the basis of an abnormal LVM index, either alone or in combination with other clinical evidence. The ECG criteria were based on recently established age-dependent normal limits. At 95% specificity, the ECG criteria have low sensitivities (<25%) when an elevated LVM index is taken as the reference for LVH. When clinical evidence is also taken into account, the sensitivity improved considerably (<43%). Sensitivities could be further improved when ECG parameters were combined. The sensitivity of the pediatric ECG in detecting LVH is low but depends strongly on the definition of the reference used for validation.

Elevated blood pressure and electrocardiographic frontal T axis and spatial QRS-T angle changes in postmenopausal women (Article)

2008-07-01T00:00:00Z

Introduction: Frontal T axis and spatial QRS-T angle are both measures of disturbances in ventricular repolarization and depolarization. We determined whether increased blood pressure is a risk factor for changes in these parameters in postmenopausal women free of left ventricular hypertrophy. Materials and Methods: This cross-sectional study included 969 women. A standard 12-lead electrocardiogram (ECG) was recorded, and frontal T axes and spatial QRS-T angles were computed from vectorcardiography. Logistic regression analysis was used to assess the relationship between systolic and diastolic blood pressures on the one hand and both ECG parameters on the other. Results: Odds ratios were 1.08 (95% confidence interval [CI], 0.99-1.18) and 1.12 (95% CI, 1.03-1.23) per 10 mm Hg systolic blood pressure for frontal T axis and QRS-T angle, respectively. These values were 1.05 (95% CI, 0.95-1.16) and 1.12 (95% CI, 1.02-1.23) per 5 mm Hg diastolic blood pressure for frontal T-axis and QRS-T angle, respectively. Conclusion: Elevated blood pressure may lead to ventricular depolarization and repolarization disturbances before overt ECG left ventricular hypertrophy has developed.

High free thyroxine levels are associated with QTc prolongation in males (Article)

2008-07-01T00:00:00Z

The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T4) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T4/TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0.8 ms (95% confidence interval (Cl) -3.5, 5.2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T4did not have an increased QTc interval (3.2 ms (95% Cl - 1.1, 7.6)); stratification on gender showed an increment of 10.9 ms (95% Cl 3.4, 18.3) in the fifth quintile in men and 1.1 ms (95% Cl - 4.2, 6.3) in the fifth quintile of free T4in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T4had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2.40 (95% Cl 1.20, 4.80)). High levels of free T4are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T4is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.

Literature-aided meta-analysis of microarray data: A compendium study on muscle development and disease (Article)

2008-06-24T00:00:00Z

Background: Comparative analysis of expression microarray studies is difficult due to the large influence of technical factors on experimental outcome. Still, the identified differentially expressed genes may hint at the same biological processes. However, manually curated assignment of genes to biological processes, such as pursued by the Gene Ontology (GO) consortium, is incomplete and limited. We hypothesised that automatic association of genes with biological processes through thesaurus-controlled mining of Medline abstracts would be more effective. Therefore, we developed a novel algorithm (LAMA: Literature-Aided Meta-Analysis) to quantify the similarity between transcriptomics studies. We evaluated our algorithm on a large compendium of 102 microarray studies published in the field of muscle development and disease, and compared it to similarity measures based on gene overlap and over-representation of biological processes assigned by GO. Results: While the overlap in both genes and overrepresented GO-terms was poor, LAMA retrieved many more biologically meaningful links between studies, with substantially lower influence of technical factors. LAMA correctly grouped muscular dystrophy, regeneration and myositis studies, and linked patient and corresponding mouse model studies. LAMA also retrieves the connecting biological concepts. Among other new discoveries, we associated cullin proteins, a class of ubiquitinylation proteins, with genes down-regulated during muscle regeneration, whereas ubiquitinylation was previously reported to be activated during the inverse process: muscle atrophy. Conclusion: Our literature-based association analysis is capable of finding hidden common biological denominators in microarray studies, and circumvents the need for raw data analysis or curated gene annotation databases.

Anni 2.0: A multipurpose text-mining tool for the life sciences (Article)

2008-06-12T00:00:00Z

Anni 2.0 is an online tool (http://biosemantics.org/anni/) to aid the biomedical researcher with a broad range of information needs. Anni provides an ontology-based interface to MEDLINE and retrieves documents and associations for several classes of biomedical concepts, including genes, drugs and diseases, with established text-mining technology. In this article we illustrate Anni's usability by applying the tool to two use cases: interpretation of a set of differentially expressed genes, and literature-based knowledge discovery.

Unrecognized myocardial infarction in relation to risk of dementia and cerebral small vessel disease (Article)

