Reward ignorant modeling of dynamic treatment regimes

Personalized medicine optimizes patient outcome by tailoring treatments to patient‐level characteristics. This approach is formalized by dynamic treatment regimes (DTRs): decision rules that take patient information as input and output recommended treatment decisions. The DTR literature has seen the development of increasingly sophisticated causal inference techniques that attempt to address the limitations of our typically observational datasets. Often overlooked, however, is that in practice most patients may be expected to receive optimal or near‐optimal treatment, and so the outcome used as part of a typical DTR analysis may provide limited information. In light of this, we propose considering a more standard analysis: ignore the outcome and elicit an optimal DTR by modeling the observed treatment as a function of relevant covariates. This offers a far simpler analysis and, in some settings, improved optimal treatment identification. To distinguish this approach from more traditional DTR analyses, we term it reward ignorant modeling, and also introduce the concept of multimethod analysis, whereby different analysis methods are used in settings with multiple treatment decisions. We demonstrate this concept through a variety of simulation studies, and through analysis of data from the International Warfarin Pharmacogenetics Consortium, which also serve as motivation for this work.     

Response definition criteria for ELISPOT assays revisited

No consensus has been reached on how to determine if an immune response has been detected based on raw data from an ELISPOT assay. The goal of this paper is to enable investigators to understand and readily implement currently available methods for response determination. We describe empirical and statistical approaches, identifying the strengths and limitations of each approach to allow readers to rationally select and apply a scientifically sound method appropriate to their specific laboratory setting. Five representative approaches were applied to data sets from the CIMT Immunoguiding Program and the response detection and false positive rates were compared. Simulation studies were also performed to compare empirical and statistical approaches. Based on these, we recommend the use of a non-parametric statistical test. Further, we recommend that six medium control wells or four wells each for both medium control and experimental conditions be performed to increase the sensitivity in detecting a response, that replicates with large variation in spot counts be filtered out, and that positive responses arising from experimental spot counts below the estimated limit of detection be interpreted with caution. Moreover, a web-based user interface was developed to allow easy access to the recommended statistical methods. This interface allows the user to upload data from an ELISPOT assay and obtain an output file of the binary responses.     

Effect of rAd5-Vector HIV-1 Preventive Vaccines on HIV-1 Acquisition: A Participant-Level Meta-Analysis of Randomized Trials

Background

Three phase 2b, double-blind, placebo-controlled, randomized efficacy trials have tested recombinant Adenovirus serotype-5 (rAd5)-vector preventive HIV-1 vaccines: MRKAd5 HIV-1 gag/pol/nef in Step and Phambili, and DNA/rAd5 HIV-1 env/gag/pol in HVTN505. Due to efficacy futility observed at the first interim analysis in Step and HVTN505, participants of all three studies were unblinded to their vaccination assignments during the study but continued follow–up. Rigorous meta-analysis can provide crucial information to advise the future utility of rAd5-vector vaccines.

Methods

We included participant-level data from all three efficacy trials, and three Phase 1–2 trials evaluating the HVTN505 vaccine regimen. We predefined two co-primary analysis cohorts for assessing the vaccine effect on HIV-1 acquisition. The modified-intention-to-treat (MITT) cohort included all randomly assigned participants HIV-1 uninfected at study entry, who received at least the first vaccine/placebo, and the Ad5 cohort included MITT participants who received at least one dose of rAd5-HIV vaccine or rAd5-placebo. Multivariable Cox regression models were used to estimate hazard ratios (HRs) of HIV-1 infection (vaccine vs. placebo) and evaluate HR variation across vaccine regimens, time since vaccination, and subgroups using interaction tests.

Findings

Results are similar for the MITT and Ad5 cohorts; we summarize MITT cohort results. Pooled across the efficacy trials, over all follow-up time 403 (n = 224 vaccine; n = 179 placebo) of 6266 MITT participants acquired HIV-1, with a non-significantly higher incidence in vaccine recipients (HR 1.21, 95% CI 0.99–1.48, P = 0.06). The HRs significantly differed by vaccine regimen (interaction P = 0.03; MRKAd5 HR 1.41, 95% CI 1.11–1.78, P = 0.005 vs. DNA/rAd5 HR 0.88, 95% CI 0.61–1.26, P = 0.48). Results were similar when including the Phase 1–2 trials. Exploratory analyses based on the efficacy trials supported that the MRKAd5 vaccine-increased risk was concentrated in Ad5-positive or uncircumcised men early in follow-up, and in Ad5-negative or circumcised men later. Overall, MRKAd5 vaccine-increased risk was evident across subgroups except in circumcised Ad5-negative men (HR 0.97, 95% CI 0.58−1.63, P = 0.91); there was little evidence that the DNA/rAd5 vaccine, that was tested in this subgroup, increased risk (HR 0.88, 95% CI 0.61–1.26, P = 0.48). When restricting the analysis of Step and Phambili to follow-up time before unblinding, 114 (n = 65 vaccine; n = 49 placebo) of 3770 MITT participants acquired HIV-1, with a non-significantly higher incidence in MRKAd5 vaccine recipients (HR 1.30, 95% CI 0.89–1.14, P = 0.18).

