Nagelkerke, N.J.D.

The Mantel-Haenszel Procedure Revisited: Models and Generalizations (Article)

2013-03-13T00:00:00Z

Several statistical methods have been developed for adjusting the Odds Ratio of the relation between two dichotomous variables X and Y for some confounders Z. With the exception of the Mantel-Haenszel method, commonly used methods, notably binary logistic regression, are not symmetrical in X and Y. The classical Mantel-Haenszel method however only works for confounders with a limited number of discrete strata, which limits its utility, and appears to have no basis in statistical models. Here we revisit the Mantel-Haenszel method and propose an extension to continuous and vector valued Z. The idea is to replace the observed cell entries in strata of the Mantel-Haenszel procedure by subject specific classification probabilities for the four possible values of (X,Y) predicted by a suitable statistical model. For situations where X and Y can be treated symmetrically we propose and explore the multinomial logistic model. Under the homogeneity hypothesis, which states that the odds ratio does not depend on Z, the logarithm of the odds ratio estimator can be expressed as a simple linear combination of three parameters of this model. Methods for testing the homogeneity hypothesis are proposed. The relationship between this method and binary logistic regression is explored. A numerical example using survey data is presented.

HIV, HSV-2 and syphilis among married couples in India: Patterns of discordance and concordance (Article)

2011-10-01T00:00:00Z

Objectives: Differences in sexual networks probably explain the disparity in the scale of HIV epidemics in sub- Saharan Africa and India. HIV and sexually transmitted infection (STI) discordant couple studies provide insights into important aspects of these sexual networks. The authors quantify the role of male sexual behaviour in HIV transmission in married couples in India. Methods: The authors analysed patterns of HIV and STI discordance in married couples from two community surveys in India: the National Family Health Study-3 for HIV-1 and the Centre for Global Health Research health check-up for HSV-2 and syphilis. A statistical model was used to estimate the fraction of infections introduced by each of the two partners. Results: Only 0.8%, 16.0% and 3.5% of couples were infected (either partner or both) with HIV-1, HSV-2 and syphilis, respectively. A large proportion of infected couples were discordant (73.0%, 56.3% and 84.2% for HIV-1, HSV-2 and syphilis, respectively). This model estimated that, among couples with any STI, the male partner introduced the infection the majority of the time (HIV-1: 85.4%, HSV-2: 64.1%, syphilis: 75.0%). Conclusions: Male sexual activity outside of marriage appears to be a driving force for the Indian HIV/STI epidemic. Male client and female sex worker contacts should remain a primary target of the National AIDS Control Program in India.

The potential impact of RV144-like vaccines in rural South Africa: A study using the STDSIM microsimulation model (Article)

2011-08-18T00:00:00Z

Background: The only successful HIV vaccine trial to date is the RV144 trial of the ALVAC/AIDSVAX vaccine in Thailand, which showed an overall incidence reduction of 31%. Most cases were prevented in the first year, suggesting a rapidly waning efficacy. Here, we predict the population level impact and cost-effectiveness of practical implementation of such a vaccine in a setting of a generalised epidemic with high HIV prevalence and incidence. Methods: We used STDSIM, an established individual-based microsimulation model, tailored to a rural South African area with a well-functioning HIV treatment and care programme. We estimated the impact of a single round of mass vaccination for everybody aged 15-49, as well as 5-year and 2-year re-vaccination strategies for young adults (aged 15-29). We calculated proportion of new infections prevented, cost-effectiveness indicators, and budget impact estimates of combined ART and vaccination programmes. Results: A single round of mass vaccination with a RV144-like vaccine will have a limited impact, preventing only 9% or 5% of new infections after 10 years at 60% and 30% coverage levels, respectively. Revaccination strategies are highly cost-effective if vaccine prices can be kept below 150 US/vaccine for 2-year revaccination strategies, and below 200 US/vaccine for 5-year revaccination strategies. Net cost-savings through reduced need for HIV treatment and care occur when vaccine prices are kept below 75 US/vaccine. These results are sensitive to alternative assumptions on the underlying sexual network, background prevention interventions, and individual's propensity and consistency to participate in the vaccination campaign. Discussion: A modestly effective vaccine can be a cost-effective intervention in highly endemic settings. To predict the impact of vaccination strategies in other endemic situations, sufficient knowledge of the underlying sexual network, prevention and treatment interventions, and individual propensity and consistency to participate, is key. These issues are all best addressed in an individual-based microsimulation model.

