Finding the best subgroup with differential treatment effect with multiple outcomes.

Precision medicine aims to identify specific patient subgroups that may benefit the most from a particular treatment than the whole population. Existing definitions for the best subgroup in subgroup analysis are based on a single outcome and do not consider multiple outcomes; specifically, outcomes of different types. In this article, we introduce a definition for the best subgroup under a multiple-outcome setting with continuous, binary, and censored time-to-event outcomes. Our definition provides a trade-off between the subgroup size and the conditional average treatment effects (CATE) in the subgroup with respect to each of the outcomes while taking the relative contribution of the outcomes into account. We conduct simulations to illustrate the proposed definition. By examining the outcomes of urinary tract infection and renal scarring in the RIVUR clinical trial, we identify a subgroup of children that would benefit the most from long-term antimicrobial prophylaxis.

Antimicrobial prophylaxis for vesicoureteral reflux: which subgroups of children benefit the most?

BACKGROUND: While the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial found that long-term antimicrobial prophylaxis reduced the risk of urinary tract infection (UTI) recurrences by 50%, 10 children had to be treated for one to benefit (i.e., observed number needed to treat (NNT) of 10). Accordingly, we re-analyzed RIVUR data to systematically identify subgroups of children with vesicoureteral reflux (VUR) with a smaller NNT. METHODS: Using patient-level data from the RIVUR trial, we applied penalized regression methods including the baseline age, VUR grade, type of index UTI, and bowel-bladder dysfunction (BBD) as covariates to identify subgroups. RESULTS: We identified four relevant subgroups of children that appear to benefit from long-term antimicrobial prophylaxis, all with observed NNTs smaller than or equal to 5: children with grade IV VUR, BBD, and febrile index UTI (1% of the sample), children with BBD and febrile index UTI (7% of the sample), children with BBD (12% of the sample), and children with grade IV VUR (8% of the sample). CONCLUSIONS: Use of long-term antimicrobial prophylaxis appears to be particularly relevant for children with BBD (and any grade of VUR) and those with grade IV VUR (regardless of BBD status). However, because details regarding the treatment of BBD are not available, further studies are needed to fully determine the role of prophylactic antimicrobials in the management of children with VUR who have BBD.

Inference on subgroups identified based on a heterogeneous treatment effect in a post hoc analysis of a clinical trial.

Due to the many benefits of understanding treatment effect heterogeneity in a clinical trial, an exploratory post hoc subgroup analysis is often performed to find subpopulations of patients with conditional average treatment effect that suggests better treatment efficacy than in the overall population. A naive re-substitution approach uses all available data to identify a subgroup and then proceeds with estimation and inference using the same data set. This approach generally leads to an overly optimistic estimate of conditional average treatment effect. In this article, in a post hoc analysis, we estimate the target optimal subgroup through maximizing a utility function, from candidates systematically identified with a penalized regression. We then compare two resampling-based bias-correction methods, cross-validation and debiasing bootstrap, for obtaining approximately unbiased estimates and valid inference of conditional average treatment effect in the identified subgroup, with either an empirical or an augmented estimator. Our results show that both the cross-validation and the debiasing bootstrap methods reduce the re-substitution bias effectively. The cross-validation method appears to have less biased point estimates, smaller standard error estimates, but poorer coverages than the debiasing bootstrap method when using the empirical estimator and the sample size is moderate. Using the augmented estimator in the debiasing bootstrap method leads to less biased point estimates but poorer coverages. We conclude that bias correction should be a part of every exploratory post hoc subgroup analysis to eliminate re-substitution bias and to obtain a proper confidence interval for the estimated conditional average treatment effect in the selected subgroup.

Retaining Hispanics: Lessons From the Hispanic Community Health Study/Study of Latinos.

We aimed to examine the retention of Hispanics/Latinos participating in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a prospective cohort study of 16,415 adults in 4 US cities who were enrolled between 2008 and 2011. We summarized retention strategies and examined contact, response, and participation rates over 5 years of annual follow-up interviews. We then evaluated motivations for participation and satisfaction with retention efforts among participants who completed a second in-person interview approximately 6 years after their baseline interview. Finally, we conducted logistic regression analyses estimating associations of demographic, health, and interview characteristics at study visit 1 (baseline) with participation, high motivation, and high satisfaction at visit 2. Across 5 years, the HCHS/SOL maintained contact, response, and participation rates over 80%. The most difficult Hispanic/Latino populations to retain included young, single, US-born males with less than a high school education. At visit 2, we found high rates of motivation and satisfaction. HCHS/SOL participants primarily sought to help their community and learn more about their health. High rates of retention of Hispanics/Latinos can be facilitated through the employment of bilingual/bicultural staff and the development of culturally tailored retention materials.

Antimicrobial prophylaxis for vesicoureteral reflux: which subgroups of children benefit the most?

