Heather J. Whitaker

The methodology of self-controlled case series studies.

The self-controlled case series method is increasingly being used in pharmacoepidemiology, particularly in vaccine safety studies. This method is typically used to evaluate the association between a transient exposure and an acute event, using only cases. We present both parametric and semiparametric models using a motivating example on MMR vaccine and bleeding disorders. We briefly describe approaches for interferent events and a sequential version of the method for prospective surveillance of drug safety. The efficiency of the self-controlled case series method is compared to the that of cohort and case control studies. Some further extensions, to long or indefinite exposures and to bivariate counts, are described.

Relation of Trihalomethane Concentrations in Public Water Supplies to Stillbirth and Birth Weight in Three Water Regions in England

We investigated the association between total trihalomethanes (TTHMs) and risk of stillbirth and low and very low birth weight in three water regions in England, 1992–1998; associations with individual trihalomethanes (THMs) were also examined. Modeled estimates of quarterly TTHM concentrations in water zones, categorized as low (< 30 μg/L), medium (30–59 μg/L), or high (≥60 μg/L), were linked to approximately 1 million routine birth and stillbirth records using maternal residence at time of birth. In one region, where there was a positive socioeconomic deprivation gradient across exposure categories, there was also a positive, significant association of TTHM with risk of stillbirth and low and very low birth weight. Overall summary estimates across the three regions using a random-effects model to allow for between-region heterogeneity in exposure effects showed small excess risks in areas with high TTHM concentrations for stillbirths [odds ratio (OR) = 1.11; 95% confidence interval (CI), 1.00–1.23), low birth weight (OR = 1.09; 95% CI, 0.93–1.27), and very low birth weight (OR = 1.05; 95% CI, 0.82–1.34). Among the individual THMs, chloroform showed a similar pattern of risk as TTHM, but no association was found with concentrations of bromodichloromethane or total brominated THMs. Our findings overall suggest a significant association of stillbirths with maternal residence in areas with high TTHM exposure. Further work is needed looking at cause-specific stillbirths and effects of other disinfection by-products and to help differentiate between alternative (noncausal) explanations and those that may derive from the water supply.

Case series analysis for censored, perturbed, or curtailed post-event exposures

A new method is developed for analyzing case series data in situations where occurrence of the event censors, curtails, or otherwise affects post-event exposures. Unbiased estimating equations derived from the self-controlled case series model are adapted to allow for exposures whose occurrence or observation is influenced by the event. The method applies to transient point exposures and rare nonrecurrent events. Asymptotic efficiency is studied in some special cases. A computational scheme based on a pseudo-likelihood is proposed to make the computations feasible in complex models. Simulations, a validation study, and 2 applications are described.

Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding?

Background:  A 15‐fold increased risk of gastrointestinal bleeding has been reported with concurrent use of selective serotonin reuptake inhibitors and non‐steroidal anti‐inflammatory drugs. Recent guidance cautions against concurrent prescription, particularly in older people.

Influenza Infection and Risk of Acute Myocardial Infarction in England and Wales: A CALIBER Self-Controlled Case Series Study

Background. An association between infections and vascular events has been observed, but the specific effect of influenza and influenza-like illnesses on triggering acute myocardial infarction (AMI) is unclear. Methods. Episodes of first AMI from 1 January 2003 through 31 July 2009 were identified using linked anonymized electronic medical records from the Myocardial Ischaemia National Audit Project and the General Practice Research Database. Self-controlled case series analysis was used to investigate AMI risks after consultation for acute respiratory infection. Infections were stratified by influenza virus circulation, diagnostic code, and vaccination status to assess whether influenza was more likely than other infections to trigger AMI. Results. Of 22 024 patients with acute coronary syndrome, 11 208 met the criterion of having had their first AMI at the age of ≥40 years, and 3927 had also consulted for acute respiratory infection. AMI risks were significantly raised during days 1–3 after acute respiratory infection (incidence ratio, 4.19 [95% confidence interval, 3.18–5.53], with the effect tapering over time. The effect was greatest in those aged ≥80 years (P = .023). Infections occurring when influenza was circulating and those coded as influenza-like illness were associated with consistently higher incidence ratios for AMI (P = .012). Conclusions. Influenza and other acute respiratory infections can act as a trigger for AMI. This effect may be stronger for influenza than for other infections. Clinical trials registration. NCT01106196.