The potential impact of an HIV vaccine with limited protection on HIV incidence in Thailand: A modeling study (Article)

2011-08-18T00:00:00Z

Background: The RV144 trial on the ALVAC/AIDSVAX candidate HIV vaccine, carried out in Thailand, showed short-lived protection against infection. Methods: Using a deterministic compartmental model we explored the potential impact of this vaccine on heterosexual HIV transmission in Thailand. Both one-off vaccination strategies, as well as strategies with regular boosting, either annually or every two years, were explored. Both targeting the general adult population and prioritizing sex workers were modeled. The impact of risk compensation among high risk groups, as well as whether higher levels of safe sex in high risk groups could be an alternative to vaccination, was studied. Results: One-off vaccination campaigns had only transient effects, and boosting appears to be a key component of successful vaccination campaigns. Intensive vaccination campaigns may reduce HIV incidence by up to 75% after 10 years of vaccination. Targeting only sex workers has a smaller impact but has a more favorable cost-benefit ratio. Risk compensation has the potential of undoing much of the benefits of a vaccination program and may even increase incidence. In contrast, higher levels of safe sex among sex workers would provide a viable alternative to vaccinating this group. Discussion: The new vaccine holds promise for controlling HIV in Thailand and similar countries. In view of the short lived protection of the vaccine, regular boosting of immunity as well as avoidance of risk compensation are essential. Targeting sex workers would achieve the greatest reduction in incidence per vaccination and may be considered for expensive vaccines but its cost-effectiveness has to be compared to alternatives.

In search of hidden Q-fever outbreaks: Linking syndromic hospital clusters to infected goat farms (Article)

2011-01-01T00:00:00Z

Large Q-fever outbreaks were reported in The Netherlands from May 2007 to 2009, with dairy-goat farms as the putative source. Since Q-fever outbreaks at such farms were first reported in 2005, we explored whether there was evidence of human outbreaks before May 2007. Space-time scan statistics were used to look for clusters of lower-respiratory infections (LRIs), hepatitis, and/or endocarditis in hospitalizations, 2005-2007. We assessed whether these were plausibly caused by Q fever, using patients' age, discharge diagnoses, indications for other causes, and overlap with reported Q fever in goats/humans. For seven detected LRI clusters and one hepatitis cluster, we considered Q fever a plausible cause. One of these clusters reflected the recognized May 2007 outbreak. Real-time syndromic surveillance would have detected four of the other clusters in 2007, one in 2006 and two in 2005, which might have resulted in detection of Q-fever outbreaks up to 2 years earlier.

Determinants of carriage of resistant Staphylococcus aureus among S. aureus carriers in the Indonesian population inside and outside hospitals (Article)

