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Understanding vaccine effects on post-infection outcomes is critical for evaluating the full value proposition of a vaccine. However, defining appropriate causal effects on such outcomes is challenging because infection is affected by…

Cluster-randomized trials are often conducted to assess vaccine effects. Defining estimands of interest before conducting a trial is integral to the alignment between a study's objectives and the data to be collected and analyzed. This…

Methodology · Statistics 2019-10-10 Kayla W. Kilpatrick , Michael G. Hudgens , M. Elizabeth Halloran

Real-world vaccine effectiveness has increasingly been studied using matching-based approaches, particularly in observational cohort studies following the target trial emulation framework. Although matching is appealing in its simplicity,…

Methodology · Statistics 2026-04-07 Emily Wu , Elizabeth Rogawski McQuade , Mats Stensrud , Razieh Nabi , David Benkeser

We review vaccine efficacy (VE) estimands for susceptibility in individual randomized trials with natural (unmeasured) exposure, where individual responses are measured as time from vaccination until an event (e.g., disease from the…

Methodology · Statistics 2026-01-27 Michael P. Fay , Dean Follmann , Bruce J. Swihart , Lauren E. Dang

Many research questions involve time-to-event outcomes that can be prevented from occurring due to competing events. In these settings, we must be careful about the causal interpretation of classical statistical estimands. In particular,…

Methodology · Statistics 2020-09-01 Torben Martinussen , Mats Julius Stensrud

Vaccines not only directly protect vaccinated individuals but also contribute to protect the entire population via indirect herd-immunity benefits. However, researchers have long struggled to quantify these indirect effects at the…

Populations and Evolution · Quantitative Biology 2025-08-13 Lixin Lin , Haydar Demirhan , Peter Eizenberg , James M. Trauer , Lewi Stone

Causal mediation analysis provides techniques for defining and estimating effects that may be endowed with mechanistic interpretations. With many scientific investigations seeking to address mechanistic questions, causal direct and indirect…

Vaccination campaigns have both direct and indirect effects that act to control an infectious disease as it spreads through a population. Indirect effects arise when vaccinated individuals block disease transmission in any infection chains…

Populations and Evolution · Quantitative Biology 2024-05-08 Lixin Lin , Homayoun Hamedmoghadam , Robert Shorten , Lewi Stone

The interpretation of vaccine efficacy estimands is subtle, even in randomized trials designed to quantify immunological effects of vaccination. In this article, we introduce terminology to distinguish between different vaccine efficacy…

Applications · Statistics 2023-11-15 Mats Stensrud , Daniel Nevo , Uri Obolski

Results from randomized controlled trials (RCTs) help determine vaccination strategies and related public health policies. However, defining and identifying estimands that can guide policies in infectious disease settings is difficult, even…

Methodology · Statistics 2023-01-24 Mats J. Stensrud , Louisa H. Smith

Vaccine randomized trials are typically designed to be blinded, ensuring that the estimated vaccine efficacy (VE) reflects the immunological effect of the vaccine. When blinding is broken, however, the estimated VE reflects not only the…

Methodology · Statistics 2026-03-12 Rachel Axelrod , Uri Obolski , Daniel Nevo

Inferring causal effects from an observational study is challenging because participants are not randomized to treatment. Observational studies in infectious disease research present the additional challenge that one participant's treatment…

Methodology · Statistics 2020-12-25 Brian G. Barkley , Michael G. Hudgens , John D. Clemens , Mohammad Ali , Michael E. Emch

Understanding how the causal effect of a treatment evolves over time, including the potential for waning, is important for informed decisions on treatment discontinuation or repetition. For example, waning vaccine protection influences…

Methodology · Statistics 2025-11-25 Eni Musta , Joris Mooij

Defining and identifying causal intervention effects for transmissible infectious disease outcomes is challenging because a treatment -- such as a vaccine -- given to one individual may affect the infection outcomes of others.…

Applications · Statistics 2019-12-11 Xiaoxuan Cai , Wen Wei Loh , Forrest W. Crawford

Many interventions are both beneficial to initiate and harmful to stop. Traditionally, to determine whether to deploy that intervention in a time-limited way depends on if, on average, the increase in the benefits of starting it outweigh…

Pathogens usually exist in heterogeneous variants, like subtypes and strains. Quantifying treatment effects on the different variants is important for guiding prevention policies and treatment development. Here we ground analyses of…

Applications · Statistics 2024-08-15 Gellert Perenyi , Mats J. Stensrud

In studies of discrimination, researchers often seek to estimate a causal effect of race or gender on outcomes. For example, in the criminal justice context, one might ask whether arrested individuals would have been subsequently charged or…

Methodology · Statistics 2022-04-06 Johann Gaebler , William Cai , Guillaume Basse , Ravi Shroff , Sharad Goel , Jennifer Hill

Knowing the true effect size of clinical interventions in randomised clinical trials is key to informing the public health policies. Vaccine efficacy is defined in terms of the relative risk or the ratio of two disease risks. However, only…

Methodology · Statistics 2021-02-03 Yasin Memari

Defining a causal estimand for a longitudinal outcome truncated by death is challenging, because the outcome may be undefined at the end of follow-up. Although a range of estimands and several estimators have been proposed, guidance on the…

Methodology · Statistics 2026-04-30 Juliette Ortholand , Young Lee , Marie-Abele C Bind

In settings where units' outcomes are affected by others' treatments, there has been a proliferation of ways to quantify effects of treatments on outcomes, including via indirect exposure to other units' treatments. Here we consider two…

Methodology · Statistics 2026-03-10 Sahil Loomba , Dean Eckles
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