Comparison of nested case-control and survival analysis methodologies for analysis of time-dependent exposure

BACKGROUND: Epidemiological studies of exposures that vary with time require an additional level of methodological complexity to account for the time-dependence of exposure. This study compares a nested case-control approach for the study of time-dependent exposure with cohort analysis using Cox regression including time-dependent covariates. METHODS: A cohort of 1340 subjects with four fixed and seven time-dependent covariates was used for this study. Nested case-control analyses were repeated 100 times for each of 4, 8, 16, 32, and 64 controls per case, and point estimates were compared to those obtained using Cox regression on the full cohort. Computational efficiencies were evaluated by comparing central processing unit times required for analysis of the cohort at sizes 1, 2, 4, 8, 16, and 32 times its initial size. RESULTS: Nested case-control analyses yielded results that were similar to results of Cox regression on the full cohort. Cox regression was found to be 125 times slower than the nested case-control approach (using four controls per case). CONCLUSIONS: The nested case-control approach is a useful alternative for cohort analysis when studying time-dependent exposures. Its superior computational efficiency may be particularly useful when studying rare outcomes in databases, where the ability to analyze larger sample sizes can improve the power of the study

The incidence of first-episode schizophrenia-spectrum psychosis in adolescents and young adults in Montreal: An estimate from an administrative claims database

Objective: There has been increasing interest in the psychiatric literature on research and service delivery focused on first-episode psychosis (FEP), and accurate information on the incidence of FEP is crucial for the development of services targeting patients in the early stages of illness. We sought to obtain a population-based estimate of the incidence of first-episode schizophrenia-spectrum psychosis (SSP) among adolescents and young adults in Montreal. Methods: Population-based administrative data from physician billings, hospitalizations, pharmacies, and public health clinics were used to estimate the incidence of first-episode SSP in Montreal. A 3-year period (2004-2006) was used to identify patients with SSP aged 14 to 25 years. We used a 4- to 6-year clearance period to remove patients with a history of any psychotic disorder or prescription for an antipsychotic. Results: We identified 456 patients with SSP, yielding a standardized annual incidence of 82.9 per 100 000 for males (95% CI 73.7 to 92.1), and 32.2 per 100 000 for females (95% CI 26.7 to 37.8). Using ecologic indicators of material and social deprivation, we found a higher-incidence proportion of SSP among people living in the most deprived areas, relative to people living in the least deprived areas. Conclusions: Clinical samples obtained from psychiatric services are unlikely to capture all treatment-seeking patients, and epidemiologic surveys have resource-intensive constraints, making this approach challenging for rare forms of psychopathology; therefore, population-based administrative data may be a useful tool for studying the frequency of psychotic disorders

A review of spline function procedures in R

Background: With progress on both the theoretical and the computational fronts the use of spline modelling has become an established tool in statistical regression analysis. An important issue in spline modelling is the availability of user friendly, well documented software packages. Following the idea of the STRengthening Analytical Thinking for Observational Studies initiative to provide users with guidance documents on the application of statistical methods in observational research, the aim of this article is to provide an overview of the most widely used spline-based techniques and their implementation in R. Methods: In this work, we focus on the R Language for Statistical Computing which has become a hugely popular statistics software. We identified a set of packages that include functions for spline modelling within a regression framework. Using simulated and real data we provide an introduction to spline modelling and an overview of the most popular spline functions. Results: We present a series of simple scenarios of univariate data, where different basis functions are used to identify the correct functional form of an independent variable. Even in simple data, using routines from different packages would lead to different results. Conclusions: This work illustrate challenges that an analyst faces when working with data. Most differences can be attributed to the choice of hyper-parameters rather than the basis used. In fact an experienced user will know how to obtain a reasonable outcome, regardless of the type of spline used. However, many analysts do not have sufficient knowledge to use these powerful tools adequately and will need more guidance

Analysis of time-to-event for observational studies: Guidance to the use of intensity models

This paper provides guidance for researchers with some mathematical background on the conduct of time-to-event analysis in observational studies based on intensity (hazard) models. Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing time-dependent covariates. We discuss prediction based on hazard models and difficulties when attempting to draw proper causal conclusions from such models. Finally, we present a series of examples where the methods and check lists are exemplified. Computational details and implementation using the freely available R software are documented in Supplementary Material. The paper was prepared as part of the STRATOS initiative.Comment: 28 pages, 12 figures. For associated Supplementary material, see http://publicifsv.sund.ku.dk/~pka/STRATOSTG8

Saguenay Youth Study : a multi-generational approach to studying virtual trajectories of the brain and cardio-metabolic health

This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents

Prenatal exposure to maternal cigarette smoking, amygdala volume, and fat intake in adolescence