2010-10-01T00:00:00Z

OBJECTIVES: To identify determinants of carriage of resistant Staphylococcus aureus in both hospitalized patients and individuals from the community in two urban centres in Indonesia. METHODS: Staphylococcus aureus cultures and data on recent antibiotic use, demographic, socioeconomic, disease-related and healthcare-related variables were collected from 3995 community dwellers and hospitalized persons. Nasal S. aureus carriage was found in 362 persons (9.1%). Logistic regression analysis was performed to identify which variables were independently associated with carriage of resistant S. aureus. RESULTS: The penicillins were the most frequently used antibiotics both in the community and in hospitalized patients. In the community, admission to a hospital was associated with carriage of S. aureus resistant to any of the tested antibiotics [odds ratio (OR) 2.5, 95% confidence interval (95% CI) 1.3-4.9] and any tetracycline resistance (OR 2.4, 95% CI 1.1-5.1). Having no symptoms was associated with less carriage of S. aureus with resistance to any of the tested antibiotics (OR 0.5, 95% CI 0.3-0.9) and any tetracycline resistance (OR 0.5, 95% CI 0.3-0.9). Crowding (OR 4.5, 95% CI 1.2-4.9) and low income (OR 8.9, 95% CI 1.8-43.9) were associated with multidrug resistance. In hospitalized patients, the use of penicillins was associated with resistance to any of the tested antibiotics (OR 3.9, 95% CI 1.4-11.6) and any tetracycline resistance (OR 3.7, 95% CI 1.1-12.0). CONCLUSIONS: Antibiotic policies including proper diagnosis, treatment and drug delivery process should be made by healthcare providers in Indonesia to help limit the emergence of antibiotic resistance.

Syndromic surveillance for local outbreaks of lower-respiratory infections: Would it work? (Article)

2010-09-14T00:00:00Z

Background: Although syndromic surveillance is increasingly used to detect unusual illness, there is a debate whether it is useful for detecting local outbreaks. We evaluated whether syndromic surveillance detects local outbreaks of lower-respiratory infections (LRIs) without swamping true signals by false alarms. Methods and Findings: Using retrospective hospitalization data, we simulated prospective surveillance for LRI-elevations. Between 1999-2006, a total of 290762 LRIs were included by date of hospitalization and patients place of residence (>80% coverage, 16 million population). Two large outbreaks of Legionnaires disease in the Netherlands were used as positive controls to test whether these outbreaks could have been detected as local LRI elevations. We used a space-time permutation scan statistic to detect LRI clusters. We evaluated how many LRI-clusters were detected in 1999-2006 and assessed likely causes for the cluster-signals by looking for significantly higher proportions of specific hospital discharge diagnoses (e.g. Legionnaires disease) and overlap with regional influenza elevations. We also evaluated whether the number of space-time signals can be reduced by restricting the scan statistic in space or time. In 1999-2006 the scan-statistic detected 35 local LRI clusters, representing on average 5 clusters per year. The known Legionnaires' disease outbreaks in 1999 and 2006 were detected as LRI-clusters, since cluster-signals were generated with an increased proportion of Legionnaires disease patients (p:<0.0001). 21 other clusters coincided with local influenza and/or respiratory syncytial virus activity, and 1 cluster appeared to be a data artifact. For 11 clusters no likely cause was defined, some possibly representing as yet undetected LRI-outbreaks. With restrictions on time and spatial windows the scan statistic still detected the Legionnaires' disease outbreaks, without loss of timeliness and with less signals generated in time (up to 42% decline). Conclusions: To our knowledge this is the first study that systematically evaluates the performance of space-time syndromic surveillance with nationwide high coverage data over a longer period. The results show that syndromic surveillance can detect local LRI-outbreaks in a timely manner, independent of laboratory-based outbreak detection. Furthermore, since comparatively few new clusters per year were observed that would prompt investigation, syndromic hospital-surveillance could be a valuable tool for detection of local LRI-outbreaks.

Heterogeneity in host HIV susceptibility as a potential contributor to recent HIV prevalence declines in Africa (Article)

2009-01-02T00:00:00Z

Background: HIV prevalence has recently declined in several African countries, and prior to this the risk of HIV acquisition per unprotected sex contact also declined in Kenyan sex workers. We hypothesized that heterogeneity in HIV host susceptibility might underpin both of these observations. Methods: A compartmental mathematical model was used to explore the potential impact of heterogeneity in susceptibility to HIV infection on epidemic behavior, in the absence of other causative mechanisms. Results: Studies indicated that a substantial heterogeneity in susceptibility to HIV infection may lead to an epidemic that peaks and then declines due to a depletion of the most susceptible individuals, even without changes in sexual behavior. This effect was most notable in high-risk groups such as female sex workers and was consistent with empirical data. Discussion: Declines in HIV prevalence may have other causes in addition to behavior change, including heterogeneity in host HIV susceptibility. There is a need to further study this heterogeneity and its correlates, particularly as it confounds the ability to attribute HIV epidemic shifts to specific interventions, including behavior change.

