RISE: Two-Stage Rank-Based Identification of High-Dimensional Surrogate Markers Applied to Vaccinology.

In vaccine trials with long-term participant follow-up, it is of great importance to identify surrogate markers that accurately infer long-term immune responses. These markers offer practical advantages such as providing early, indirect evidence of vaccine efficacy, and can accelerate vaccine development while identifying potential biomarkers. High-throughput technologies such as RNA-sequencing have emerged as promising tools for understanding complex biological systems and informing new treatment strategies.

Avoiding the Surrogate Paradox: An Empirical Framework for Assessing Assumptions.

The use of surrogate markers to replace a primary outcome in clinical trials has the potential to allow earlier decisions about the effectiveness of a treatment when a direct measurement of the primary outcome is difficult to obtain. However, the surrogate paradox, which occurs when a treatment has a positive effect on the surrogate marker but a negative effect on the primary outcome, may lead researchers to make incorrect conclusions about the treatment benefit. In this paper, we propose a formal nonparametric framework to empirically examine and test assumptions that ensure avoidance of the surrogate paradox.

Semiparametric joint modeling to estimate the treatment effect on a longitudinal surrogate with application to chronic kidney disease trials.

In clinical trials where long follow-up is required to measure the primary outcome of interest, there is substantial interest in using an accepted surrogate outcome that can be measured earlier in time or with less cost to estimate a treatment effect. For example, in clinical trials of chronic kidney disease, the effect of a treatment is often demonstrated on a longitudinal surrogate, the change of the longitudinal outcome (glomerular filtration rate, GFR) per year or GFR slope. However, estimating the effect of a treatment on the GFR slope is complicated by the fact that GFR measurement can be terminated by the occurrence of a terminal event, such as death or kidney failure.

Robust evaluation of longitudinal surrogate markers with censored data.

The development of statistical methods to evaluate surrogate markers is an active area of research. In many clinical settings, the surrogate marker is not simply a single measurement but is instead a longitudinal trajectory of measurements over time, e.g.

Surrogate Marker Evaluation: A Tutorial Using R.

The practice of using a surrogate marker to replace a primary outcome in clinical studies has become widespread. Typically, the primary outcome requires long-term patient follow-up, is expensive, or is invasive or burdensome for patients to measure, while the surrogate marker is not (or less so). Of course, a surrogate marker must be validated before it should be used to make a decision about the effectiveness of a treatment.

Biomechanical profiling of in vitro blood clots: sensitivity to sex, age, and blood composition in a healthy adult population.

Blood clots' mechanical properties are important in both their physiological role and in the initiation and progression of thromboembolic diseases. Because studying blood clot properties in vivo is difficult, many prior studies have investigated the properties of in vitro clots instead. However, much remains to be understood about in vitro clots, especially those derived from human blood.

Association between out-of-sequence allocation and deceased donor kidney nonuse across organ procurement organizations.

Out-of-sequence (OOS) kidney allocation has become increasingly prevalent since 2021. We examined the relationship between organ procurement organization (OPO) OOS allocation frequency and kidney nonuse rates. Among 57 OPOs between March 2021 and December 2023, we analyzed trends in OOS utilization and its association with kidney nonuse rates.

A General Framework to Assess Complex Heterogeneity in the Strength of a Surrogate Marker.

A surrogate marker is a biological measurement in a clinical trial that aims to replace the primary outcome in evaluating the treatment effect, and can be measured earlier, with less cost, or with less patient burden. In theory, once a surrogate is validated, future studies can evaluate treatment efficacy using only the surrogate. While there are many methods to evaluate a surrogate, these methods rarely account for heterogeneity in surrogacy, that is, when a surrogate is valid for only certain people.

Updated Adjustment of the HCAHPS Survey for New Modes of Survey Administration and Patient Mix.

Background: Web-first multimode survey protocols increase Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey response rates and representativeness but may result in different HCAHPS scores because of survey mode effects and selective email address availability. A variable absent from many patient-mix adjustment models that may result in more positive patient experiences is whether the hospital admission was planned; adjustment for planned stays may better measure hospital performance.

Objectives: Develop adjustments for new Web-first survey protocols and planned admissions to facilitate comparisons across hospitals.

Variation Across Organ Procurement Organizations in Deceased-Donor Kidney Offer Notification Practices.

Introduction: How offer notifications are distributed early in the kidney allocation timeline, including how widely they are offered, is unclear. A better understanding of offer notification practices across organ procurement organizations (OPOs) may identify opportunities for more efficient allocation.

Methods: We merged the Scientific Registry of Transplant Recipients potential transplant recipient file with additional offer notification time stamps to identify 54 631 deceased-donor kidney match runs from 2017 to 2023.

Group sequential testing of a treatment effect using a surrogate marker.

The identification of surrogate markers is motivated by their potential to make decisions sooner about a treatment effect. However, few methods have been developed to actually use a surrogate marker to test for a treatment effect in a future study. Most existing methods consider combining surrogate marker and primary outcome information to test for a treatment effect, rely on fully parametric methods where strict parametric assumptions are made about the relationship between the surrogate and the outcome, and/or assume the surrogate marker is measured at only a single time point.

Assessing heterogeneity in surrogacy using censored data.