Context : Prenatal exposure to maternal cigarette smoking is a well-established risk factor for obesity, but the underlying mechanisms are not known. Preference for fatty foods, regulated in part by the brain reward system, may contribute to the development of obesity. Objective : To examine whether prenatal exposure to maternal cigarette smoking is associated with enhanced fat intake and risk for obesity, and whether these associations may be related to subtle structural variations in brain regions involved in reward processing. Design : Cross-sectional study of a population-based cohort. Setting : The Saguenay Youth Study, Quebec, Canada. Participants : A total of 378 adolescents (aged 13 to 19 years; Tanner stage 4 and 5 of sexual maturation), half of whom were exposed prenatally to maternal cigarette smoking (mean [SD], 11.1 [6.8] cigarettes/d). Main Outcome Measures : Fat intake was assessed with a 24-hour food recall (percentage of energy intake consumed as fat). Body adiposity was measured with anthropometry and multifrequency bioimpedance. Volumes of key brain structures involved in reward processing, namely the amygdala, nucleus accumbens, and orbitofrontal cortex, were measured with magnetic resonance imaging. Results : Exposed vs nonexposed subjects exhibited a higher total body fat (by approximately 1.7 kg; P = .009) and fat intake (by 2.7%; P = .001). They also exhibited a lower volume of the amygdala (by 95 mm3; P < .001) but not of the other 2 brain structures. Consistent with its possible role in limiting fat intake, amygdala volume correlated inversely with fat intake (r = −0.15; P = .006). Conclusions : Prenatal exposure to maternal cigarette smoking may promote obesity by enhancing dietary preference for fat, and this effect may be mediated in part through subtle structural variations in the amygdala

Using linked administrative, clinical and primary data to explore the impact of and factors associated with non-adherence to in-hospital medication changes in 30-days post hospital discharge

Introduction Identifying strategies to prevent hospital readmissions remains elusive since the reasons for returning to hospital can include a number of interlinked patient, health provider and system level factors. The impact of patient medications are of significant interest since a large proportion of re-admissions are related to adverse drug events. Objectives and Approach The objective was to determine which factors are associated with non-adherence to in-hospital medications and the impact of non-adherence on re-hospitalization, emergency department visits and death in the 30-days post discharge for patients admitted at two tertiary care academic hospitals in Montreal, Quebec between October 2014 and May 2016. Non-adherence to in-hospital changes was measured by comparing patient discharge prescriptions (patient chart) to medications filled in community 30-days post-discharge (dispensing data) and included i) community medications stopped in-hospital and filled post-discharge, ii) community medications modified in-hospital but not filled at the modified daily-dose, and iii) new medications not filled post-discharge. Results Among 2,895 included patients, mean age was 70 (SD 15) and 58% were males. A median of 4 in-hospital medication changes were made (IQR:3-6) and 54% of patients were non-adherent to at least one change. Multivariable Poisson models suggested that the most important factor associated with the number of new medications not filled post discharge was out of pocket cost; for each additional $10 increase in costs there was a 20% increase in the number of new medications not filled. Multivariable time-varying Cox models suggested that in patients who filled medications post-discharge, selective non-adherence to new and discontinued medications reduced the risk adverse health outcomes in 30-days, while not filling any medications post discharge more than doubled the risk of an adverse event in 30-days. Conclusion/Implications Not only did the majority of patients not follow all medication changes that were made during hospitalization, the extent to which this occurred significantly impacted the risk of hospital re-admissions and ED visits. Policy and patient level interventions should be developed specifically targeting barriers for adherence to medication changes

Validation of population-based disease simulation models: a review of concepts and methods

Abstract Background Computer simulation models are used increasingly to support public health research and policy, but questions about their quality persist. The purpose of this article is to review the principles and methods for validation of population-based disease simulation models. Methods We developed a comprehensive framework for validating population-based chronic disease simulation models and used this framework in a review of published model validation guidelines. Based on the review, we formulated a set of recommendations for gathering evidence of model credibility. Results Evidence of model credibility derives from examining: 1) the process of model development, 2) the performance of a model, and 3) the quality of decisions based on the model. Many important issues in model validation are insufficiently addressed by current guidelines. These issues include a detailed evaluation of different data sources, graphical representation of models, computer programming, model calibration, between-model comparisons, sensitivity analysis, and predictive validity. The role of external data in model validation depends on the purpose of the model (e.g., decision analysis versus prediction). More research is needed on the methods of comparing the quality of decisions based on different models. Conclusion As the role of simulation modeling in population health is increasing and models are becoming more complex, there is a need for further improvements in model validation methodology and common standards for evaluating model credibility