Assessing Heterogeneity of Treatment Effects in Observational Studies.

Here we describe methods for assessing heterogeneity of treatment effects over prespecified subgroups in observational studies, using outcome-model-based (g-formula), inverse probability weighting, doubly robust, and matching estimators of subgroup-specific potential outcome means, conditional average treatment effects, and measures of heterogeneity of treatment effects. We compare the finite-sample performance of different estimators in simulation studies where we vary the total sample size, the relative frequency of each subgroup, the magnitude of treatment effect in each subgroup, and the distribution of baseline covariates, for both continuous and binary outcomes. We find that the estimators' bias and variance vary substantially in finite samples, even when there is no unobserved confounding and no model misspecification. As an illustration, we apply the methods to data from the Coronary Artery Surgery Study (August 1975-December 1996) to compare the effect of surgery plus medical therapy with that of medical therapy alone for chronic coronary artery disease in subgroups defined by previous myocardial infarction or left ventricular ejection fraction.

GINOM: A statistical framework for assessing interval overlap of multiple genomic features.

A common problem in genomics is to test for associations between two or more genomic features, typically represented as intervals interspersed across the genome. Existing methodologies can test for significant pairwise associations between two genomic intervals; however, they cannot test for associations involving multiple sets of intervals. This limits our ability to uncover more complex, yet biologically important associations between multiple sets of genomic features. We introduce GINOM (Genomic INterval Overlap Model), a new method that enables testing of significant associations between multiple genomic features. We demonstrate GINOM's ability to identify higher-order associations with both simulated and real data. In particular, we used GINOM to explore L1 retrotransposable element insertion bias in lung cancer and found a significant pairwise association between L1 insertions and heterochromatic marks. Unlike other methods, GINOM also detected an association between L1 insertions and gene bodies marked by a facultative heterochromatic mark, which could explain the observed bias for L1 insertions towards cancer-associated genes.

Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial.

In the PREVENT-19 phase 3 trial of the NVX-CoV2373 vaccine (NCT04611802), anti-spike binding IgG concentration (spike IgG), anti-RBD binding IgG concentration (RBD IgG), and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks post-dose two are assessed as correlates of risk and as correlates of protection against COVID-19. Analyses are conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases. All markers are inversely associated with COVID-19 risk and directly associated with vaccine efficacy. In vaccine recipients with nAb ID50 titers of 50, 100, and 7230 international units (IU50)/ml, vaccine efficacy estimates are 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), and 96.8% (88.3%, 99.3%). The results support potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use.

Immune correlates analysis of a phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine.

In the phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine conducted in the U.S., Chile, and Peru, anti-spike binding IgG concentration (spike IgG) and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured four weeks after two doses were assessed as correlates of risk and protection against PCR-confirmed symptomatic SARS-CoV-2 infection (COVID-19). These analyses of SARS-CoV-2 negative participants were based on case-cohort sampling of vaccine recipients (33 COVID-19 cases by 4 months post dose two, 463 non-cases). The adjusted hazard ratio of COVID-19 was 0.32 (95% CI: 0.14, 0.76) per 10-fold increase in spike IgG concentration and 0.28 (0.10, 0.77) per 10-fold increase in nAb ID50 titer. At nAb ID50 below the limit of detection (< 2.612 IU50/ml), 10, 100, and 270 IU50/ml, vaccine efficacy was -5.8% (-651%, 75.6%), 64.9% (56.4%, 86.9%), 90.0% (55.8%, 97.6%) and 94.2% (69.4%, 99.1%). These findings provide further evidence towards defining an immune marker correlate of protection to help guide regulatory/approval decisions for COVID-19 vaccines.