biostatistics

August 26, 2021: Li Receives PCORI Award to Study Methods for Cluster Randomized Trials

Posted on by Damon Seils
Headshot of Dr. Fan Li
Dr. Fan Li

Dr. Fan Li, a longtime member of the NIH Collaboratory’s Biostatistics and Study Design Core, has received approval for a $1 million grant award from the Patient-Centered Outcomes Research Institute (PCORI) to develop methods and software for designing cluster randomized trials. Li is an assistant professor of biostatistics in the Yale School of Public Health.

The study, entitled “New Methods for Planning Cluster Randomized Trials to Detect Treatment Effect Heterogeneity,” will contribute new methods, guidance, and user-friendly software for planning parallel and stepped-wedge cluster randomized trials to enable confirmatory “heterogeneity of treatment effect” (HTE) analyses with sufficient statistical power.

HTE occurs when there is systematic variation in treatment effect across predefined patient or provider subgroups that can arise due to diverse practices, varying responses to treatment, or differing vulnerability to certain diseases, among other reasons. While understanding of HTE has been a recognized goal in individually randomized trials, methods for planning cluster randomized trials with HTE analyses are limited. This PCORI-funded study will expand the current cluster randomized design toolbox to accommodate confirmatory HTE analysis and meet a growing interest in better understanding how patient- and provider-level characteristics moderate the impact of new care innovations in pragmatic trials.

The award has been approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract.

Joining Li on the research team are coinvestigators Dr. Patrick Heagerty of the University of Washington, Dr. Rui Wang of Harvard Medical School and the Harvard Pilgrim Health Care Institute, and Dr. Denise Esserman of the Yale School of Public Health. Heagerty and Wang are members of the NIH Collaboratory’s Biostatistics and Study Design Core. The team will work closely with other NIH Collaboratory colleagues and stakeholders, including Dr. Adrian Hernandez of Duke University, Dr. Jerry Jarvik of the University of Washington, and Dr. Richard Platt of Harvard Medical School and the Harvard Pilgrim Health Care Institute.

August 19, 2021: Biostatistics Core Helps Projects ‘Roll With the Punches’ of the Pandemic

Posted on by Damon Seils

Leaders of the NIH Collaboratory’s Biostatistics and Study Design Core Working Group spoke in a recent interview about the impacts of the COVID-19 pandemic on the NIH Collaboratory Trials, including the 2 newest projects, BeatPain Utah and GRACE.

“BeatPain Utah and GRACE are fascinating studies, as all our NIH Collaboratory Trials are, and are giving us lots of food for thought at the Biostatistics Core,” said Dr. Liz Turner, associate professor of biostatistics and bioinformatics at Duke University and a cochair of the Core. View the full video.

The 2 studies “have been pretty well positioned to roll with some of the distancing required or the lack of in-person visits,” said Dr. Patrick Heagerty, professor of biostatistics at the University of Washington and the other cochair of the Core. “The BeatPain project had a remote delivery from the beginning, so I think the impact of COVID was not as dramatic as it’s been for other projects. But GRACE, where acupuncture is part of it, they have to figure out what are the elements of the research protocol they can do remotely but still need to get folks in person to do that acupuncture,” Heagerty said.

“There really have been some considerable challenges for several of the other NIH Collaboratory Trials,” said Turner. “Good examples of these challenges are those faced by 2 stepped-wedge cluster randomized trials, ACP PEACE and PRIM-ER. …They had to really restructure the design and respond very quickly to what was happening in practice out in the field. Interestingly, on the flip side, the disruptions last spring in 2020 did provide opportunities to address other research questions and perhaps generate other interesting evidence,” Turner said.

(Learn more about the ACP PEACE study’s COVID-19 supplement: “Can a Primary Care Telehealth Intervention Change the Paradigm for Advance Care Planning?”)

Heagerty and Turner also described ongoing projects of the Core to support pragmatic research, including guidance on longitudinal analysis in randomized trials, considerations for studies with multiple outcomes, and handing of studies with variable cluster sizes. Learn more about the Biostatistics and Study Design Core.

