William R. Harlan

The PhenX Toolkit: Get the Most From Your Measures

The potential for genome-wide association studies to relate phenotypes to specific genetic variation is greatly increased when data can be combined or compared across multiple studies. To facilitate replication and validation across studies, RTI International (Research Triangle Park, North Carolina) and the National Human Genome Research Institute (Bethesda, Maryland) are collaborating on the consensus measures for Phenotypes and eXposures (PhenX) project. The goal of PhenX is to identify 15 high-priority, well-established, and broadly applicable measures for each of 21 research domains. PhenX measures are selected by working groups of domain experts using a consensus process that includes input from the scientific community. The selected measures are then made freely available to the scientific community via the PhenX Toolkit. Thus, the PhenX Toolkit provides the research community with a core set of high-quality, well-established, low-burden measures intended for use in large-scale genomic studies. PhenX measures will have the most impact when included at the experimental design stage. The PhenX Toolkit also includes links to standards and resources in an effort to facilitate data harmonization to legacy data. Broad acceptance and use of PhenX measures will promote cross-study comparisons to increase statistical power for identifying and replicating variants associated with complex diseases and with gene-gene and gene-environment interactions.

PhenX: a toolkit for interdisciplinary genetics research.

Purpose of review To highlight standard PhenX (consensus measures for Phenotypes and eXposures) measures for nutrition, dietary supplements, and cardiovascular disease research and to demonstrate how these and other PhenX measures can be used to further interdisciplinary genetics research. Recent findings PhenX addresses the need for standard measures in large-scale genomic research studies by providing investigators with high-priority, well established, low-burden measurement protocols in a web-based toolkit (https://www.phenxtoolkit.org). Cardiovascular and Nutrition and Dietary Supplements are just 2 of 21 research domains and accompanying measures included in the PhenX Toolkit. Summary Genome-wide association studies (GWAS) provide promise for the identification of genomic markers associated with different disease phenotypes, but require replication to validate results. Cross-study comparisons typically increase statistical power and are required to understand the roles of comorbid conditions and environmental factors in the progression of disease. However, the lack of comparable phenotypic, environmental, and risk factor data forces investigators to infer and to compare metadata rather than directly combining data from different studies. PhenX measures provide a common currency for collecting data, thereby greatly facilitating cross-study analysis and increasing statistical power for identification of associations between genotypes, phenotypes, and exposures.

Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group

Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option.

Using the PhenX Toolkit to Add Standard Measures to a Study

The PhenX (consensus measures for Phenotypes and eXposures) Toolkit (https://www.phenxtoolkit.org/) offers high‐quality, well‐established measures of phenotypes and exposures for use by the scientific community. The goal is to promote the use of standard measures, enhance data interoperability, and help investigators identify opportunities for collaborative and translational research. The Toolkit contains 395 measures drawn from 22 research domains (fields of research), along with additional collections of measures for Substance Abuse and Addiction (SAA) research, Mental Health Research (MHR), and Tobacco Regulatory Research (TRR). Additional measures for TRR that are expected to be released in 2015 include Obesity, Eating Disorders, and Sickle Cell Disease. Measures are selected by working groups of domain experts using a consensus process that includes input from the scientific community. The Toolkit provides a description of each PhenX measure, the rationale for including it in the Toolkit, protocol(s) for collecting the measure, and supporting documentation. Users can browse measures in the Toolkit or can search the Toolkit using the Smart Query Tool or a full text search. PhenX Toolkit users select measures of interest to add to their Toolkit. Registered Toolkit users can save their Toolkit and return to it later to revise or complete. They then have options to download a customized Data Collection Worksheet that specifies the data to be collected, and a Data Dictionary that describes each variable included in the Data Collection Worksheet. The Toolkit also has a Register Your Study feature that facilitates cross‐study collaboration by allowing users to find other investigators using the same PhenX measures.

Hyperforin plasma level as a marker of treatment adherence in the National Institutes of Health Hypericum Depression Trial

Background: A previously reported clinical trial of Hypericum perforatum (St Johns wort) in depression did not demonstrate efficacy. We assessed treatment adherence by measuring plasma hyperforin and evaluated the possible impact of adherence on study results. Methods: Outpatients with major depression (N = 340) were randomized to an 8-week trial of H. perforatum (900-1500 mg/d), sertraline (50-100 mg/d) as active comparator, or placebo. Plasma was available from 292 patients (86% of randomized). Samples from the placebo and H. perforatum groups were assayed for hyperforin, and samples from the sertraline group for sertraline/N-desmethyl-sertraline. Results: Of the 104 patients randomized to placebo, 18 (17%) had detectable plasma hyperforin. Of the 97 patients randomized to H. perforatum, 17 (17%) had no detectable plasma hyperforin. All the assayed sertraline patients (N = 91) had plasma sertraline/N-desmethyl-sertraline. The clinical trial conclusions remained unchanged when only patients with plasma assay consistent with random assignment were included in the analyses. Conclusions: One of every 6 patients assigned to placebo had plasma hyperforin, and 1 of every 6 patients assigned to H. perforatum had no detectable plasma hyperforin. The finding underscores the difficulty of enforcing treatment adherence in clinical trials of preparations that are readily available in the community.