Survey of antibiotic use of individuals visiting public healthcare facilities in Indonesia (Article)

2008-11-01T00:00:00Z

Objectives: To estimate the antibiotic use of individuals visiting public healthcare facilities in Indonesia and to identify determinants of use against a background of high resistance rates. Methods: Patients on admission to hospital (group A), visiting a primary health center (group B), and healthy relatives (group C) were included in the study. A questionnaire on demographic, socioeconomic, and healthcare-related items including health complaints and consumption of antibiotics was used. Logistic regression was performed to determine the co-variables of antibiotic use. Results: Of 2996 individuals interviewed, 486 (16%) had taken an antibiotic. Compared to group C (7% consumption), groups B and A exhibited a three-fold and four-fold higher use of antibiotics, respectively. Respiratory (80%) and gastrointestinal (13%) symptoms were most frequent. Aminopenicillins and tetracyclines accounted for 80% of the prescribed antibiotics. Similar antibiotics were self-medicated (17% of users). Age less than 18 years and health insurance were independent determinants of antibiotic use. Urban provenance, being adult, male, and having no health insurance were independent determinants of self-medication. Conclusions: In addition to health complaints, other factors determined antibiotic consumption. In view of the likely viral origin of respiratory complaints and the resistance of intestinal pathogens, most antibiotic use was probably unnecessary or ineffective. Future interventions should be directed towards healthcare providers.

Audit of antibiotic prescribing in two governmental teaching hospitals in Indonesia (Article)

2008-07-01T00:00:00Z

This article estimates the magnitude and quality of antibiotic prescribing in Indonesian hospitals and aims to identify demographic, socio-economic, disease-related and healthcare-related determinants of use. An audit on antibiotic use of patients hospitalized for 5days or more was conducted in two teaching hospitals (A and B) in Java. Data were collected by review of records on the day of discharge. The method was validated through concurrent data collection in Hospital A. Multivariate logistic regression analysis was performed to determine variables to explain antibiotic prescribing. Prescriptions were assessed by three reviewers using standardized criteria. A high proportion (84%) of 999 patients (499 in Hospital A and 500 in Hospital B) received an antibiotic. Prescriptions could be categorized as therapeutic (53%) or prophylactic (15%), but for 32% the indication was unclear. Aminopenicillins accounted for 54%, and cephalosporins (mostly third generation) for 17%. The average level of antibiotic use amounted to 39DDD/100patient-days. Validation revealed that 30% of the volume could be underestimated due to incompleteness of the records. Predictors of antibiotic use were diagnosis of infection, stay in surgical or paediatric departments, low-cost nursing care, and urban residence. Only 21% of prescriptions were considered to be definitely appropriate; 15% were inappropriate regarding choice, dosage or duration, and 42% of prescriptions, many for surgical prophylaxis and fever without diagnosis of infection, were deemed to be unnecessary. Agreement among assessors was low (kappa coefficients 0.13 - 0.14). Despite methodological limitations, recommendations could be made to address the need for improving diagnosis, treatment and drug delivery processes in this setting.

The impact of pre-exposure prophylaxis (PrEP) on HIV epidemics in Africa and India: A simulation study (Article)