2008-05-01T00:00:00Z

BACKGROUND AND PURPOSE: Men, but not women, with unrecognized myocardial infarction (MI) have an increased risk of cardiac events and stroke compared with those without MI or with recognized MI. We investigated whether unrecognized MI is also a risk factor for dementia and cerebral small vessel disease (white matter lesions and brain infarction) in 2 population-based cohort studies. METHODS: In the Rotterdam Study, 6347 participants were classified at baseline (1990 to 1993) into those with recognized MI (subdivided into Q-wave and non-Q-wave MI), with unrecognized MI, and without MI based on electrocardiography and interview and were followed for incident dementia (n=613) until January 1, 2005. In the Rotterdam Scan Study, 436 nondemented persons were similarly classified based on electrocardiography and interview and underwent brain MRI for the assessment of white matter lesions and brain infarction. RESULTS: In men, unrecognized MI was associated with an increased risk of dementia (compared with men without MI hazard ratio, 2.14; 95% CI, 1.37 to 3.35) and with more white matter lesions and more often brain infarction on MRI. In women, no associations were found with unrecognized MI. Recognized MI was not associated with the risk of dementia in either sex. Men, but not women, with recognized MI had more often any brain infarction or asymptomatic brain infarction, especially if they had Q-wave MI. No consistent associations were found between recognized Q-wave or non-Q-wave MI and severity of white matter lesions. Additional adjustment for cardiovascular risk factors did not change the results. CONCLUSIONS: Men with unrecognized MI have an increased risk of dementia and more cerebral small vessel disease.

Intraindividual variability in electrocardiograms (Article)

2008-05-01T00:00:00Z

The electrocardiogram (ECG) can be affected by intraindividual variations from various sources that may confuse the diagnosis of the underlying cardiac condition and impair the accuracy of ECG interpretation. Intraindividual variability is a hindrance in serial ECG analysis, where ECGs of the same individual, but taken at different times, are compared. Two sources of intraindividual variability can be distinguished as follows: variability related to the technical circumstances during ECG recording (technical sources) and nonpathologic biologic variability (biological sources). Among the technical sources, variation in electrode positioning between recordings is the most confusing. Of the biological sources, respiratory variations are effective at any time scale, but the most important are age and weight that work on prolonged time scales. Technical problems are best prevented by rigorously sticking to a standard acquisition protocol. Criteria can be adapted to changing circumstances (age, weight), and by computer modeling, it may be possible to correct the ECG diagnosis for some sources of intraindividual variability.

Mirror image electrocardiograms and additional electrocardiographic leads: new wine in old wineskins? (Article)

2008-05-01T00:00:00Z

Background: Mirror image electrocardiograms (ECGs), obtained by inverting the original signals, and additional precordial leads have been proposed as means to improve ECG diagnosis. The theoretical backgrounds of these proposals are discussed. Methods: In 746 body surface potential maps, the mirror areas of the 6 precordial leads, V3R, and 2 more leads higher up and 1 lower down the thorax have been determined. The similarity between the original signal and its mirror image was expressed by a similarity index. This was done separately for QRS and ST-T; for the first and second parts of QRS; and for the categories normal, left ventricular hypertrophy, and infarct. Results: In general, high similarity scores were obtained. The mirror images of V1and V2are almost diametrically located on the back. Inverting these leads could render the V8and V9leads. The other mirror areas may deviate considerably from where generally expected. Conclusion: Mirror images can be obtained consistently from all locations, supporting the dipole representation of cardiac electrical activity. Neither mirror image ECGs nor additional chest leads contribute essentially to ECG diagnosis.

Simultaneous comparison of 3 derived 12-lead electrocardiograms with standard electrocardiogram at rest and during percutaneous coronary occlusion (Article)

2008-05-01T00:00:00Z

Aim: The aim of the study was to simultaneously test the EASI lead system and two other derived ECG methods against the standard 12-lead ECG during percutaneous coronary intervention (PCI). Methods: During 44 percutaneous coronary interventions, a simultaneously recorded 12-lead and EASI ECG were marked at the start of the PCI (baseline) and at known ischemia caused by balloon inflation (peak). ST deviations were measured 60 ms after the J point at baseline and peak in all leads and were summated (SUMST) to assess overall changes. For regional changes, the lead with the highest ST deviation (PEAKST) was marked. For each patient, derived 12-lead ECGs were computed from the EASI leads and a lead subset using patient-specific coefficients (PS) and coefficients based on a patient population (GEN). Absolute differences were computed between each derived and routine ECG for SUMST and PEAKST. Results: SUMST was at baseline 567 μV (range: 150-1707) and increased at peak to 871 μV (range: 350-2101). SUMST difference at peak was for EASI: 163 μV (CI: 90-236, P <.001), GEN: 46 μV (CI: 2-91, P = .40), and PS: 16 μV (CI: 3-30, P = .15). PEAKST difference at peak was for EASI: 49 μV (CI: 19-220, P = .02), GEN: 48 μV (CI: -43-154, P = .26), and PS: 20 μV (CI: -51-32, P = .65). Conclusion: Simultaneous direct comparison of three derived ECG methods shows overall and regional differences in accuracy across PS, GEN, and EASI. Median SUMST and PEAKST differences for PS are lower than for GEN and EASI, and show a more accurate reconstruction.

