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Concept: Nested case-control study


To investigate the association between use of combined oral contraceptives and risk of venous thromboembolism, taking the type of progestogen into account.

Concepts: Combined oral contraceptive pill, The Association, Case-control study, Nested case-control study


Standard use of Cox regression requires collection of covariate information for all individuals in a cohort even when only a small fraction of them experiences the event of interest (fail). This may be very expensive for large cohorts. Further in biomarker studies, it will imply a waste of valuable biological material that one may want to save for future studies. A nested case-control study offers a useful alternative. For this design, covariate information is only needed for the failing individuals (cases) and a sample of controls selected from the cases' at-risk sets. Methods based on martingale residuals are useful for checking the fit of Cox’s regression model for cohort data. But similar methods have so far not been developed for nested case-control data. In this article, it is described how one may define martingale residuals for nested case-control data, and it is shown how plots and tests based on cumulative sums of martingale residuals may be used to check model fit. The plots and tests may be obtained using available software.

Concepts: Regression analysis, Cohort study, Experimental design, Epidemiology, Confounding, Case-control study, Study design, Nested case-control study



In epidemiological cohorts, there is an increased interest for the implementation of biobanks. The potential role of biological determinants of diseases needs to be investigated before the onset of the event of interest in order to limit the problems encountered when examining biological determinants in classical case-control studies. Biobank is now a very sophisticated system that consists of a programmed storage of biological material and related data. Our aim in this paper is to document how biobank constitution is useful for studying biological determinants of aging and to give some indications on methodological issues that can be helpful to optimize the constitution and use of biobanks in aging cohorts. Optimization of sampling through two-phase designs (nested case control or case-cohort studies) allows better efficiency. These elements are, for most of them, not specific to aging populations but are useful more generally for the epidemiology of chronic diseases. Our purpose will be illustrated with some examples and results obtained in an ongoing aging cohort, the Three-City Study.

Concepts: Medicine, Experimental design, Epidemiology, Biology, Demography, Case-control study, Study design, Nested case-control study


Background. The results obtained from various point-of-care (POC) test devices for estimating C-reactive protein (CRP) levels in a laboratory setting differ when compared to a laboratory reference test. We aimed to determine whether such differences meaningfully affect the accuracy and added diagnostic value in predicting radiographic pneumonia in adults presenting with acute cough in primary care. Methods. A nested case control study of adult patients presenting with acute cough in 12 different European countries (the Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe [GRACE] Network). Venous blood samples from 100 patients with and 100 patients without pneumonia were tested with five different POC CRP tests and a laboratory analyzer. Single test accuracy values and the added value of CRP to symptoms and signs were calculated. Results. Single test accuracy values showed similar results for all five POC CRP tests and the laboratory analyzer. The area under the curve of the different POC CRP tests and the laboratory analyzer (range 0.79-0.80) were all comparable and higher than the clinical model without CRP (0.70). Multivariable odds ratios were the same (1.2) for all CRP tests. Conclusions. Five POC CRP test devices and the laboratory analyzer performed with similar accuracy in detecting pneumonia both as single test, and when used in addition to clinical findings. Variability in results obtained from standard CRP laboratory and POC test devices do not translate into clinically relevant differences when used for prediction of pneumonia in patients with acute cough in primary care.

Concepts: Experimental design, Epidemiology, Value added, Confounding, Case-control study, Study design, C-reactive protein, Nested case-control study


In a nested case-control study, controls are selected for each case from the individuals who are at risk at the time at which the case occurs. We say that the controls are matched on study time. To adjust for possible confounding, it is common to match on other variables as well. The standard analysis of nested case-control data is based on a partial likelihood which compares the covariates of each case to those of its matched controls. It has been suggested that one may break the matching of nested case-control data and analyse them as case-cohort data using an inverse probability weighted (IPW) pseudo likelihood. Further, when some covariates are available for all individuals in the cohort, multiple imputation (MI) makes it possible to use all available data in the cohort. In the paper we review the standard method and the IPW and MI approaches, and compare their performance using simulations that cover a range of scenarios, including one and two endpoints.