Prevention Research at the National Institutes of Health

Prevention of disease and disability and preservation of health are compelling strategies that are endorsed by the public, health care providers, and researchers. Despite this general acceptance of the concept, the devil is in the details. What can and should be recommended with confidence to the public and health care providers regarding prevention and how can these recommendations be implemented? Prevention programs should be based on durable evidence of efficacy and should assure that the benefits of interventions and changes exceed the risks. The latter is particularly important for population-based primary prevention because many are influenced but fewer may benefit. Prevention research must provide the evidence of benefit and risk. The responsibility of the National Institutes of Health (NIH) is to develop the scientific basis for prevention and to train prevention scientists who are responsible for creating this science base. The interpretation and dissemination of information from research studies are important and necessary aspects to assure translation of the science into personal and public health practices. The components of prevention research are investigation of the factors that place individuals and groups at risk of disease and disability; trials of the interventions that can modify this risk; and testing the approaches that can effectively implement beneficial changes. NIH is committed to addressing these endeavors, and its individual Institutes and Centers support a broad portfolio of prevention research. This paper will provide an overview of NIH support, the functional relationships of prevention research within NIH, and background information that can be useful to those interested in research.

A Perspective on School-Based Cardiovascular Research

William R. Harlan is Director, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute. Address reprint requests to William R. Harlan, MD, Director, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892. The National Heart, Lung. and Blood Institute (NHLBI) has sustained a long and productive commitment to research in the prevention of disease. The NHLBI has supported observational and interventional efforts related to heart, lung, and blood conditions, but the focus of this presentation is cardiovascular disease. Great progress has been made and the pace has been increasing as an increasingly experienced cadre of investigators address a broad range of challenges. In this presentation, the author will review the scientific background for the study of school-based programs and comment on future challenges in prevention. The NHLBI has supported development of the science base for intervention and the application of this knowledge to prevention and education of cardiovascular diseases.

The PhenX Toolkit pregnancy and birth collections

PURPOSEnPregnancy and childbirth are normal conditions, but complications and adverse outcomes are common. Both genetic and environmental factors influence the course of pregnancy. Genetic epidemiologic research into pregnancy outcomes could be strengthened by the use of common measures, which would allow data from different studies to be combined or compared. Here, we introduce perinatal researchers to the PhenX Toolkit and the Collections related to pregnancy and childbirth.nnnMETHODSnThe Pregnancy and Birth Collections were drawn from measures in the PhenX Tooklit. The lead author selected a list of measures for each Collection, which was reviewed by the remaining authors and revised on the basis of their comments. We chose the measures we thought were most relevant for perinatal research and had been linked most strongly to perinatal outcomes.nnnRESULTSnThe Pregnancy and Birth Health Conditions Collection includes 24 measures related to pregnancy and fertility history, maternal complications, and infant complications. The Pregnancy and Birth Outcome Risk Factors Collection includes 43 measures of chemical, medical, psychosocial, and personal factors associated with pregnancy outcomes.nnnCONCLUSIONSnThe biological complexity of pregnancy and its sensitivity to environmental and genomic influences suggest that multidisciplinary approaches are needed to generate new insights or practical interventions. To fully exploit new research methods and resources, we encourage the biomedical research community to adopt standard measures to facilitate pooled or meta-analyses.

UNIT 1.21 Using the PhenX Toolkit to Add Standard Measures to a Study

The PhenX (consensus measures for Phenotypes and eXposures) Toolkit (https://www.phenxtoolkit.org/) offers high‐quality, well‐established measures of phenotypes and exposures for use by the scientific community. The Toolkit contains 295 measures drawn from 21 research domains (fields of research). The measures were selected by Working Groups of domain experts using a consensus process that included input from the scientific community. The Toolkit provides a description of each PhenX measure, the rationale for including it in the Toolkit, protocol(s) for collecting the measure, and supporting documentation. Users can browse by measures, domains, or collections, or can search the Toolkit using the Smart Query Tool. Once users have selected some measures, they can download a customized Data Collection Worksheet that specifies what information needs to be collected, and a Data Dictionary that describes each variable included in their Data Collection Worksheet. To help researchers find studies with comparable data, PhenX measures and variables are being mapped to studies in the database of Genotypes and Phenotypes (dbGaP). Curr. Protoc. Hum. Genet. 71:1.21.1‐1.21.18

Menopause: Epidemiologic Aspects

Menopause is the physiologic, psychological, and social transition from reproductive years to nonreproductive years. The interest and attention directed to the perimenopausal and postmenopausal years is increasing as life expectancy expands. At the turn of the last century, in 1900, the life expectancy of women in industrialized countries averaged just over 50 years. At the turn of this century, the expectancy will average about 80 years. Thus, in 1900, menopause heralded for many women an approaching end to life, but today it announces for women the start of a period of life that will comprise about one-third of their expected life span. Health providers and medical researchers should direct efforts not only to extending these years but to improving the quality of life.