Literature-based concept profiles for gene annotation: The issue of weighting (Article)

2008-05-01T00:00:00Z

Background: Text-mining has been used to link biomedical concepts, such as genes or biological processes, to each other for annotation purposes or the generation of new hypotheses. To relate two concepts to each other several authors have used the vector space model, as vectors can be compared efficiently and transparently. Using this model, a concept is characterized by a list of associated concepts, together with weights that indicate the strength of the association. The associated concepts in the vectors and their weights are derived from a set of documents linked to the concept of interest. An important issue with this approach is the determination of the weights of the associated concepts. Various schemes have been proposed to determine these weights, but no comparative studies of the different approaches are available. Here we compare several weighting approaches in a large scale classification experiment. Methods: Three different techniques were evaluated: (1) weighting based on averaging, an empirical approach; (2) the log likelihood ratio, a test-based measure; (3) the uncertainty coefficient, an information-theory based measure. The weighting schemes were applied in a system that annotates genes with Gene Ontology codes. As the gold standard for our study we used the annotations provided by the Gene Ontology Annotation project. Classification performance was evaluated by means of the receiver operating characteristics (ROC) curve using the area under the curve (AUC) as the measure of performance. Results and discussion: All methods performed well with median AUC scores greater than 0.84, and scored considerably higher than a binary approach without any weighting. Especially for the more specific Gene Ontology codes excellent performance was observed. The differences between the methods were small when considering the whole experiment. However, the number of documents that were linked to a concept proved to be an important variable. When larger amounts of texts were available for the generation of the concepts' vectors, the performance of the methods diverged considerably, with the uncertainty coefficient then outperforming the two other methods.

Jane: Suggesting journals, finding experts (Article)

2008-03-01T00:00:00Z

With an exponentially growing number of articles being published every year, scientists can use some help in determining which journal is most appropriate for publishing their results, and which other scientists can be called upon to review their work. Jane (Journal/Author Name Estimator) is a freely available web-based application that, on the basis of a sample text (e.g. the title and abstract of a manuscript), can suggest journals and experts who have published similar articles.

Automatic mining of the literature to generate new hypotheses for the possible link between periodontitis and atherosclerosis: Lipopolysaccharide as a case study (Article)

2007-12-01T00:00:00Z

Aim: The aim of the current report was to generate and explore new hypotheses into how, in a pathophysiological sense, atherosclerosis and periodontitis could be linked. Material and Methods: Two different biomedical informatics techniques were used: an association-based technique that generated a ranked list of genes associated with the diseases, and a natural language processing tool that extracted the relationships between the retrieved genes and lipopolysaccharide (LPS). Results: This combined approach of association-based and natural language processing-based literature mining identified a hit list of 16 candidate genes, with PON1 as the primary candidate. Conclusions: Further study of the literature prompted the hypothesis that PON1 might connect periodontitis with atherosclerosis in both an LPS-dependent and a non-LPS-dependent manner. Furthermore, the resulting genes not only confirmed already known associations between the two diseases, but also provided genes or gene products that have only been investigated separately in the two disease states, and genes or gene products previously reported to be involved in atherosclerosis. These findings remain to be investigated through clinical studies. This example of multidisciplinary research illustrates how collaborative efforts of investigators from different fields of expertise can result in the discovery of new hypotheses.

Measurement of coronary calcium scores or exercise testing as initial screening tool in asymptomatic subjects with ST-T changes on the resting ECG: An evaluation study (Article)

2007-07-13T00:00:00Z

Background: Asymptomatic subjects at intermediate coronary risk may need diagnostic testing for risk stratification. Both measurement of coronary calcium scores and exercise testing are well established tests for this purpose. However, it is not clear which test should be preferred as initial diagnostic test. We evaluated the prevalence of documented coronary artery disease (CAD) according to calcium scores and exercise test results. Methods: Asymptomatic subjects with ST-T changes on a rest ECG were selected from the population based PREVEND cohort study and underwent measurement of calcium scores by electron beam tomography and exercise testing. With calcium scores ≥10 or a positive exercise test, myocardial perfusion imaging (MPS) or coronary angiography (CAG) was recommended. The primary endpoint was documented obstructive CAD (≥50% stenosis). Results: Of 153 subjects included, 149 subjects completed the study protocol. Calcium scores ≥400, 100-399, 10-99 and <10 were found in 16, 29, 18 and 86 subjects and the primary endpoint was present in 11 (69%), 12 (41%), 0 (0%) and 1 (1%) subjects, respectively. A positive, nondiagnostic and negative exercise test was present in 33, 27 and 89 subjects and the primary endpoint was present in 13 (39%), 5 (19%) and 6 (7%) subjects, respectively. Receiver operator characteristics analysis showed that the area under the curve, as measure of diagnostic yield, of 0.91 (95% CI 0.84-0.97) for calcium scores was superior to 0.74 (95% CI 0.64-0.83) for exercise testing (p = 0.004). Conclusion: Measurement of coronary calcium scores is an appropriate initial non-invasive test in asymptomatic subjects at increased coronary risk.

Common NOS1AP variants are associated with a prolonged QTc interval in the rotterdam study (Article)

2007-07-01T00:00:00Z

BACKGROUND - QT prolongation is an important risk factor for sudden cardiac death. About 35% of QT-interval variation is heritable. In a recent genome-wide association study, a common variant (rs10494366) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was found to be associated with QT-interval variation. We tested for association of 2 NOS1AP variants with QT duration and sudden cardiac death. METHODS AND RESULTS - The Rotterdam Study is a population-based, prospective cohort study of individuals ≥55 years of age. The NOS1AP variants rs10494366 T>G and rs10918594 C>G were genotyped in 6571 individuals. Heart rate-corrected QT interval (QTc) was determined with ECG analysis software on up to 3 digital ECGs per individual (total, 11108 ECGs from 5374 individuals). The association with QTc duration was estimated with repeated-measures analyses, and the association with sudden cardiac death was estimated by Cox proportional-hazards analyses. The rs10494366 G allele (36% frequency) was associated with a 3.8-ms (95% confidence interval, 3.0 to 4.6; P=7.8×10) increase in QTc interval duration for each additional allele copy, and the rs10918594 G allele (31% frequency) was associated with a 3.6-ms (95% confidence interval, 2.7 to 4.4; P=6.9×10) increase per additional allele copy. None of the inferred NOS1AP haplotypes showed a stronger effect than the individual single-nucleotide polymorphisms. There were 233 sudden cardiac deaths over 11.9 median years of follow-up. No significant association was observed with sudden cardiac death risk. CONCLUSIONS - Common variants in NOS1AP are strongly associated with QT-interval duration in an elderly population. Larger sample sizes are needed to confirm or exclude an effect on sudden cardiac death risk.