Interpretation and Significance

The data support increased risk of HIV-1 infection by MRKAd5 over all follow-up time, but do not support increased risk of HIV-1 infection by DNA/rAd5. This study provides a rationale for including monitoring plans enabling detection of increased susceptibility to infection in HIV-1 at-risk populations.     

Continued Follow-Up of Phambili Phase 2b Randomized HIV-1 Vaccine Trial Participants Supports Increased HIV-1 Acquisition among Vaccinated Men

Background

The Phase 2b double-blinded, randomized Phambili/HVTN 503 trial evaluated safety and efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine vs placebo in sexually active HIV-1 seronegative participants in South Africa. Enrollment and vaccinations stopped and participants were unblinded but continued follow-up when the Step study evaluating the same vaccine in the Americas, Caribbean, and Australia was unblinded for non-efficacy. Final Phambili analyses found more HIV-1 infections amongst vaccine than placebo recipients, impelling the HVTN 503-S recall study.

Methods

HVTN 503-S sought to enroll all 695 HIV-1 uninfected Phambili participants, provide HIV testing, risk reduction counseling, physical examination, risk behavior assessment and treatment assignment recall. After adding HVTN 503-S data, HIV-1 infection hazard ratios (HR vaccine vs. placebo) were estimated by Cox models.

Results

Of the 695 eligible, 465 (67%) enrolled with 230 from the vaccine group and 235 from the placebo group. 38% of the 184 Phambili dropouts were enrolled. Enrollment did not differ by treatment group, gender, or baseline HSV-2. With the additional 1286 person years of 503-S follow-up, the estimated HR over Phambili and HVTN 503-S follow-up was 1.52 (95% CI 1.08–2.15, p = 0.02, 82 vaccine/54 placebo infections). The HR was significant for men (HR = 2.75, 95% CI 1.49, 5.06, p = 0.001) but not for women (HR = 1.12, 95% CI 0.73, 1.72, p = 0.62).

Conclusion

The additional follow-up from HVTN 503-S supported the Phambili finding of increased HIV-1 acquisition among vaccinated men and strengthened the evidence of lack of vaccine effect among women.

Trial Registration

clinicaltrials.gov NCT00413725 SA National Health Research Database DOH-27-0207-1539     

A prospective study of diet quality and mental health in adolescents

Objectives

A number of cross-sectional and prospective studies have now been published demonstrating inverse relationships between diet quality and the common mental disorders in adults. However, there are no existing prospective studies of this association in adolescents, the onset period of most disorders, limiting inferences regarding possible causal relationships.

Methods

In this study, 3040 Australian adolescents, aged 11–18 years at baseline, were measured in 2005–6 and 2007–8. Information on diet and mental health was collected by self-report and anthropometric data by trained researchers.

Results

There were cross-sectional, dose response relationships identified between measures of both healthy (positive) and unhealthy (inverse) diets and scores on the emotional subscale of the Pediatric Quality of Life Inventory (PedsQL), where higher scores mean better mental health, before and after adjustments for age, gender, socio-economic status, dieting behaviours, body mass index and physical activity. Higher healthy diet scores at baseline also predicted higher PedsQL scores at follow-up, while higher unhealthy diet scores at baseline predicted lower PedsQL scores at follow-up. Improvements in diet quality were mirrored by improvements in mental health over the follow-up period, while deteriorating diet quality was associated with poorer psychological functioning. Finally, results did not support the reverse causality hypothesis.

Conclusion

This study highlights the importance of diet in adolescence and its potential role in modifying mental health over the life course. Given that the majority of common mental health problems first manifest in adolescence, intervention studies are now required to test the effectiveness of preventing the common mental disorders through dietary modification.     

A phase IIA randomized clinical trial of a multiclade HIV-1 DNA prime followed by a multiclade rAd5 HIV-1 vaccine boost in healthy adults (HVTN204)

Background

The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean.

Methods

480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (10¹⁰ PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost.

Results

The vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%–94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients.

Conclusion

The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies.

Trial Registration:

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00125970","term_id":"NCT00125970"}}NCT00125970     

Demystifying optimal dynamic treatment regimes

A dynamic regime is a function that takes treatment and covariate history and baseline covariates as inputs and returns a decision to be made. Murphy (2003, Journal of the Royal Statistical Society, Series B 65, 331-366) and Robins (2004, Proceedings of the Second Seattle Symposium on Biostatistics, 189-326) have proposed models and developed semiparametric methods for making inference about the optimal regime in a multi-interval trial that provide clear advantages over traditional parametric approaches. We show that Murphy's model is a special case of Robins's and that the methods are closely related but not equivalent. Interesting features of the methods are highlighted using the Multicenter AIDS Cohort Study and through simulation.