Adaptive HIV pre-exposure prophylaxis adherence interventions for young women in Johannesburg, South Africa: a sequential multiple-assignment randomised trial.

Background: Adherence to daily oral pre-exposure prophylaxis (PrEP) is low among African young women, and layered support strategies are needed to improve PrEP adherence in this population. We aimed to evaluate potentially scalable adherence-support strategies for young women aged 18-25 years who initiated PrEP in Johannesburg, South Africa.

Methods: We conducted a sequential multiple-assignment randomised trial at Ward 21 of the Wits Reproductive Health and HIV Institute clinical research site, affiliated with University of the Witwatersrand, Johannesburg, South Africa.

Factors Associated With Mailed Fecal Immunochemical Test Completion in an Integrated Academic-Community Healthcare System.

Introduction: Mailed fecal immunochemical test (FIT) outreach is an effective strategy to increase colorectal cancer (CRC) screening. The aim of this study was to determine the patient-level, clinic-level, and geographic-level factors associated with CRC screening completion in a mailed FIT outreach program.

Methods: This retrospective cohort study was conducted in the integrated healthcare system of University of Washington Medicine and included patients aged 50-75 years, who were due for CRC screening, and had a primary care encounter in the past 3 years.

Estimating the Effect of PrEP in Black Men Who Have Sex with Men: A Framework to Utilize Data from Multiple Non-Randomized Studies to Estimate Causal Effects.

Black men who have sex with men (MSM) are disproportionately burdened by the HIV epidemic in the US. The effectiveness of pre-exposure prophylaxis (PrEP) in preventing HIV infection has been demonstrated through randomized placebo-controlled clinical trials in several populations. Importantly, no such trial has been conducted exclusively among Black MSM in the US, and it would be unethical and infeasible to do so now.

Duration of viral infectiousness and correlation with symptoms and diagnostic testing in non-hospitalized adults during acute SARS-CoV-2 infection: A longitudinal cohort study.

Background: Guidelines for SARS-CoV-2 have relied on limited data on duration of viral infectiousness and correlation with COVID-19 symptoms and diagnostic testing.

Methods: We enrolled ambulatory adults with acute SARS-CoV-2 infection and performed serial measurements of COVID-19 symptoms, nasal swab viral RNA, nucleocapsid (N) and spike (S) antigens, and replication-competent SARS-CoV-2 by viral growth in culture. We determined average time from symptom onset to a first negative test result and estimated risk of infectiousness, as defined by positive viral growth in culture.

PrEP uptake and HIV viral suppression when PrEP is integrated into Ugandan ART clinics for HIV-negative members of HIV-serodifferent couples: A stepped wedge cluster randomized trial.

Background: Global scale-up of HIV pre-exposure prophylaxis (PrEP) includes services to HIV-negative people in partnerships with people living with HIV (serodifferent couples). Data are needed on HIV outcomes, including uptake and adherence to PrEP and antiretroviral treatment (ART), to describe the impact of integrating PrEP into an existing HIV program.

Methods: Using a stepped-wedge cluster randomized trial design, we launched PrEP delivery for HIV-negative members of serodifferent couples in Uganda by integrating PrEP into existing ART programs for people living with HIV.

Integrating PrEP delivery in public health family planning clinics: a protocol for a pragmatic stepped wedge cluster randomized trial in Kenya.

Background: Adolescent girls and young women account for a disproportionate fraction of new HIV infections in Africa and are a priority population for HIV prevention, including provision of pre-exposure prophylaxis (PrEP). Anchoring PrEP delivery to care settings like family planning (FP) services that women already access routinely may offer an efficient platform to reach HIV at-risk women. However, context-specific implementation science evaluation is needed.

Combining biomarkers by maximizing the true positive rate for a fixed false positive rate.

Biomarkers abound in many areas of clinical research, and often investigators are interested in combining them for diagnosis, prognosis, or screening. In many applications, the true positive rate (TPR) for a biomarker combination at a prespecified, clinically acceptable false positive rate (FPR) is the most relevant measure of predictive capacity. We propose a distribution-free method for constructing biomarker combinations by maximizing the TPR while constraining the FPR.

Developing biomarker combinations in multicenter studies via direct maximization and penalization.

Motivated by a study of acute kidney injury, we consider the setting of biomarker studies involving patients at multiple centers where the goal is to develop a biomarker combination for diagnosis, prognosis, or screening. As biomarker studies become larger, this type of data structure will be encountered more frequently. In the presence of multiple centers, one way to assess the predictive capacity of a given combination is to consider the center-adjusted area under the receiver operating characteristic curve (aAUC), a summary of the ability of the combination to discriminate between cases and controls in each center.

Combined Utility of 25 Disease and Risk Factor Polygenic Risk Scores for Stratifying Risk of All-Cause Mortality.

While genome-wide association studies have identified susceptibility variants for numerous traits, their combined utility for predicting broad measures of health, such as mortality, remains poorly understood. We used data from the UK Biobank to combine polygenic risk scores (PRS) for 13 diseases and 12 mortality risk factors into sex-specific composite PRS (cPRS). These cPRS were moderately associated with all-cause mortality in independent data within the UK Biobank: the estimated hazard ratios per standard deviation were 1.

Case-Only Analysis of Gene-Environment Interactions Using Polygenic Risk Scores.

