The overall objective of this research is to develop statistical methods for quantifying the effects of interventions to prevent infectious diseases. The main motivating examples are studies of vaccine effectiveness. Two particularly challenging problems in vaccine studies entail assessing (i) indirect effects of vaccination and (ii) vaccine effects on post-infection endpoints. Evaluating (i) is a non-standard problem because indirect effects measure the effect of vaccinating one individual on another individual's health outcome. Assessing (ii) is challenging because infected vaccinees may not be comparable to infected controls. This specific proposal is to adapt and develop modern causal inference methodology for use in evaluating (i) and (ii). Similar research will be conducted motivated by studies to prevent transmission of HIV from mother to child where issues similar to (ii) arise.
Specific Aim 1 is to develop statistical methods in causal inference with interference for application in evaluating direct, indirect, total, and overall vaccine effects. Areas of particular emphasis will be development of nonparametric tests and confidence intervals, incorporating baseline covariates, and analysis of data from observational studies. A motivating data set is from a trial of cholera vaccines in Bangladesh.
Specific Aim 2 is to develop exact statistical methods in causal inference with principal stratification for application in evaluating vaccine effects on post-infection endpoints. This research will focus on applying the ideas of principal stratification in the small sample setting under minimal assumptions. Comparisons will be conducted between the proposed methods and existing large-sample methods as well as traditional intent-to-treat approaches. The research for this aim is motivated by proof-of-concept clinical trials of vaccines where few events are expected.
Specific Aim 3 is to develop causal inference methodology to assess vaccine effects on infectiousness. This research will combine aspects of Aims 1 and 2 since studies to assess vaccine effects on infectiousness typically entail conditioning on infection of primary cases (Aim 2) and the vaccination status of the primary case can affect the infection outcome in exposed close contacts (Aim 1). Methods developed in this aims will be used to estimate the causal effect of pertussis vaccination on infectiousness using data from a study in Senegal.
Specific Aim 4 is to develop statistical methods for causal inference with principal stratification and competing risks. This research is motivated by studies to prevent postnatal mother-to-child transmission (MTCT) of HIV where HIV-free death and weaning are competing risks. In such studies, investigators are often interested in comparing intervention strategies conditional on survival to a certain time point such that this aim will utilize the principal stratification framework. The methods developed under this aim will be used to estimate the causal effect of antiretroviral therapy on MTCT using data from a recent study in Malawi. 1

Public Health Relevance

This statistical methods developed in this research will lead to improved estimation of the effects of interventions to prevent infectious diseases. Accurate and precise quantification of intervention effects are important in regulatory decisions and public health policy regarding infectious disease control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI085073-03
Application #
8197245
Study Section
Biostatistical Methods and Research Design Study Section (BMRD)
Program Officer
Gezmu, Misrak
Project Start
2009-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$314,812
Indirect Cost
$49,297
Name
University of North Carolina Chapel Hill
Department
Biostatistics & Other Math Sci
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Perez-Heydrich, Carolina; Hudgens, Michael G; Halloran, M Elizabeth et al. (2014) Assessing effects of cholera vaccination in the presence of interference. Biometrics 70:731-44
Liu, Lan; Hudgens, Michael G (2014) Large sample randomization inference of causal effects in the presence of interference. J Am Stat Assoc 109:288-301
Halloran, M Elizabeth; Hudgens, Michael G (2012) Causal inference for vaccine effects on infectiousness. Int J Biostat 8:
Cole, Stephen R; Hudgens, Michael G; Tien, Phyllis C et al. (2012) Marginal structural models for case-cohort study designs to estimate the association of antiretroviral therapy initiation with incident AIDS or death. Am J Epidemiol 175:381-90
Nolen, Tracy L; Hudgens, Michael G (2011) Randomization-Based Inference within Principal Strata. J Am Stat Assoc 106:581-593