2008-05-07T00:00:00Z

Background: Pre-exposure prophylaxis (PrEP) is a promising new HIV prevention method, especially for women. An urgent demand for implementation of PrEP is expected at the moment efficacy has been demonstrated in clinical trials. We explored the long-term impact of PrEP on HIV transmission in different HIV epidemics. Methodology/Principal Findings: We used a mathematical model that distinguishes the general population, sex workers and their clients. PrEP scenarios varying in effectiveness, coverage and target group were modeled in the epidemiological settings of Botswana, Nyanza Province in Kenya, and Southern India. We also studied the effect of condom addition or condom substitution during PrEP use. Main outcome was number of HIV infections averted over ten years of PrEP use. PrEP strategies with high effectiveness and high coverage can have a substantial impact in African settings. In Southern India, by contrast, the number of averted HIV infections in different PrEP scenarios would be much lower. The impact of PrEP may be strongly diminished or even reversed by behavioral disinhibition, especially in scenarios with low coverage and low effectiveness. However, additional condom use during low coverage and low effective PrEP doubled the amount of averted HIV infections. Conclusions/Significance: The public health impact of PrEP can be substantial. However, this impact may be diminished, or even reversed, by changes in risk behavior. Implementation of PrEP strategies should therefore come on top of current condom campaigns, not as a substitution.

Reported pertussis infection and risk of atopy in 8- to 12-yr-old vaccinated and non-vaccinated children (Article)

2008-02-01T00:00:00Z

Pertussis infection has been suspected to be a potential causal factor in the development of atopic disease because of the effect of pertussis immunization on specific IgE antibodies. Although several studies found a positive association between pertussis infection and atopic disorders, this relationship has not yet been studied in a population stratified by vaccination status. To assess the association between pertussis infection and atopic disorders in pertussis-unvaccinated children and in pertussis-vaccinated children. Using data from a previously conducted study on the relationship between the diphtheria-tetanus-pertussis-(inactivated) poliomyelitis vaccination in the first year of life and atopic disorders, the study population of 1872 8-12 yr old was divided into children pertussis-unvaccinated and children pertussis-vaccinated in the first year of life. Within each group, the association between pertussis infection and atopic disorders (both as reported by the parents) was assessed. In the unvaccinated group, there were no significant associations between pertussis infection and atopic disorders. In the vaccinated group, all associations between pertussis infection and atopic disorders were positive, the associations with asthma [odds ratio (OR) = 2.24, 95% confidence interval (CI95%): 1.36-3.70], hay fever (OR = 2.35, CI95%: 1.46-3.77) and food allergy (OR = 2.68, CI95%: 1.48-4.85) being significant. There was a positive association between pertussis infection and atopic disorders in the pertussis vaccinated group only. From the present study, it cannot be concluded whether this association is causal or due to reverse causation.

Determinants of carriage of resistant Escherichia coli in the Indonesian population inside and outside hospitals (Article)

2007-08-01T00:00:00Z

Objectives: Antibiotic resistance is a worldwide healthcare problem exacerbated by antibiotic use and transmission of resistant bacteria. Not much is known about resistance in commensal flora and about determinants for resistance in Indonesia. This study analysed recent antibiotic use as well as demographic, socioeconomic, disease-related and healthcare-related determinants of rectal carriage of resistant Escherichia coli in the community and in hospitals in Indonesia. Methods: Carriers of susceptible E. coli were compared with carriers of E. coli with resistance to any of the tested antibiotics. Logistic regression analysis was performed to determine which variables were associated with carriage of resistant E. coli. Individuals in the community with varying levels of contact with healthcare institutions and hospitalized patients were analysed as separate populations. Results and conclusions: Of 3275 individuals (community 2494, hospital 781), 54% carried resistant E. coli. Recent antibiotic use was the most important determinant of resistance in both populations [community: odds ratio (OR) 1.8, 95% confidence interval (95% CI) 1.5-2.3; hospital: OR 2.5, 95% CI 1.6_3.9]. In the community, hospitalization (OR 2.4, 95% CI 2.0-3.0), diarrhoeal symptoms (OR 1.9, 95% CI 1.3-2.7) and age under 16 years (adults: OR 0.4, 95% CI 0.3-0.5) were associated with carriage of resistant E. coli. For hospitalized patients, having no health insurance was associated with less resistance (OR 0.6, 95% CI 0.4-0.9) and differences were observed between hospitals (Semarang: OR 2.2, 95% CI 1.5-3.3) and departments (Paediatrics: OR 4.3, 95% CI 1.7-10.7). Further research is needed to investigate whether transmission is responsible for these differences.