Background: While the Randomized Intervention for children with Vesicoureteral Reflux (RIVUR) trial found that long-term antimicrobial prophylaxis reduced the risk of urinary tract infection (UTI) recurrences by 50%, 10 children had to be treated with long-term antimicrobial prophylaxis for one to benefit (i.e., observed number needed to treat (NNT) of 10). Accordingly, we re-analyzed RIVUR data to systematically identify subgroups of children with vesicoureteral reflux (VUR) with a smaller NNT. Methods: Using patient-level data from the RIVUR trial, we applied penalized regression methods including the baseline age, VUR, and bowel-bladder dysfunction (BBD) as covariates to identify subgroups that consider the trade-off between absolute risk difference and size. Results: We identified three relevant subgroups of children that appear to benefit from long-term antimicrobial prophylaxis, all with NNTs smaller than the NNT of 10. Children with grade IV VUR and BBD, 1% of the RIVUR sample, had a NNT of 2; children with BBD, 12% of the RIVUR sample, had a NNT of 4; children with BBD (and any grade VUR) or with grade IV VUR (regardless of BBD status), which was the combination of the first two subgroups and included 19% of children in the RIVUR sample, had a NNT of 4. Conclusions: Use of long-term antimicrobial prophylaxis appears to be particularly relevant for children with BBD (and any grade of VUR) or those with grade IV VUR (regardless of BBD status) who were at high risk of UTI recurrences.

Day-of-the-Week and Time-of-the-Day Patterns of Sedentary Behavior in the Hispanic Community Health Study/Study of Latinos.

PURPOSE: Existing sedentary behavior interventions have largely achieved mixed results. Conventionally, interventions have attempted to reduce sedentary behavior using a full-day approach. An alternative strategy may be to target specific periods during the day and/or week. This study examined the day-of-the-week (Monday to Sunday) and time-of-the-day patterns (3-and 6-h periods) of sedentary behavior among U.S. Hispanics/Latinos adults. METHODS: Participants ( n = 12,241) from the Hispanic Community Health Study/Study of Latinos, a multisite community-based prospective cohort study of Hispanic/Latino adults, were studied. Sedentary behavior was assessed for 1 wk using a hip-mounted accelerometer through total sedentary time, sedentary time in bouts ≥60 min, and total number of sedentary breaks. The temporal patterns of sedentary behavior metrics were evaluated using linear mixed effect models accounting for the Hispanic Community Health Study/Study of Latinos complex survey design. RESULTS: There were statistically significant variations in temporal patterns across day-of-the-week and time-of-the-day periods for all three metrics ( P < 0.001). Adults were more sedentary on weekends than on weekdays and most sedentary on Sundays. The time-of-the-day patterns had a U-curve pattern wherein adults were most sedentary late at night, became less sedentary throughout the day, reached peak activeness around noon, then gradually became more sedentary into the evening. These patterns were largely robust across seasonality and most sociodemographic characteristics, including age, employment status, work shift schedule, acculturation, and field center. CONCLUSIONS: Our findings suggest that early mornings, evenings, and weekends were the more sedentary periods in this cohort of Hispanic/Latino adults, characterized by higher volumes of sedentary time, higher volumes of time in prolonged sedentary bouts, and fewer number of sedentary breaks than other time periods, highlighting important windows of opportunity to reduce sedentary behavior.

Pretherapy metabolic tumor volume is associated with response to CD30 CAR T cells in Hodgkin lymphoma.

Our group has recently demonstrated that chimeric antigen receptor T-cell therapy targeting the CD30 antigen (CD30.CAR-T) is highly effective in patients with relapsed and refractory (r/r) classical Hodgkin lymphoma (cHL). Despite high rates of clinical response, relapses and progression were observed in a subset of patients. The objective of this study was to characterize clinical and correlative factors associated with progression-free survival (PFS) after CD30.CAR-T cell therapy. We evaluated correlatives in 27 patients with r/r cHL treated with lymphodepletion and CD30.CAR-T cells. With a median follow-up of 9.5 months, 17 patients (63%) progressed, with a median PFS of 352 days (95% confidence interval: 116-not reached), and 2 patients died (7%) with a median overall survival of not reached. High metabolic tumor volume (MTV, >60 mL) immediately before lymphodepletion and CD30.CAR-T cell infusion was associated with inferior PFS (log rank, P = .02), which persisted after adjusting for lymphodepletion and CAR-T dose (log rank, P = .01 and P = .006, respectively). In contrast, receiving bridging therapy, response to bridging therapy, CD30.CAR-T expansion/persistence, and percentage of CD3+PD-1+ lymphocytes over the first 6 weeks of therapy were not associated with differences in PFS. In summary, this study reports an association between high baseline MTV immediately before lymphodepletion and CD30.CAR-T cell infusion and worse PFS in patients with r/r cHL. This trial was registered at www.clinicaltrials.gov as #NCT02690545.