 

Screen shot of interview with Patrick Heagerty and Liz Turner

March 29, 2021: New Resources from the Health Care Systems Interactions Core

Posted on by Karen Staman

The Health Care Systems (HCS) Interactions Core of the NIH Collaboratory has created a new guidance document: Resources for Frequently Asked Questions. The document compiles common questions from researchers and points to resources that provide potential solutions, including Living Textbook chapters and journal articles. The topics include evaluation strategies, anticipating and adapting to changes, dissemination and implementation, and stakeholder engagement.

The NIH Collaboratory Core Working Groups have created a series of handouts to help investigators conduct pragmatic trials:

August 28, 2020: Designing, Conducting, Monitoring, and Analyzing Data from Pragmatic Clinical Trials: Proceedings from a Multi-Stakeholder Think Tank Meeting (Trevor Lentz, PT, PhD, MHA; Lesley Curtis, PhD; Frank Rockhold, PhD)

Posted on by Gina Uhlenbrauck

Speakers

Trevor Lentz, PT, PhD, MHA
Assistant Professor in Orthopaedic Surgery
Duke Clinical Research Institute

Lesley Curtis, PhD
Chair and Professor, Department of Population Health Sciences
Duke University School of Medicine

Frank Rockhold, PhD, ScM, FASA, FSCT
Professor of Biostatistics and Bioinformatics
Duke Clinical Research Institute

Topic

Designing, Conducting, Monitoring, and Analyzing Data from Pragmatic Clinical Trials: Proceedings from a Multi-Stakeholder Think Tank Meeting

Keywords

Pragmatic clinical trials; Think tank; Risk-based monitoring; Data quality; Real-world data; Electronic health records

Key Points

  • Pragmatism in study design is not a binary concept: some trial elements are purely explanatory (to establish efficacy in ideal settings) and some elements are purely practical (to establish effectiveness in the real world). The study design must serve the research question.
  • Findings from the think tank discussions on best practices and actionable steps included:
    • Ask precise research questions, and select the appropriate degree of pragmatism.
    • Optimize data quality through study design.
    • Focus on primary endpoints in data capture to maximize likelihood of success.
    • Innovate on mechanisms for data capture.
    • Promote adherence to the study protocol.
    • Evolve trial operations staff to focus on data science and informatics.
    • Share learning experiences openly and widely.

Discussion Themes

There is a misconception that PCTs, because they pursue pragmatism, are less rigorous and conducted without proper oversight or adherence to a protocol. Quality by design and good clinical practice principles apply equally to PCTs.

Risk-based monitoring is a potentially dynamic system that could improve study safety and quality, and make better use of study resources.

There is great interest from regulators, sponsors, and the academic research community to move PCT methods forward. To achieve this, we need to see more examples of successful PCTs in a context of regulatory decision-making.

Read the proceedings from the think tank meeting published in Therapeutic Innovation & Regulatory Science.

Tags

#pctGR, @Collaboratory1

August 31, 2020: Newly Validated Sample Size Formula Detects Heterogeneity of Treatment Effect in Cluster Randomized Trials

Posted on by Damon Seils

Cover of Statistics in MedicineIn a study supported by the NIH Collaboratory, researchers developed and validated a new sample size formula for detecting heterogeneity of treatment effect in cluster randomized trials. The work was published this month in Statistics in Medicine.

Cluster randomization is frequently used in pragmatic clinical trials embedded in healthcare systems. Although cluster randomized trials are typically designed to evaluate the overall treatment effect in a study population, investigators are increasingly interested in studying differential treatment effects among subgroups.

The NIH Collaboratory investigators used extensive computer simulations to validate the new formula. They illustrate the procedure in a dataset from a large clinical trial.

In a previous study published last year, the same research team used computer simulation models validated by real-data simulations to reveal the influence of baseline covariate imbalance on treatment effect bias.

This work was supported within the NIH Collaboratory by the NIH Common Fund through a cooperative agreement from the Office of Strategic Coordination within the Office of the NIH Director, and by a research supplement from the NIH Common Fund to promote diversity in health-related research.

June 30, 2020: Special Issue of JAGS Features NIA IMPACT Collaboratory’s Work on Embedded Pragmatic Trials and Dementia Care

Posted on by Karen Staman

Members of the National Institute on Aging (NIA) IMPACT Collaboratory (Imbedded Pragmatic Alzheimer’s Disease [AD] and AD-Related Dementias [AD/ADRD] Clinical Trials) recently contributed 10 articles to a special issue of the Journal of the American Geriatrics Society. The articles support the IMPACT Collaboratory’s mission to “build the nation’s capacity to conduct ePCTs within healthcare systems for people living with dementia and their caregivers.”

The NIA IMPACT Collaboratory was modeled after the NIH Collaboratory; it has Working Group Cores to help advance the mission and support pilot and NIH Collaboratory Trials. The Cores include Administration, Design and Statistics, Dissemination and Implementation, Health Care Systems, Health Equity, Patient/Caregiver Reported Outcomes, Pilot Studies, Regulation and Ethics, Stakeholder Engagement, Technical Data, and Training.

Each of the Cores contributed an article to the special issue to describe how they are working to improve the quality and effectiveness of ePCTs for people living with dementia and their care partners.

The full list of articles (below) also includes an introductory article by leadership of the NIA IMPACT Collaboratory, Drs. Susan Mitchell, Vincent Mor, Ellen McCarthy, and Jill Harrison.

  • Embedded Pragmatic Trials in Dementia Care: Realizing the Vision of the NIA IMPACT Collaboratory
  • Achieving Health Equity in Embedded Pragmatic Trials for People Living with Dementia and Their Family Caregivers
  • Building a National Program for Pilot Studies of Embedded Pragmatic Clinical Trials in Dementia Care
  • Training the Workforce to Conduct Embedded Pragmatic Clinical Trials to Improve Care for People Living with Dementia and Their Caregivers
  • Dissemination and Implementation of Evidence-Based Dementia Care Using Embedded Pragmatic Trials
  • Ethical and Regulatory Issues for Embedded Pragmatic Trials Involving People Living with Dementia
  • Transforming Dementia Care Through Pragmatic Clinical Trials Embedded in Learning Healthcare Systems
  • Using Healthcare Data in Embedded Pragmatic Clinical Trials among People Living with Dementia and Their Caregivers: State of the Art
  • Selecting Outcomes to Ensure Pragmatic Trials Are Relevant to People Living with Dementia
  • Engaging Stakeholders in the Design and Conduct of Embedded Pragmatic Clinical Trials for Alzheimer’s Disease and Alzheimer’s Disease–Related Dementias
  • Statistical Considerations for Embedded Pragmatic Clinical Trials in People Living with Dementia

Drs. Mitchell and Mor are also co–principal investigators of the Pragmatic Trial of Video Education in Nursing Homes (PROVEN), an NIH Collaboratory Trial. See the Living Textbook for more on the NIH Collaboratory Core Working Groups and NIH Collaboratory Trials.

June 19, 2020: Living Textbook Grand Rounds Series: Part 4-Demystifying Biostatistical Concepts for Embedded Pragmatic Clinical Trials (Elizabeth Turner, PhD; Patrick Heagerty, PhD; David Murray, PhD)

Posted on by Gina Uhlenbrauck

Speakers

Elizabeth Turner, PhD
Associate Professor
Department of Biostatistics & Bioinformatics
Duke Global Health Institute
Duke University  

Patrick Heagerty, PhD
Professor Department of Biostatistics
University of Washington  

David Murray, PhD
Associate Director for Prevention
Director, Office of Disease Prevention National Institutes of Health

Topic

Demystifying Biostatistical Concepts for Embedded Pragmatic Clinical Trials

Keywords

Embedded PCTs; Biostatistics; Trial design; Cluster-randomized trial (CRT); Stepped-wedge; Intraclass correlation coefficient; NIH Collaboratory Trial; Sample size; Individually randomized group treatment

Key Points

  • Focus on the research question, because that will drive the design, and the design will drive the analysis.
  • Select design features with analysis in mind, and collaborate early with a statistician. Weigh statistical choices against the challenges of implementation.
  • If possible, choose individual randomization. However, sometimes there is a strong rationale for choosing cluster/group randomization. Clustering must be accounted for in both design and analysis for CRTs and individually randomized group treatment (IRGT) trials.
  • The intraclass correlation coefficient (ICC) is a common measure of outcome clustering. Estimating the ICC is needed for study planning and power.
  • Increasing the number of clusters has more impact on power than increasing the number of patients per cluster.

