Dynamic inference in general nested case‐control designs

Nested case‐control designs are attractive in studies with a time‐to‐event endpoint if the outcome is rare or if interest lies in evaluating expensive covariates. The appeal is that these designs restrict to small subsets of all patients at risk just prior to the observed event times. Only these small subsets need to be evaluated. Typically, the controls are selected at random and methods for time‐simultaneous inference have been proposed in the literature. However, the martingale structure behind nested case‐control designs allows for more powerful and flexible non‐standard sampling designs. We exploit that structure to find simultaneous confidence bands based on wild bootstrap resampling procedures within this general class of designs. We show in a simulation study that the intended coverage probability is obtained for confidence bands for cumulative baseline hazard functions. We apply our methods to observational data about hospital‐acquired infections.     

Global DNA hypomethylation is associated with NTD‐affected pregnancy: A case‐control study

BACKGROUND: Neural tube defects are severe, common birth defects that result from failure of neural tube closure. They are considered to be a multifactorial disorder, and our knowledge of causal mechanisms remains limited. We hypothesized that abnormal DNA methylation occurs in NTD‐affected fetuses. The correlations of global DNA methylation levels with complexity of NTDs and known risk factors of NTDs, MTHFR genotype and fever, were analyzed. METHODS: A hospital‐based case‐control study was performed. Epidemiologic data, pathologic diagnosis, and methylenetetrahydrofolate reductase (MTHFR) genotype analysis were completed. Array comparative genomic hybridization was used to exclude cytogenetic abnormalities. Global DNA methylation statuses were determined for both brain and skin tissue. RESULTS: Sixty‐five NTD‐affected fetuses and 65 normal controls matched for gestational and maternal ages were collected. In brain tissue, global DNA methylation levels were significantly decreased in cases compared with controls (4.12 vs. 4.99%; p < 0.001). DNA hypomethylation (<4.35%) resulted in a significant 5.736‐fold increased risk for NTDs (95% confidence interval, 1.731–19.009; p = 0.004). Nonisolated NTDs had lower levels of global DNA methylation than did isolated NTDs (3.77 vs. 4.70%; p = 0.022). After stratifying subjects by MTHFR genotype, we observed a skewed distribution of global DNA methylation levels. For genotype C/C, global DNA methylation status was the same in the two groups (4.51 vs. 4.72%; p = 0.687). For T/T, cases had significantly lower global methylation levels than did controls (5.23 vs. 3.79%; p < 0.001). CONCLUSIONS: Global DNA hypomethylation in fetal brain tissue was associated with NTD‐affected pregnancy. DNA methylation levels were correlated with NTD complexity. The MTHFR genotype contributed to global DNA hypomethylation. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.     

Evaluating the Predictive Value of Biomarkers with Stratified Case‐Cohort Design

Summary Identification of novel biomarkers for risk assessment is important for both effective disease prevention and optimal treatment recommendation. Discovery relies on the precious yet limited resource of stored biological samples from large prospective cohort studies. Case‐cohort sampling design provides a cost‐effective tool in the context of biomarker evaluation, especially when the clinical condition of interest is rare. Existing statistical methods focus on making efficient inference on relative hazard parameters from the Cox regression model. Drawing on recent theoretical development on the weighted likelihood for semiparametric models under two‐phase studies ( Breslow and Wellner, 2007 ), we propose statistical methods to evaluate accuracy and predictiveness of a risk prediction biomarker, with censored time‐to‐event outcome under stratified case‐cohort sampling. We consider nonparametric methods and a semiparametric method. We derive large sample properties of proposed estimators and evaluate their finite sample performance using numerical studies. We illustrate new procedures using data from Framingham Offspring Study to evaluate the accuracy of a recently developed risk score incorporating biomarker information for predicting cardiovascular disease.     

Analysis of continuous covariables in epidemiological studies: Dose‐response modelling and confounder adjustment

The analysis of continuous covariables with regression models commonly used in epidemiology are reviewed and compared. While some methods have been in use for decades, other more recent methods are not yet common or have not yet been formally described. It is shown that recently developed methods such as fractional polynomials and others are very useful to obtain dose‐response curves or for confounder adjustment. Different methods have their specific merits making it difficult to give general recommendations. The application of some of the methods is demonstrated with real data examples from epidemiological studies. Some suggestions for practical strategies in analysing continuous covariables are given.     

Maternal factors in the origin of isolated oesophageal atresia: A population‐based case–control study

Background: In most patients affected by isolated oesophageal atresia (IOA) the etiology is largely unknown. Thus, the aim of this study was to analyze potential risk factors in mothers. Methods: The study samples included 221 cases with IOA, 356 matched and 38,151 population controls without any defect in the population‐based dataset of the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980 to 1996. Only those exposures were evaluated that were medically recorded in prenatal maternity logbooks during the critical period of IOA. Results: The findings of this case–control study suggested that the mothers of cases with IOA had a higher proportion of first delivery and lower socioeconomic status. Acute respiratory diseases (odds ratio [OR] 95% confidence interval [CI], 3.8, 1.8–8.1) and essential hypertension treated with nifedipine (OR 95% CI, 3.8, 1.7–8.7) in the mothers of cases associated with a higher risk for IOA in their children. Conclusion: First delivery, lower socioeconomic status, acute respiratory diseases and essential hypertension treated with nifedipine in the mothers may associate with a higher risk for IOA in their children. Birth Defects Research (Part A) 103:804–813, 2015. © 2015 Wiley Periodicals, Inc.     

Time‐kill studies with a ceftazidime‐treated mixed culture consisting of Pseudomonas aeruginosa,Burkholderia cepacia and Staphylococcus aureus

So far, time‐kill analyses were mostly done with isolates of bacteria. Here, we used a mixed culture consisting of Pseudomonas aeruginosa, Burkholderia cepacia, and Staphylococcus aureus to investigate the impact of ceftazidime treatment. Following an earlier study with the same strains, the influence of different ceftazidime concentrations as well as repeated ceftazidime treatment was tested. In order to assess the influence of substrate competition, which might be relevant to interpret mixed‐culture time‐kill studies, the major metabolites of the chemically defined cultivation medium were measured additionally. Time‐kill experiments were conducted in shake flasks with the chemically defined and modified medium M199. The cell concentration in the mixed culture was analyzed on the single‐species level using a quantitative terminal restriction fragment (qT‐RFLP) method. The amount of gluconate produced in mixed culture positively correlated with increased ceftazidime concentrations (5, 15, 30, 60 mg/L). Burkholderia cepacia developed resistance after repeated ceftazidime addition and reached the highest cell concentration of the three cultivated strains. Pseudomonas aeruginosa showed a pronounced regrowth phase after removal of ceftazidime, while growth of S. aureus was not influenced by medium exchange. In conclusion, growth of B. cepacia was dominant in the ceftazidime‐treated mixed culture over the observed time range, due to low susceptibility against ceftazidime as well as advantages in substrate usage.