Investigations of gene (G)-environment (E) interactions have led to limited findings to date, possibly due to weak effects of individual genetic variants. Polygenic risk scores (PRS), which capture the genetic susceptibility associated with a set of variants, can be a powerful tool for detecting global patterns of interaction. Motivated by the case-only method for evaluating interactions with a single variant, we propose a case-only method for the analysis of interactions with a PRS in case-control studies.

Using ordinal outcomes to construct and select biomarker combinations for single-level prediction.

Background: Biomarker studies may involve an ordinal outcome, such as no, mild, or severe disease. There is often interest in predicting one particular level of the outcome due to its clinical significance.

Methods: A simple approach to constructing biomarker combinations in this context involves dichotomizing the outcome and using a binary logistic regression model.

Development of biomarker combinations for postoperative acute kidney injury via Bayesian model selection in a multicenter cohort study.

Background: Acute kidney injury (AKI) is a frequent complication of cardiac surgery. We sought prognostic combinations of postoperative biomarkers measured within 6 h of surgery, potentially in combination with cardiopulmonary bypass time (to account for the degree of insult to the kidney). We used data from a large cohort of patients and adapted methods for developing biomarker combinations to account for the multicenter design of the study.

Biomarker combinations for diagnosis and prognosis in multicenter studies: Principles and methods.

Many investigators are interested in combining biomarkers to predict a binary outcome or detect underlying disease. This endeavor is complicated by the fact that many biomarker studies involve data from multiple centers. Depending upon the relationship between center, the biomarkers, and the target of prediction, care must be taken when constructing and evaluating combinations of biomarkers.

Evaluating biomarkers for prognostic enrichment of clinical trials.

Background/aims: A potential use of biomarkers is to assist in prognostic enrichment of clinical trials, where only patients at relatively higher risk for an outcome of interest are eligible for the trial. We investigated methods for evaluating biomarkers for prognostic enrichment.

Methods: We identified five key considerations when considering a biomarker and a screening threshold for prognostic enrichment: (1) clinical trial sample size, (2) calendar time to enroll the trial, (3) total patient screening costs and the total per-patient trial costs, (4) generalizability of trial results, and (5) ethical evaluation of trial eligibility criteria.

Urinalysis findings and urinary kidney injury biomarker concentrations.

Introduction: Urinary biomarkers of kidney injury are presumed to reflect renal tubular damage. However, their concentrations may be influenced by other factors, such as hematuria or pyuria. We sought to examine what non-injury related urinalysis factors are associated with urinary biomarker levels.

Pre-diagnostic circulating sex hormone levels and risk of prostate cancer by ERG tumour protein expression.

Background: Experimental studies have shown androgen receptor stimulation to facilitate formation of the TMPRSS2:ERG gene fusion in prostate cell lines. No study has tested whether higher pre-diagnostic circulating sex hormone levels in men increase risk of developing TMPRSS2:ERG-positive prostate cancer specifically.

Methods: We conducted a nested case-control study of 200 prostate cancer cases and 1057 controls from the Physicians' Health Study and Health Professionals Follow-up Study.

Validity of a Neurological Scoring System for Canine X-Linked Myotubular Myopathy.

A simple clinical neurological test was developed to evaluate response to gene therapy in a preclinical canine model of X-linked myotubular myopathy (XLMTM). This devastating congenital myopathy is caused by mutation in the myotubularin (MTM1) gene. Clinical signs include muscle weakness, early respiratory failure, and ventilator dependence.

RiGoR: reporting guidelines to address common sources of bias in risk model development.

Reviewing the literature in many fields on proposed risk models reveals problems with the way many risk models are developed. Furthermore, papers reporting new risk models do not always provide sufficient information to allow readers to assess the merits of the model. In this review, we discuss sources of bias that can arise in risk model development.

Androgen receptor CAG repeat polymorphism and risk of TMPRSS2:ERG-positive prostate cancer.

Background: The androgen receptor (AR) is an essential gene in prostate cancer pathogenesis and progression. Genetic variation in AR exists, including a polymorphic CAG repeat sequence that is inversely associated with transcriptional activity. Experimental data suggest that heightened AR activity facilitates formation of TMPRSS2:ERG, a gene fusion present in approximately 50% of tumors of patients with prostate cancer.

Developing risk prediction models for kidney injury and assessing incremental value for novel biomarkers.

The field of nephrology is actively involved in developing biomarkers and improving models for predicting patients' risks of AKI and CKD and their outcomes. However, some important aspects of evaluating biomarkers and risk models are not widely appreciated, and statistical methods are still evolving. This review describes some of the most important statistical concepts for this area of research and identifies common pitfalls.

Modification of the association between obesity and lethal prostate cancer by TMPRSS2:ERG.

Background: TMPRSS2:ERG is a hormonally regulated gene fusion present in about half of prostate tumors. We investigated whether obesity, which deregulates several hormonal pathways, interacts with TMPRSS2:ERG to impact prostate cancer outcomes.

Methods: The study included 1243 participants in the prospective Physicians' Health Study and Health Professionals Follow-Up Study diagnosed with prostate cancer between 1982 and 2005.

A single nucleotide polymorphism in inflammatory gene RNASEL predicts outcome after radiation therapy for localized prostate cancer.

Purpose: To study associations between single nucleotide polymorphisms (SNP) in Ribonuclease L (RNASEL), a gene implicated in inflammation and prostate cancer risk, and outcomes after radiation therapy.

Experimental Design: We followed participants in the prospective US Health Professionals Follow-Up Study treated with radiation therapy for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance.