Tabitha Hendershot

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.

Risk factors for Kaposi's sarcoma among HHV-8 seropositive homosexual men with AIDS

Kaposis sarcoma (KS) is a frequent complication of the acquired immunodeficiency syndrome (AIDS) in homosexual men. Risk factors for developing this malignancy are uncertain, other than immunosuppression and coinfection with human herpesvirus 8 (HHV‐8). We therefore examined factors associated with KS in a cross‐sectional analysis of 99 cases among 503 HHV‐8 seropositive homosexual men with AIDS. Data were collected by computer‐assisted personal interviews and medical chart reviews. HHV‐8 seroreactivity was determined by enzyme‐linked immunosorbent assay for antibodies against HHV‐8 K8.1 glycoprotein. KS was significantly less common in blacks compared to whites [risk ratio (RR) = 0.4; 95% CI = 0.2 =0.8] and more common in subjects who had completed college (RR = 1.7; 95% CI = 1.1–2.7) or had annual income greater than

The National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC): results from phase I and scientific opportunities in phase II.

30,000 (RR = 1.5; 95% CI = 1.1–2.2). KS was less common in cigarette smokers (RR = 0.6; 95% CI = 0.5–0.9) and users of crack cocaine (RR = 0.4; 95% CI = 0.1–0.8). KS was less common in bisexual men compared to men who were exclusively homosexual (estimated RR = 0.6; 95% CI = 0.4–0.9) and inversely associated with number of female partners. KS was also less common in men who had received pay for sex (RR = 0.6; 95% CI = 0.4–1.0). These cross‐sectional associations could be biased by potential differences in relative timing of HHV‐8 and HIV infection, a postulated determinant of KS risk. Alternatively, our findings may reflect factors protective against KS in individuals infected with HHV‐8. Future research should focus on identifying practical measures for countering KS that do not increase the risk of other diseases. Published 2005 Wiley‐Liss, Inc.

Aortic Complications Associated With Pregnancy in Marfan Syndrome: The NHLBI National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC)

BACKGROUND Genetically triggered thoracic aortic conditions (GenTACs) represent an important problem for patients and their families. Accordingly, the National Heart, Lung, and Blood Institute established the first phase of its national GenTAC Registry in 2006. ENROLLMENT AND DIAGNOSES Between 2007 and 2010, 6 enrolling centers established the GenTAC I Registry consisting of 2,046 patients (Marfan syndrome 576 [28.2%], bicuspid aortic valve disease 504 [24.6%], aneurysm or dissection age <50 years 369 [18%], and others). Biologic samples for DNA analyses (white blood cells or saliva) are available in 97%, and stored plasma is available in 60% of enrollees. RESULTS Initial scientific inquiry using the GenTAC Registry has included validation studies of genetic causes for aortic syndromes, potential usefulness of transforming growth factor beta (TGFB) blood levels in Marfan subjects, and current surgical approaches to ascending aortic conditions. FUTURE OPPORTUNITY The second phase of GenTAC will allow biannual follow-up of GenTAC I enrollees for up to 9 years, enrollment of an additional 1,500 subjects, further integration of imaging findings with clinical and genetic data through utilization of an imaging core laboratory, important validation of phenotype-genotype correlations through a phenotyping core laboratory, and integration of a scientific advisory committee to help define the full range and depth of the Registrys scientific capabilities. The registry resources are available to the external scientific community through an application process accessible at https://gentac.rti.org.

GenTAC registry report: Gender differences among individuals with genetically triggered thoracic aortic aneurysm and dissection:

Background The risk of aortic complications associated with pregnancy in women with Marfan syndrome (MFS) is not fully understood. Methods and Results MFS women participating in the large National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) were evaluated. Among 184 women with MFS in whom pregnancy information was available, 94 (51%) had a total of 227 pregnancies. Among the women with pregnancies, 10 (10.6%) experienced a pregnancy‐related aortic complication (4 type A and 3 type B dissections, 1 coronary artery dissection, and 2 with significant [≥3 mm] aortic growth). Five of 7 aortic dissections, including all 3 type B, and the coronary dissection (75% of all dissections) occurred in the postpartum period. Only 5 of 8 women with pregnancy‐associated dissection were aware of their MFS diagnosis. The rate of aortic dissection was higher during the pregnancy and postpartum period (5.4 per 100 person‐years vs 0.6 per 100 person‐years of nonpregnancy; rate ratio, 8.4 [95% CI=3.9, 18.4]; P<0.0001). Conclusions Pregnancy in MFS is associated with an increased risk of aortic dissection, both types A and B, particularly in the immediate postpartum period. Lack of knowledge of underlying MFS diagnosis before aortic dissection is a major contributing factor. These findings underscore the need for early diagnosis, prepregnancy risk counseling, and multidisciplinary peripartum management.

Marfan Syndrome and Quality of Life in the GenTAC Registry

Previous data suggest women are at increased risk of death from aortic dissection. Therefore, we analyzed data from the GenTAC registry, the NIH‐sponsored program that collects information about individuals with genetically triggered thoracic aortic aneurysms and cardiovascular conditions. We performed cross‐sectional analyses in adults with Marfan syndrome (MFS), familial thoracic aortic aneurysm or dissection (FTAAD), bicuspid aortic valve (BAV) with thoracic aortic aneurysm or dissection, and subjects under 50 years of age with thoracic aortic aneurysm or dissection (TAAD <50 years). Women comprised 32% of 1,449 subjects and were 21% of subjects with BAV, 34% with FTAAD, 22% with TAAD <50 years, and 47% with MFS. Thoracic aortic dissections occurred with equal gender frequency yet women with BAV had more extensive dissections. Aortic size was smaller in women but was similar after controlling for BSA. Age at operation for aortic valve dysfunction, aneurysm or dissection did not differ by gender. Multivariate analysis (adjusting for age, BSA, hypertension, study site, diabetes, and subgroup diagnoses) showed that women had fewer total aortic surgeries (OR = 0.65, P < 0.01) and were less likely to receive angiotensin converting enzyme inhibitors (ACEi; OR = 0.68, P < 0.05). As in BAV, other genetically triggered aortic diseases such as FTAAD and TAAD <50 are more common in males. In women, decreased prevalence of aortic operations and less treatment with ACEi may be due to their smaller absolute aortic diameters. Longitudinal studies are needed to determine if women are at higher risk for adverse events.

PhenX measures for phenotyping rare genetic conditions

BACKGROUND Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL. OBJECTIVES This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data. METHODS QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity. RESULTS In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL. CONCLUSIONS In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity.

Surgical Treatment of Patients Enrolled in the National Registry of Genetically Triggered Thoracic Aortic Conditions

Introduction:The PhenX Toolkit, an online resource of well-established measures of phenotypes and exposures, now has 16 new measures recommended for assessing rare genetic conditions.Materials and Methods:These measures and their protocols were selected by a working group of domain experts with input from the scientific community.Results:The measures, which cover life stages from birth through adulthood, include clinical scales, characterization of rare genetic conditions, bioassays, and questionnaires. Most are broadly applicable to rare genetic conditions (e.g., family history, growth charts, bone age, and body proportions). Some protocols (e.g., sweat chloride test) target specific conditions.Discussion:The rare genetic condition measures complement the existing measures in the PhenX Toolkit that cover anthropometrics, demographics, mental health, and reproductive history. They are directed at research pertaining to common and complex diseases. PhenX measures are publicly available and are recommended to help standardize assessments across a range of biomedical study designs. To facilitate incorporation of measures into human subjects’ research, the Toolkit offers data collection worksheets and compatible data dictionaries.Conclusion:Widespread use of standard PhenX measures in clinical, translational, and epidemiological research will enable more uniform cross-study comparisons and increase statistical power with the potential for enhancing scientific discovery.Genet Med advance online publication 12 January 2017