Evaluation of techniques for increasing recall in a dictionary approach to gene and protein name identification (Article)

2007-06-01T00:00:00Z

Gene and protein name identification in text requires a dictionary approach to relate synonyms to the same gene or protein, and to link names to external databases. However, existing dictionaries are incomplete. We investigate two complementary methods for automatic generation of a comprehensive dictionary: combination of information from existing gene and protein databases and rule-based generation of spelling variations. Both methods have been reported in literature before, but have hitherto not been combined and evaluated systematically. We combined gene and protein names from several existing databases of four different organisms. The combined dictionaries showed a substantial increase in recall on three different test sets, as compared to any single database. Application of 23 spelling variation rules to the combined dictionaries further increased recall. However, many rules appeared to have no effect and some appear to have a detrimental effect on precision.

Optimizing the 12-lead electrocardiogram: a data driven approach to locating alternative recording sites (Article)

2007-05-01T00:00:00Z

Background: Despite its widespread use, the limitations of the 12-lead electrocardiogram (ECG) are undisputed. The main deficiency is that just a small area of the precordium is interrogated and for some abnormalities information may be transmitted to a region of the body surface where information is not recorded. In this study, we attempted to optimize the 12-lead ECG by using a data-driven approach to suggest alternate recording sites. Methods: A sequential lead selection algorithm was applied to a set of 744 body surface potential maps (BSPMs), consisting of recordings from subjects with myocardial infarction, left ventricular hypertrophy, and no apparent disease. A number of scenarios were investigated in which pairs of precordial leads were repositioned; these pairs were V3and V5, V4and V5, and V4and V6. The algorithm was also used to find optimal positions for all 6 precordial leads. Result: Through estimation of entire surface potential distributions it was found that each of the scenarios, with 2 leads repositioned, captured more information than the standard 12-lead ECG. The scenario with V4and V6repositioned performed best with a root mean square error of 22.3 microvolts and a correlation coefficient of 0.967. This configuration also fared favorably when compared to the scenario where all 6 precordial leads were repositioned as optimizing all 6 leads offered no significant improvement. Conclusion: This study demonstrated the use of a lead selection algorithm in enhancing the 12-lead ECG. The results also indicated that repositioning just 2 precordial leads can provide the same level of information capture as that observed when all precordial leads are optimally placed.

Prevalence and prognostic significance of heart failure stages: Application of the American College of Cardiology/American Heart Association heart failure staging criteria in the community (Article)

2007-03-01T00:00:00Z

BACKGROUND - Heart failure (HF) is a progressive disorder associated with frequent morbidity and mortality. An American Heart Association/American College of Cardiology staging classification of HF has been developed to emphasize early detection and prevention. The prevalence of HF stages and their association with mortality are unknown. We sought to estimate HF stage prevalence in the community and to measure the association of HF stages with mortality. METHODS AND RESULTS - A population-based, cross-sectional, random sample of 2029 Olmsted County, Minnesota, residents aged ≥45 years was identified. Participants were classified by medical record review, symptom questionnaire, physical examination, and echocardiogram as follows: stage 0, healthy; stage A, HF risk factors; stage B, asymptomatic cardiac structural or functional abnormalities; stage C, HF symptoms; and stage D, severe HF. In the cohort, 32% were stage 0, 22% stage A, 34% stage B, 12% stage C, and 0.2% stage D. Mean B-type natriuretic peptide concentrations (in pg/mL) increased by stages: stage 0=26, stage A=32, stage B=53, stage C=137, and stage D=353. Survival at 5 years was 99% in stage 0, 97% in stage A, 96% in stage B, 75% in stage C, and 20% in stage D. CONCLUSIONS - The present study provides prevalence estimates and prognostic validation for HF staging in a community cohort. Of note, 56% of adults ≥45 years of age were classified as being in stage A (risk factors) or B (asymptomatic ventricular dysfunction). HF staging underscores the magnitude of the population at risk for progression to overt HF.

Assignment of protein function and discovery of novel nucleolar proteins based on automatic analysis of MEDLINE (Article)

2007-03-01T00:00:00Z

Attribution of the most probable functions to proteins identified by proteomics is a significant challenge that requires extensive literature analysis. We have developed a system for automated prediction of implicit and explicit biologically meaningful functions for a proteomics study of the nucleolus. This approach uses a set of vocabulary terms to map and integrate the information from the entire MEDLINE database. Based on a combination of cross-species sequence homology searches and the corresponding literature, our approach facilitated the direct association between sequence data and information from biological texts describing function. Comparison of our automated functional assignment to manual annotation demonstrated our method to be highly effective. To establish the sensitivity, we defined the functional subtleties within a family containing a highly conserved sequence. Clustering of the DEAD-box protein family of RNA helicases confirmed that these proteins shared similar morphology although functional subfamilies were accurately identified by our approach. We visualized the nucleolar proteome in terms of protein functions using multi-dimensional scaling, showing functional associations between nucleolar proteins that were not previously realized. Finally, by clustering the functional properties of the established nucleolar proteins, we predicted novel nucleolar proteins. Subsequently, non-proteomics studies confirmed the predictions of previously unidentified nucleolar proteins.