Discussion Themes

With the move to virtual healthcare, the boundaries between clinic-based clusters have become more fluid. What approaches should trials use to describe contamination and estimate the impact of contamination on outcomes?

Read more about ICC in a Living Textbook resource and visit the Training Resources page for practical help on how to plan and conduct ePCTs.

Learn more in the Living Textbook about considerations for trial design and analysis for ePCTs.

Visit the NIH Collaboratory’s Biostatistics and Study Design Core webpage for more resources around design and analysis issues in ePCTs.

The NIH hosts a Research Methods Resources website with materials on this topic.

Tags

#pctGR, @Collaboratory1

June 22, 2020: NIH Offers Methods Webinar on Stepped-Wedge Cluster Randomized Trials

Posted on by Damon Seils

The NIH Office of Disease Prevention will continue its Methods: Mind the Gap webinar series on July 14 with “Overview of Statistical Models for the Design and Analysis of Stepped Wedge Cluster Randomized Trials.” Dr. Fan Li of Yale University, a longtime participant in the NIH Collaboratory’s Biostatistics and Study Design Core Working Group, will lead the webinar.

The Methods: Mind the Gap series explores research design, measurement, intervention, data analysis, and other methods of interest in prevention science. The July 14 session will address the stepped-wedge cluster randomized design, which has received increasing attention in pragmatic clinical trials (PCTs) and implementation science research. Since the design’s introduction, a variety of mixed-effects model extensions have been proposed for the design and analysis of PCTs. Dr. Li will provide a general model representation and discuss model extensions as alternative ways to characterize secular trends, intervention effects, and sources of heterogeneity. He will also review key model ingredients and clarify their implications for the design and analysis of stepped-wedge cluster randomized trials.

Register in advance to join the online presentation. Registration is required.

June 17, 2020: Living Textbook Grand Rounds Series Continues With “Demystifying Biostatistical Concepts”

Posted on by Damon Seils

Join us Friday, June 19, for “Demystifying Biostatistical Concepts for Embedded Pragmatic Clinical Trials,” the fourth session in our special 5-part Grand Rounds series focused on the Living Textbook. NIH Collaboratory investigators Drs. Liz Turner, Patrick Heagerty, and David Murray will discuss statistical design considerations, choosing the right design, and implications for the analysis. Topics covered will include:

  • RCTs, CRTs, and IRGTs: selecting the right trial design
  • Clustering and statistical power
  • Other analytical issues

See below for the full schedule of Living Textbook sessions and a special message from Dr. Kevin Weinfurt.

Living Textbook Grand Rounds Series
Date Title Speakers
January 31, 2020 Pragmatic Clinical Trials: How Do I Start?
  • Greg Simon, MD, MPH, Kaiser Permanente Washington Health Research Institute
  • Lesley H. Curtis, PhD, Duke University
February 28, 2020 Preparing for the Unknown: Conducting Pragmatic Research in Real-World Contexts
  • Jerry Jarvik, MD, MPH, University of Washington
  • Vince Mor, PhD, Brown University
  • Leah Tuzzio, MPH, Kaiser Permanente Washington Health Research Institute
March 27, 2020 Tips for Putting Together a Successful PCT Grand Application
  • Wendy Weber, ND, PhD, MPH, National Center for Complementary and Integrative Health
June 19, 2020 Demystifying Biostatistical Concepts for Embedded Pragmatic Clinical Trials
  • Liz Turner, PhD, Duke University
  • Patrick Heagerty, PhD, University of Washington
  • David M. Murray, PhD, National Institutes of Health
July 17, 2020 Choosing What to Measure and Making It Happen: Your Keys to Pragmatic Trial Success
  • Rachel Richesson, PhD, MPH, Duke University
  • Emily O’Brien, PhD, Duke University