Determining whether a surrogate marker can be used to replace a primary outcome in a clinical study is complex. While many statistical methods have been developed to formally evaluate a surrogate marker, they generally do not provide a way to examine heterogeneity in the utility of a surrogate marker. Similar to treatment effect heterogeneity, where the effect of a treatment varies based on a patient characteristic, heterogeneity in surrogacy means that the strength or utility of the surrogate marker varies based on a patient characteristic.

A rank-based approach to evaluate a surrogate marker in a small sample setting.

In clinical studies of chronic diseases, the effectiveness of an intervention is often assessed using "high cost" outcomes that require long-term patient follow-up and/or are invasive to obtain. While much progress has been made in the development of statistical methods to identify surrogate markers, that is, measurements that could replace such costly outcomes, they are generally not applicable to studies with a small sample size. These methods either rely on nonparametric smoothing which requires a relatively large sample size or rely on strict model assumptions that are unlikely to hold in practice and empirically difficult to verify with a small sample size.

Survey Protocols, Response Rates, and Representation of Underserved Patients: A Randomized Clinical Trial.

Importance: Surveys often underrepresent certain patients, such as underserved patients. Methods that improve their response rates (RRs) would help patient surveys better represent their experiences and assess equity and equity-targeted quality improvement efforts.

Objective: To estimate the effect of adding an initial web mode to existing Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey protocols and extending the fielding period on RR and representativeness of underserved patient groups.

Flexible evaluation of surrogate markers with Bayesian model averaging.

When long-term follow up is required for a primary endpoint in a randomized clinical trial, a valid surrogate marker can help to estimate the treatment effect and accelerate the decision process. Several model-based methods have been developed to evaluate the proportion of the treatment effect that is explained by the treatment effect on the surrogate marker. More recently, a nonparametric approach has been proposed allowing for more flexibility by avoiding the restrictive parametric model assumptions required in the model-based methods.

Statistical Methods to Evaluate Surrogate Markers.

Background: There is tremendous interest in evaluating surrogate markers given their potential to decrease study time, costs, and patient burden.

Objectives: The purpose of this statistical workshop article is to describe and illustrate how to evaluate a surrogate marker of interest using the proportion of treatment effect (PTE) explained as a measure of the quality of the surrogate marker for: (1) a setting with a general fully observed primary outcome (eg, biopsy score); and (2) a setting with a time-to-event primary outcome which may be censored due to study termination or early drop out (eg, time to diabetes).

Methods: The methods are motivated by 2 randomized trials, one among children with nonalcoholic fatty liver disease where the primary outcome was a change in biopsy score (general outcome) and another study among adults at high risk for Type 2 diabetes where the primary outcome was time to diabetes (time-to-event outcome).

Lower socioeconomic status may help explain racial disparities in asthma and atopic dermatitis prevalence: A mediation analysis.

Background: Racial disparities in atopic disease (atopic dermatitis [AD], asthma, and allergies) prevalence are well documented. Despite strong associations between race and socioeconomic deprivation in the United States, and socioeconomic status (SES) and atopic diseases, the extent to which SES explains these disparities is not fully understood.

Objective: We sought to identify racial disparities in childhood atopic disease prevalence and determine what proportion of those disparities is mediated by SES.

Can earlier biomarker measurements explain a treatment effect on diabetes incidence? A robust comparison of five surrogate markers.

Introduction: We measured and compared five individual surrogate markers-change from baseline to 1 year after randomization in hemoglobin A1c (HbA1c), fasting glucose, 2-hour postchallenge glucose, triglyceride-glucose index (TyG) index, and homeostatic model assessment of insulin resistance (HOMA-IR)-in terms of their ability to explain a treatment effect on reducing the risk of type 2 diabetes mellitus at 2, 3, and 4 years after treatment initiation.

Research Design And Methods: Study participants were from the Diabetes Prevention Program study, randomly assigned to either a lifestyle intervention (n=1023) or placebo (n=1030). The surrogate markers were measured at baseline and 1 year, and diabetes incidence was examined at 2, 3, and 4 years postrandomization.

Exploring Which Patients Use Their Closest Emergency Departments Using Geocoded Data.

Background: Each year, roughly 20% of U.S. adults visit an emergency department (ED), but little is known about patients' choice of ED.

Improving the Quality of Written Discharge Instructions: A Multisite Collaborative Project.

Background And Objectives: Written discharge instructions help to bridge hospital-to-home transitions for patients and families, though substantial variation in discharge instruction quality exists. We aimed to assess the association between participation in an Institute for Healthcare Improvement Virtual Breakthrough Series collaborative and the quality of pediatric written discharge instructions across 8 US hospitals.

Methods: We conducted a multicenter, interrupted time-series analysis of a medical records-based quality measure focused on written discharge instruction content (0-100 scale, higher scores reflect better quality).

Association of Hospice Profit Status With Family Caregivers' Reported Care Experiences.

Importance: Expansive growth in the US hospice market has been driven almost exclusively by an increase in for-profit hospices. Prior research found that, in contrast to not-for-profit hospices, for-profit hospices focus on delivering care to patients in nursing homes, provide fewer nursing visits, and use less skilled staff. However, prior studies have not reported on the associations of these differences in care patterns with hospice care quality.