Text-derived concept profiles support assessment of DNA microarray data for acute myeloid leukemia and for androgen receptor stimulation (Article)

2007-02-19T00:00:00Z

Background: High-throughput experiments, such as with DNA microarrays, typically result in hundreds of genes potentially relevant to the process under study, rendering the interpretation of these experiments problematic. Here, we propose and evaluate an approach to find functional associations between large numbers of genes and other biomedical concepts from free-text literature. For each gene, a profile of related concepts is constructed that summarizes the context in which the gene is mentioned in literature. We assign a weight to each concept in the profile based on a likelihood ratio measure. Gene concept profiles can then be clustered to find related genes and other concepts. Results: The experimental validation was done in two steps. We first applied our method on a controlled test set. After this proved to be successful the datasets from two DNA microarray experiments were analyzed in the same way and the results were evaluated by domain experts. The first dataset was a gene-expression profile that characterizes the cancer cells of a group of acute myeloid leukemia patients. For this group of patients the biological background of the cancer cells is largely unknown. Using our methodology we found an association of these cells to monocytes, which agreed with other experimental evidence. The second data set consisted of differentially expressed genes following androgen receptor stimulation in a prostate cancer cell line. Based on the analysis we put forward a hypothesis about the biological processes induced in these studied cells: secretory lysosomes are involved in the production of prostatic fluid and their development and/or secretion are androgen-regulated processes. Conclusion: Our method can be used to analyze DNA microarray datasets based on information explicitly and implicitly available in the literature. We provide a publicly available tool, dubbed Anni, for this purpose.

Dynamic changes of the TU complex in the electrocardiogram (Article)

2007-01-01T00:00:00Z

Abstract: The dynamicity of the repolarization process is reflected in the beat-to-beat variation of the TU complex. In short term (≤5 minutes) recordings this variability is measured on a beat by beat basis. The recordings were obtained from 86 healthy subjects and 13 patients with the long QT syndrome. No effect of preceding RR on T or U amplitude could be demonstrated, although these amplitudes show a substantial intraindividual variation. Peak T and U do show a (weak) correlation. Patients with the long QT syndrome have an instability of the repolarization process which is expressed in substantial variation in QT duration and the appearance of TU wavelets well beyond the classical end of T wave.

Cardiovascular disease, risk factors, and heart rate variability in the general population (Article)

2007-01-01T00:00:00Z

Abstract: The results of studies into the prognostic value of heart rate variability (HRV) for cardiac and all-cause mortality in the general population are briefly reviewed, and the effect of various recording durations of the electrocardiogram (ECG) on HRV parameters is assessed. Heart rate variability parameters offer prognostic information beyond that of traditional risk factors. In the elderly, increased HRV measured on a 10-second ECG is an even stronger indicator of cardiac death than decreased HRV. Estimated of HRV obtained from 10-second ECGs have moderate to poor correlation with those from 5- or 20-minute ECGs.

Impaired functional status and echocardiographic abnormalities signifying global dysfunction enhance the prognostic significance of previously unrecognized myocardial infarction detected by electrocardiography (Article)

2007-01-01T00:00:00Z

Background: The relationship between electrocardiographic unrecognized myocardial infarction (UMI), abnormal functional status, echocardiographic abnormalities, and mortality has not been evaluated. Methods: A population-based random sample of 2042 Olmsted County residents, age ≥45 years, was studied by self-administered questionnaire, chart review, ECG and echocardiogram, and 5 year follow-up for all-cause mortality. UMI (n = 81) was diagnosed if ECG-MI criteria were met without previous documented myocardial infarction. Functional Status was assessed by the Goldman Specific Activity Scale. Results: UMI subjects had an increased prevalence of abnormal functional status compared to no MI controls (22% vs 11%, P < 0.05). This association was independent of sex, obesity, smoking, diabetes, and pulmonary disease. It became insignificant after stratifying for echocardiographic abnormalities. Compared to no MI controls, UMI subjects with impaired functional status had a higher mortality hazard ratio (HR 7.2; P<0.0001) than those without impaired functional status (HR 2.7; P = 0.02). In UMI subjects with impaired functional status and any echocardiographic abnormality signifying global ventricular dysfunction (systolic or diastolic dysfunction, left atrial or left ventricular enlargement), the mortality risk was even higher (HR 9.5; P<0.001) and persisted in multivariate analyses. This increased mortality risk was unaffected by adjustment for regional wall motion abnormalities. Conclusions: The assessment of impaired functional status and echocardiographic abnormalities improves the prognostic significance of UMI. Even in the absence of regional wall motion abnormalities, structural abnormalities of global dysfunction may play a role in mediating the increased mortality associated with UMI.

The relation of thyroid function and ventricular repolarization: decreased serum thyrotropin levels are associated with short rate-adjusted QT intervals. (Article)

2006-12-01T00:00:00Z

CONTEXT: The linkage of thyroid dysfunction with ventricular repolarization properties has not been investigated extensively, although alterations might be associated with an increased ventricular vulnerability. OBJECTIVE: The objective of the study was to investigate whether there is an association between functional thyroid status and rate-adjusted QT intervals (QTc). DESIGN, SETTING, AND PARTICIPANTS: The population-based Study of Health in Pomerania included 4310 subjects aged 20-79 yr. Data of 3610 subjects (1862 women and 1748 men) without branch bundle blocks or pacemaker were available for the present analyzes. MAIN OUTCOME MEASURES: QTc with respect to thyroid status. Short QTc was defined below the 25th percentile, and long QTc above the 75th percentile of the gender-specific distribution. RESULTS: TSH levels were positively associated with QTc independent from potential confounders in multivariable analyses (P for trend = 0.001). Subjects with decreased TSH levels had shorter QTc than those with normal TSH levels (426.4 +/- 8.2 vs. 430.2 +/- 8.2; P < 0.001). Adjusted odds ratios for short QTc in subjects with elevated, normal, and decreased TSH were 0.87 (95% confidence interval 0.58-1.31), 1.00 (reference), and 1.53 (95% confidence interval 1.16-2.03), respectively (P for trend = 0.008). CONCLUSION: TSH levels were positively related to QTc in a population-based sample. Subjects with decreased serum TSH levels had an increased risk for short QTc. Whether these findings are of clinical significance has to be investigated by further studies.

Storing, linking, and mining microarray databases using SRS. (Article)

2005-07-27T00:00:00Z

BACKGROUND: SRS (Sequence Retrieval System) has proven to be a valuable platform for storing, linking, and querying biological databases. Due to the availability of a broad range of different scientific databases in SRS, it has become a useful platform to incorporate and mine microarray data to facilitate the analyses of biological questions and non-hypothesis driven quests. Here we report various solutions and tools for integrating and mining annotated expression data in SRS. RESULTS: We devised an Auto-Upload Tool by which microarray data can be automatically imported into SRS. The dataset can be linked to other databases and user access can be set. The linkage comprehensiveness of microarray platforms to other platforms and biological databases was examined in a network of scientific databases. The stored microarray data can also be made accessible to external programs for further processing. For example, we built an interface to a program called Venn Mapper, which collects its microarray data from SRS, processes the data by creating Venn diagrams, and saves the data for interpretation. CONCLUSION: SRS is a useful database system to store, link and query various scientific datasets, including microarray data. The user-friendly Auto-Upload Tool makes SRS accessible to biologists for linking and mining user-owned databases.

Thesaurus-based disambiguation of gene symbols. (Article)

2005-06-16T00:00:00Z

BACKGROUND: Massive text mining of the biological literature holds great promise of relating disparate information and discovering new knowledge. However, disambiguation of gene symbols is a major bottleneck. RESULTS: We developed a simple thesaurus-based disambiguation algorithm that can operate with very little training data. The thesaurus comprises the information from five human genetic databases and MeSH. The extent of the homonym problem for human gene symbols is shown to be substantial (33% of the genes in our combined thesaurus had one or more ambiguous symbols), not only because one symbol can refer to multiple genes, but also because a gene symbol can have many non-gene meanings. A test set of 52,529 Medline abstracts, containing 690 ambiguous human gene symbols taken from OMIM, was automatically generated. Overall accuracy of the disambiguation algorithm was up to 92.7% on the test set. CONCLUSION: The ambiguity of human gene symbols is substantial, not only because one symbol may denote multiple genes but particularly because many symbols have other, non-gene meanings. The proposed disambiguation approach resolves most ambiguities in our test set with high accuracy, including the important gene/not a gene decisions. The algorithm is fast and scalable, enabling gene-symbol disambiguation in massive text mining applications.

Co-occurrence based meta-analysis of scientific texts: retrieving biological relationships between genes (Article)

2005-05-01T00:00:00Z

MOTIVATION: The advent of high-throughput experiments in molecular biology creates a need for methods to efficiently extract and use information for large numbers of genes. Recently, the associative concept space (ACS) has been developed for the representation of information extracted from biomedical literature. The ACS is a Euclidean space in which thesaurus concepts are positioned and the distances between concepts indicates their relatedness. The ACS uses co-occurrence of concepts as a source of information. In this paper we evaluate how well the system can retrieve functionally related genes and we compare its performance with a simple gene co-occurrence method. RESULTS: To assess the performance of the ACS we composed a test set of five groups of functionally related genes. With the ACS good scores were obtained for four of the five groups. When compared to the gene co-occurrence method, the ACS is capable of revealing more functional biological relations and can achieve results with less literature available per gene. Hierarchical clustering was performed on the ACS output, as a potential aid to users, and was found to provide useful clusters. Our results suggest that the algorithm can be of value for researchers studying large numbers of genes. AVAILABILITY: The ACS program is available upon request from the authors.