Concepts: Experimental design, Epidemiology, Data analysis, Confounding, Case-control study, Study design, Match, Nested case-control study


This study explores the risk factors for low birth weight (LBW) in an urban Indian setting by using a nested case-control design. Information on potential risk factors was sought from 384 pregnant women attending an antenatal clinic, and they were followed until birth. Based on birth weight, the babies of these women were categorized as cases or controls. Bivariate analyses between each risk factor and birth weight showed an unadjusted significant association (P < .05) for maternal age ≤20 years, antenatal clinic registration after the first trimester, ≤5 antenatal visits, and <80% of the recommended dietary allowance (RDA) for calories and proteins. Multiple logistic regression analysis showed an adjusted significant association for calorie intake <80% RDA (P < .048), low zinc intake (P < .001), and ≤5 antenatal visits (P < .001). This study emphasizes the continuing importance of timely and regular antenatal visits and intake of appropriate amount of calories. The role of zinc as a risk factor for LBW warrants further research.

Concepts: Regression analysis, Logistic regression, Pregnancy, Childbirth, Epidemiology, Obstetrics, Case-control study, Nested case-control study


One of the main perceived advantages of using a case-cohort design compared with a nested case-control design in an epidemiologic study is the ability to evaluate with the same subcohort outcomes other than the primary outcome of interest. In this paper, we show that valid inferences about secondary outcomes can also be achieved in nested case-control studies by using the inclusion probability weighting method in combination with an approximate jackknife standard error that can be computed using existing software. Simulation studies demonstrate that when the sample size is sufficient, this approach yields valid type 1 error and coverage rates for the analysis of secondary outcomes in nested case-control designs. Interestingly, the statistical power of the nested case-control design was comparable with that of the case-cohort design when the primary and secondary outcomes were positively correlated. The proposed method is illustrated with the data from a cohort in Cardiovascular Health Study to study the association of C-reactive protein levels and the incidence of congestive heart failure. Copyright © 2014 John Wiley & Sons, Ltd.

Concepts: Experimental design, Epidemiology, Statistics, Sample size, Case-control study, Study design, C-reactive protein, Nested case-control study


Nested case-control designs are inevitably less efficient than full cohort designs, and it is important to use available information as efficiently as possible. Reuse of controls by inverse probability weighting may be one way to obtain efficiency improvements, and it can be particularly advantageous when two or more endpoints are analyzed in the same cohort. The controls in a nested case-control design are often matched on additional factors than at risk status, and this should be taken into account when reusing controls. Although some studies have suggested methods for handling additional matching, a thorough investigation of how this affects parameter estimates and weights is lacking. Our aim is to provide such a discussion to help developing guidelines for practitioners. We demonstrate that it is important to adjust for the matching variables in regression analyses when the matching is broken. We present three types of estimators for the inverse sampling probabilities accounting for additional matching. One of these estimators was somewhat biased when the cases and controls were matched very closely. We investigated how additional matching affected estimates of interest, with varying degree of association between the matching variables and exposure/outcome. Strong associations introduced only a small bias when the matching variables were properly adjusted for. Sometimes, exposure variables, for example, blood samples, are analyzed in batches. Rather, strong batch effects had to be present before this introduced much bias when the matching was broken. All simulations are based on a study of prostate cancer and vitamin D. Copyright © 2013 John Wiley & Sons, Ltd.

Concepts: Experimental design, Epidemiology, Cancer, Estimator, Prostate cancer, Case-control study, Study design, Nested case-control study


To evaluate occurrence of adverse maternal and perinatal outcomes with different thresholds of proteinuria (300-499mg and ≥500mg/24 hours) in pre-eclamptic women, comparing outcomes against women with chronic and gestational hypertension.

Concepts: Experimental design, Hypertension, Obstetrics, 2007 albums, Thresholds, Threshold, Pre-eclampsia, Nested case-control study