Use of the self-controlled case series method in vaccine safety studies : review and recommendations for best practice

The self-controlled case-series method was originally developed to investigate potential associations between vaccines and adverse events, and is now commonly used for this purpose. This study reviews applications of the method to vaccine safety investigations in the period 1995-2010. In total, 40 studies were reviewed. The application of the self-controlled case-series method in these studies is critically examined, with particular reference to the definition of observation and risk periods, control of confounders, assumptions and potential biases, methodological and presentation issues, power and sample size, and software. Comparisons with other study designs undertaken in the papers reviewed are also highlighted. Some recommendations are presented, with the emphasis on promoting good practice.

Use of routinely collected data on trihalomethane in drinking water for epidemiological purposes

OBJECTIVES To explore the use of routinely collected trihalomethane (THM) measurements for epidemiological studies. Recently there has been interest in the relation between byproducts of disinfection of public drinking water and certain adverse reproductive outcomes, including stillbirth, congenital malformations, and low birth weight. METHOD Five years of THM readings (1992–6), collected for compliance with statutory limits, were analysed. One water company in the north west of England, divided into 288 water zones, provided 15 984 observations for statistical analysis. On average each zone was sampled 11.1 times a year. Five year, annual, monthly, and seasonal variation in THMs were examined as well as the variability within and between zones. RESULTS Between 1992 and 1996 the total THM (TTHM) annual zone means were less than half the statutory concentration, at approximately 46 μg/l. Differences in annual water zone means were within 7%. Over the study period, the maximum water zone mean fell from 142.2 to 88.1 μg/l. Mean annual concentrations for individual THMs (μg/l) were 36.6, 8.0, and 2.8 for chloroform, bromodichloromethane (BDCM), and dibromochloromethane (DBCM) respectively. Bromoform data were not analysed, because a high proportion of the data were below the detection limit. The correlation between chloroform and TTHM was 0.98, between BDCM and TTHM 0.62, and between DBCM and TTHM −0.09. Between zone variation was larger than within zone variation for chloroform and BDCM, but not for DBCM. There was only little seasonal variation (<3%). Monthly variation was found although there were no consistent trends within years. CONCLUSION In an area where the TTHM concentrations were less than half the statutory limit (48 μg/l) chloroform formed a high proportion of TTHM. The results of the correlation analysis suggest that TTHM concentrations provided a good indication of chloroform concentrations, a reasonable indication of BDCM concentrations, but no indication of DBCM. Zone means were similar over the years, but the maximum concentrations reduced considerably, which suggests that successful improvements in treatment have been made to reduce high TTHM concentrations in the area. For chloroform and BDCM, the main THMs, the component between water zones was greater than variation within water zones and explained most of the overall exposure variation. Variation between months and seasons was low and showed no clear trends within years. The results indicate that routinely collected data can be used to obtain exposure estimates for epidemiological studies at a small area level.

Self-Controlled Case Series Analysis With Event-Dependent Observation Periods

The self-controlled case series method may be used to study the association between a time-varying exposure and a health event. It is based only on cases, and it controls for fixed confounders. Exposure and event histories are collected for each case over a predefined observation period. The method requires that observation periods should be independent of event times. This requirement is violated when events increase the mortality rate, since censoring of the observation periods is then event dependent. In this article, the case series method for rare nonrecurrent events is extended to remove this independence assumption, thus introducing an additional term in the likelihood that depends on the censoring process. In order to remain within the case series framework in which only cases are sampled, the model is reparameterized so that this additional term becomes estimable from the distribution of intervals from event to end of observation. The exposure effect of primary interest may be estimated unbiasedly. The age effect, however, takes on a new interpretation, incorporating the effect of censoring. The model may be fitted in standard loglinear modeling software; this yields conservative standard errors. We describe a detailed application to the study of antipsychotics and stroke. The estimates obtained from the standard case series model are shown to be biased when event-dependent observation periods are ignored. When they are allowed for, antipsychotic use remains strongly positively associated with stroke in patients with dementia, but not in patients without dementia. Two detailed simulation studies are included as Supplemental Material.

The self controlled case series method.

A way to study the relation between antipsychotics and stroke

Contact Surface Models for Infectious Diseases: Estimation From Serologic Survey Data

Controlling of infectious diseases requires information about the rates at which individuals make contact. We propose a novel approach to modeling contact rates via a continuous contact surface. This provides a more realistic and flexible representation of contact rates than currently used methods. Our approach allows modeling of sources of heterogeneity due to age, individual effects, and gender. The models are fitted to serologic survey data by maximum likelihood. This involves solving an integral equation linking the contact surface to the infection hazards. The method is illustrated with two datasets, on mumps and rubella and on Epstein–Barr virus and herpes simplex virus type 1 infection. The advantages and shortcomings of the method, particularly the identifiability of the contact surface, are discussed.