Spatial QRS-T angle predicts cardiac death in a general population (Article)

2003-01-01T00:00:00Z

AIMS: The aim of this study was to assess the prognostic importance of the spatial QRS-T angle for fatal and non-fatal cardiac events. METHODS AND RESULTS: Electrocardiograms (ECGs) were recorded in 6134 men and women aged 55 years and over from the prospective population-based Rotterdam Study. Spatial QRS-T angles were categorized as normal, borderline or abnormal. Using Cox's proportional hazards model, abnormal angles showed increased hazard ratios of cardiac death (age-and sex-adjusted hazard ratio 5.2 (95% CI 4.0-6.8)), non-fatal cardiac events (2.2 (1.5-3.1)), sudden death (5.6 (3.7-8.5)) and total mortality (2.3 (2.0-2.7)). None of the classical cardiovascular and ECG predictors provided larger hazard ratios. After adjustment for these predictors, the association of abnormal spatial QRS-T angles with all fatal study endpoints remained strong, but the association with non-fatal cardiac events disappeared. Computation of Akaike's information criterion showed that the angle contributed significantly to the prediction of all fatal endpoints by classical cardiovascular and ECG predictors. CONCLUSION: The spatial QRS-T angle is a strong and independent predictor of cardiac mortality in the elderly. It is stronger than any of the classical cardiovascular risk factors and ECG risk indicators and provides additional value to them in predicting fatal cardiac events.

Ambiguity of human gene symbols in LocusLink and MEDLINE: creating an inventory and a disambiguation test collection (Article)

2003-01-01T00:00:00Z

Genes are discovered almost on a daily basis and new names have to be found. Although there are guidelines for gene nomenclature, the naming process is highly creative. Human genes are often named with a gene symbol and a longer, more descriptive term; the short form is very often an abbreviation of the long form. Abbreviations in biomedical language are highly ambiguous, i.e., one gene symbol often refers to more than one gene.Using an existing abbreviation expansion algorithm,we explore MEDLINE for the use of human gene symbols derived from LocusLink. It turns out that just over 40% of these symbols occur in MEDLINE, however, many of these occurrences are not related to genes. Along the process of making an inventory, a disambiguation test collection is constructed automatically.

Mining microarray datasets aided by knowledge stored in literature (Article)

2003-01-01T00:00:00Z

DNA microarray technology produces large amounts of data. For data mining of these datasets, background information on genes can be helpful. Unfortunately most information is stored in free text. Here, we present an approach to use this information for DNA microarray data mining.

Using contextual queries (Article)

2003-01-01T00:00:00Z

Search engines generally treat search requests in isolation. The results for a given query are identical, independent of the user, or the context in which the user made the request. An approach is demonstrated that explores implicit contexts as obtained from a document the user is reading. The approach inserts into an original (web) document functionality to directly activate context driven queries that yield related articles obtained from various information sources.

New normal limits for the paediatric electrocardiogram (Article)

2001-07-19T00:00:00Z

AIMS: Previous studies that determined the normal limits for the paediatric ECG had their imperfections: ECGs were recorded at a relatively low sampling rate, ECG measurements were conducted manually, or normal limits were presented for only a limited set of parameters. The aim of this study was to establish an up-to-date and complete set of clinically relevant normal limits for the paediatric ECG. METHODS AND RESULTS: ECGs from 1912 healthy Dutch children (age 11 days to 16 years) were recorded at a sampling rate of 1200 Hz. The digitally stored ECGs were analysed using a well-validated ECG computer program. The normal limits of all clinically relevant ECG measurements were determined for nine age groups. Clinically significant differences were shown to exist, compared with previously established normal limits. Sex differences could be demonstrated for QRS duration and several amplitude measurements. CONCLUSIONS: These new normal limits differ substantially from those commonly used and suggest that diagnostic criteria for the paediatric ECG should be adjusted.

Minimum bandwidth requirements for recording of pediatric electrocardiograms (Article)

2001-01-01T00:00:00Z

BACKGROUND: Previous studies that determined the frequency content of the pediatric ECG had their limitations: the study population was small or the sampling frequency used by the recording system was low. Therefore, current bandwidth recommendations for recording pediatric ECGs are not well founded. We wanted to establish minimum bandwidth requirements using a large set of pediatric ECGs recorded at a high sampling rate. METHODS AND RESULTS: For 2169 children aged 1 day to 16 years, a 12-lead ECG was recorded at a sampling rate of 1200 Hz. The averaged beats of each ECG were passed through digital filters with different cut off points (50 to 300 Hz in 25-Hz steps). We measured the absolute errors in maximum QRS amplitude for each simulated bandwidth and determined the percentage of records with an error >25 microV. We found that in any lead, a bandwidth of 250 Hz yields amplitude errors <25 microV in >95% of the children <1 year. For older children, a gradual decrease in ECG frequency content was demonstrated. CONCLUSIONS: We recommend a minimum bandwidth of 250 Hz to record pediatric ECGs. This bandwidth is considerably higher than the previous recommendation of 150 Hz from the American Heart Association.