Modelling the public health impact of male circumcision for HIV prevention in high prevalence areas in Africa (Article)

2007-03-13T00:00:00Z

Background: Recent clinical trials in Africa, in combination with several observational epidemiological studies, have provided evidence that male circumcision can reduce HIV female-to-male transmission risk by 60% or more. However, the public health impact of large-scale male circumcision programs for HIV prevention is unclear. Methods: Two mathematical models were examined to explore this issue: a random mixing model and a compartmental model that distinguishes risk groups associated with sex work. In the compartmental model, two scenarios were developed, one calculating HIV transmission and prevalence in a context similar to the country of Botswana, and one similar to Nyanza Province, in western Kenya. Results: In both models, male circumcision programs resulted in large and sustained declines in HIV prevalence over time among both men and women. Men benefited somewhat more than women, but prevalence among women was also reduced substantially. With 80% male circumcision uptake, the reductions in prevalence ranged from 45% to 67% in the two "countries", and with 50% uptake, from 25% to 41%. It would take over a decade for the intervention to reach its full effect. Conclusion: Large-scale uptake of male circumcision services in African countries with high HIV prevalence, and where male circumcision is not now routinely practised, could lead to substantial reductions in HIV transmission and prevalence over time among both men and women.

Impact of ivermectin on onchocerciasis transmission: assessing the empirical evidence that repeated ivermectin mass treatments may lead to elimination/eradication in West-Africa (Article)

2003-01-01T00:00:00Z

BACKGROUND: The Onchocerciasis Control Program (OCP) in West Africa has been closed down at the end of 2002. All subsequent control will be transferred to the participating countries and will almost entirely be based on periodic mass treatment with ivermectin. This makes the question whether elimination of infection or eradication of onchocerciasis can be achieved using this strategy of critical importance. This study was undertaken to explore this issue. METHODS: An empirical approach was adopted in which a comprehensive analysis was undertaken of available data on the impact of more than a decade of ivermectin treatment on onchocerciasis infection and transmission. Relevant entomological and epidemiological data from 14 river basins in the OCP and one basin in Cameroon were reviewed. Areas were distinguished by frequency of treatment (6-monthly or annually), endemicity level and additional control measures such as vector control. Assessment of results were in terms of epidemiological and entomological parameters, and as a measure of inputs, therapeutic and geographical coverage rates were used. RESULTS: In all of the river basins studied, ivermectin treatment sharply reduced prevalence and intensity of infection. Significant transmission, however, is still ongoing in some basins after 10-12 years of ivermectin treatment. In other basins, transmission may have been interrupted, but this needs to be confirmed by in-depth evaluations. In one mesoendemic basin, where 20 rounds of four-monthly treatment reduced prevalence of infection to levels as low as 2-3%, there was significant recrudescence of infection within a few years after interruption of treatment. CONCLUSIONS: Ivermectin treatment has been very successful in eliminating onchocerciasis as a public health problem. However, the results presented in this paper make it almost certain that repeated ivermectin mass treatment will not lead to the elimination of transmission of onchocerciasis from West Africa. Data on 6-monthly treatments are not sufficient to draw definitive conclusions.

Analysis of rate of change of IS6110 RFLP patterns of Mycobacterium tuberculosis based on serial patient isolates (Article)

1999-12-01T00:00:00Z

The rate of change of IS6110 restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis was determined in serial isolates from 544 patients. In 25 patients (4.6%), the RFLP patterns of the follow-up isolates differed from the initial isolates. Patients with different follow-up strains were less likely to cluster with patients whose strains had indistinguishable RFLP patterns. Changes in RFLP patterns were more common for persons with extrapulmonary disease and for those who had both pulmonary and extrapulmonary isolates. Based on serial isolates spanning for the most part <3 months, the half-life was extrapolated to be 3.2 years (95% confidence interval, 2.1-5.0). The main implication of this study is that the rate of change of IS6110-based RFLP of M. tuberculosis supports the use of IS6110 typing in epidemiologic studies of recent transmission of tuberculosis.