Prolonged QT interval predicts cardiac and all-cause mortality in the elderly. The Rotterdam Study (Article)

1999-02-01T00:00:00Z

AIMS: To examine the association between heart-rate corrected QT prolongation and cardiac and all-cause mortality in the population-based Rotterdam Study among men and women aged 55 years or older and to compare the prognostic value of the QT interval, using different formulas to correct for heart rate. METHODS AND RESULTS: After exclusion of participants with arrhythmias or bundle branch block on the ECG, the study population consisted of 2083 men and 3158 women. The QT interval was computed by the Modular ECG Analysis System (MEANS). Data were analysed using Cox' proportional hazards model. Participants in the highest quartile of the heart-rate corrected QT interval had about a 70% age- and sex-adjusted increased risk for both all-cause mortality (hazard ratio (HR) 1.8; 95% CI:1.3-2.4) and cardiac mortality (HR 1.7; 95% CI:1.0-2.7) compared to those in the lowest quartile. In women, the increased risk associated with prolonged QT for cardiac death was more pronounced than in men. These risk estimates did not change after adjustment for potential confounders, including history of myocardial infarction, hypertension and diabetes mellitus. CONCLUSION: A prolonged heart-rate corrected QT interval is an independent predictor for cardiac and all-cause mortality in older men and women. The risk associated with prolonged QT is hardly affected by the heart-rate correction formula used.

QT dispersion as an attribute of T-loop morphology (Article)

1999-01-01T00:00:00Z

BACKGROUND: The suggestion that increased QT dispersion (QTD) is due to increased differences in local action potential durations within the myocardium is wanting. An alternative explanation was sought by relating QTD to vectorcardiographic T-loop morphology. METHODS AND RESULTS: The T loop is characterized by its amplitude and width (defined as the spatial angle between the mean vectors of the first and second halves of the loop). We reasoned that small, wide ("pathological") T loops produce larger QTD than large, narrow ("normal") loops. To quantify the relationship between QTD and T-loop morphology, we used a program for automated analysis of ECGs and a database of 1220 standard simultaneous 12-lead ECGs. For each ECG, QT durations, QTD, and T-loop parameters were computed. T-loop amplitude and width were dichotomized, with 250 microV (small versus large amplitudes) and 30 degrees (narrow versus wide loops) taken as thresholds. Over all 1220 ECGs, QTDs were smallest for large, narrow T loops (54.2+/-27.1 ms) and largest for small, wide loops (69. 5+/-33.5 ms; P<0.001). CONCLUSIONS: QTD is an attribute of T-loop morphology, as expressed by T-loop amplitude and width.

QTc dispersion predicts cardiac mortality in the elderly: the Rotterdam Study (Article)

1998-01-01T00:00:00Z

BACKGROUND: Increased QTc dispersion has been associated with an increased risk for ventricular arrhythmias and cardiac death in selected patient populations. We examined the association between computerized QTc-dispersion measurements and mortality in a prospective analysis of the population-based Rotterdam Study among men and women aged > or = 55 years. METHODS AND RESULTS: QTc dispersion was computed with the use of the Modular ECG Analysis System as the difference between the maximum and minimum QTc intervals in 12 and 8 leads (ie, the 6 precordial leads, the shortest extremity lead, and the median of the 5 other extremity leads). After exclusion of those without a digitally stored ECG, the population consisted of 2358 men and 3454 women. During the 3 to 6.5 years (mean, 4 years) of follow-up, 568 subjects (9.8%) died. The degree of QTc dispersion was categorized into tertiles. Data were analyzed using the Cox proportional hazards model, with adjustment for age. For QTc dispersion in 8 leads, those in the highest tertile relative to the lowest tertile had a twofold risk for cardiac death (hazard ratio, 2.5; 95% confidence interval [CI], 1.6 to 4.0) and sudden cardiac death (hazard ratio, 1.9; 95% CI, 1.0 to 3.7) and a 40% increased risk for total mortality (hazard ratio, 1.4; 95% CI, 1.2 to 1.8). Additional adjustment for potential confounders, including history of myocardial infarction, hypertension, and overall QTc, did not materially change the risk estimates. Hazard ratios for QTc dispersion in 12 leads were comparable to those found for QTc dispersion in 8 leads. CONCLUSIONS: QTc dispersion is an important predictor of cardiac mortality in older men and women.

Measurement error as a source of QT dispersion: a computerised analysis (Article)

1998-01-01T00:00:00Z

OBJECTIVE: To establish a general method to estimate the measuring error in QT dispersion (QTD) determination, and to assess this error using a computer program for automated measurement of QTD. SUBJECTS: Measurements were done on 1220 standard simultaneous 12 lead electrocardiograms. DESIGN: The computer program was validated against two observers on a random subset of 100 electrocardiograms. Simple laws of physics require that at least five of the six extremity leads have the same QT duration. This allows the direct assessment of the error in measuring QTD derived from five extremity leads (QTD5). It also enables ST-T amplitude dependent distributions of measurement error in determining QT duration to be established. These QT error distributions were then used to estimate the error in measuring QTD from all 12 leads (QTD12). MAIN OUTCOME MEASURES: Mean and standard deviation of error in measuring QTD duration, QTD5, and QTD12. RESULTS: Performance of the program was comparable to that of observers. Errors in measuring QT duration (measured QT minus reference QT) fell from a mean (SD) of 6.9 (17.1) ms for ST-T amplitudes < 50 microV to -1.4 (6.3) ms for amplitudes > 350 microV. Measurement errors of QTD5 and QTD12 were 20.4 (11.5) ms and 29.4 (14.9) ms. CONCLUSIONS: The fact that no QTD can exist between five of the six extremity leads provides a means of estimating QTD measurement error. Measuring error of QT duration is dependent on ST-T amplitude. QTD measurement error is large compared with typical QTD values reported.