Nancy Downing

A Closer Look at the Recommended Criteria for Disclosing Genetic Results: Perspectives of Medical Genetic Specialists, Genomic Researchers, and Institutional Review Board Chairs

Next generation sequencing offers benefit of improved health through knowledge, but comes with challenges, such as inevitable incidental findings (IFs). The applicability of recommended criteria for disclosure of individual results when applied to disclosure of IFs is not well known. The purpose of this study was to examine how medical genetic specialists, genomic researchers, and Institutional Review Board (IRB) chairs perceive the importance of recommended criteria when applied to genetic/genomic IFs. We conducted telephone interviews with medical genetic specialists (genetic counselors, genetic nurses, medical geneticists, laboratory professionals), genomic researchers, and IRB chairs (N = 103). Respondents rated and discussed the importance of nine recommended criteria regarding disclosure of genetic/genomic IFs. Stakeholders agreed the most important criteria for disclosure were: (1) the IF points to a life-threatening condition; (2) there is a treatment; (3) individuals indicate in writing they wanted to be informed of IFs. Criteria rated less important were: analytic validity, high penetrance, association with a young age of onset and relative risk more than 2.0. Respondents indicated that some technical criteria were confusing, and in need of context. Our findings suggest that development of guidelines regarding management of IF include multiple stakeholders’ perspectives and be based on a common language.

Milwaukee Police Department Retirees: Cardiovascular Disease Risk and Morbidity among Aging Law Enforcement Officers

This study explored the self-reported prevalence of cardiovascular disease (CVD) and accompanying risk factors among 165 male retirees 43 years and older (M = 56.2, SD = 7.1) from the Milwaukee Police Department (MPD) compared to 671 individuals of similar age and income who responded to the 2005 Wisconsin Behavioral Risk Factor Surveillance System (BRFSS). CVD and other risk factors were more prevalent in the MPD retirees than the general population (CVD 15.2% vs. 9.5%, p = .036; hypertension 51.5% vs. 36.2%, p = .001; hypercholesterolemia 62.4% vs. 44.4%, p = .001; overweight and obesity 85.1% vs. 74.7%, p = .005). In addition, other factors associated with CVD prevalence included working in law enforcement (odds ratio = 1.70; 95% confidence interval = 1.03 to 2.79). Results suggest an association between employment in law enforcement and an increase in CVD morbidity.

Researcher and Institutional Review Board Chair Perspectives on Incidental Findings in Genomic Research

AIMS Genomic research can produce findings unrelated to a studys aims. The purpose of this study was to examine researcher and Institutional Review Board (IRB) chair perspectives on genomic incidental findings (GIFs). METHODS Nineteen genomic researchers and 34 IRB chairs from 42 institutions participated in semi-structured telephone interviews. Researchers and chairs described GIFs within their respective roles. Few had direct experience with disclosure of GIFs. Researchers favored policies where a case by case determination regarding whether GIF disclosure would be offered after discovery, whereas IRB chairs preferred policies where procedures for disclosure would be determined prior to approval of the research. CONCLUSIONS Researcher and IRB chair perspectives on management of GIFs overlap, but each group provides a unique perspective on decisions regarding disclosure of GIFs in research. Engagement of both groups is essential in efforts to provide guidance for researchers and IRBs regarding disclosure of GIFs in research.

Developing strategic interventions to reduce cardiovascular disease risk among law enforcement officers: the art and science of data triangulation.

The purpose of this study was to use data triangulation to inform interventions targeted at reducing morbidity from cardiovascular disease (CVD) and associated risk factors among law enforcement officers. Using the Precede-Proceed Health Promotion Planning Model, survey data (n = 672) and focus group data (n = 8 groups) from the Milwaukee Police Department were analyzed. Narrative transcripts disclosed that law enforcement officers encounter potential barriers and motivators to a healthy lifestyle. Survey results indicated rates of overweight (71.1 % vs. 60.8%) and hypertension (27.4% vs. 17.6%) were significantly (p ⩽ .001) higher among Milwaukee Police Department law enforcement officers than the general population of Wisconsin (n = 2,855). The best predictor of CVD was diabetes (p = .030). Occupational health nurses are uniquely positioned to identify health risks, design appropriate interventions, and advocate for policy changes that improve the health of those employed in law enforcement and other high-risk professions.

Characterization of Depression in Prodromal Huntington Disease in the Neurobiological Predictors of HD (PREDICT-HD) Study

Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.

WHODAS 2.0 in prodromal Huntington disease: measures of functioning in neuropsychiatric disease

Clinical trials to improve day-to-day function in Huntington disease (HD) require accurate outcome measures. The DSM-5 recommends the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 for use in neuropsychiatric disorders. The DSM-5 also states proxy measures may be useful when cognitive function may be impaired. We tested WHODAS participant and companion ratings for differences in baseline and longitudinal function in three prodromal HD groups and a control group. Participants with prodromal HD were stratified by disease progression (low, medium, and high disease burden) based on their cytosine–adenine–guanine (CAG)-age product (CAP) score. Participant (N=726) and companion (N=630) WHODAS scores were examined for group differences, and for participant versus companion differences using linear mixed effects regression and Akaike’s information criterion to test model fit. We also compared WHODAS with the Total Functional Capacity (TFC) scale. At baseline, functioning on the WHODAS was rated worse by participants in the high group and companions compared with controls. For longitudinal changes, companions reported functional decline over time in the medium and high groups. In simultaneous analysis, participant and companion longitudinal trajectories showed divergence in the high group, suggesting reduced validity of self-report. The WHODAS showed greater longitudinal difference than the TFC in the medium group relative to controls, whereas the TFC showed greater longitudinal difference than WHODAS in the high group. Results suggest the WHODAS can identify baseline and longitudinal differences in prodromal HD and may be useful in HD clinical trials. Companions may provide more accurate data as the disease progresses.

The disclosure of incidental genomic findings: an “ethically important moment” in pediatric research and practice

Although there are numerous position papers on the issues and challenges surrounding disclosure of incidental genomic findings involving children, there is very little research. To fill this gap, the purpose of this study was to explore the perspectives of multiple professional (N = 103) and public (N = 63) stakeholders using both interviews and focus groups. Using qualitative analysis, we identified one overarching theme, “Its hard for us; its hard for them,” and three subthemes/questions: “What to disclose?,” “Who gets the information?,” and “What happens later?” Perspectives differed between professional (Institutional Review Board chairs, clinicians, and researchers) and public stakeholders. While professionals focused on the complexities of what to disclose, the lay public stated that parents should have all information laid out for them. Professionals pondered multiple parent and child situations, while the public identified parents as informational gatekeepers who know their children best. Professionals described the potential requirement for follow-up over time as a logistical “nightmare,” while the public believed that parents have the responsibility for managing their childrens health information over time. However, the parent role as gatekeeper was seen as time limited and in need of professional support and backup. Our findings present a case for needed dialogue around what we propose as an “ethically important moment,” with the goal of protecting and respecting the viewpoints of all stakeholders when policies regarding children are developed.

Perceived stress in prodromal Huntington disease

This study examines perceived stress and its relationship to depressive symptoms, life changes and functional capacity in a large sample of individuals who are positive for the Huntington disease (HD) gene expansion but not yet diagnosed. Participants were classified by estimated proximity to HD diagnosis (far, mid, near) and compared with a non-gene-expanded comparison group. Persons in the mid group had the highest stress scores. A significant interaction between age and time since HD genetic testing was also found. Secondary analyses using data from a different data collection point and including a diagnosed group showed the highest stress scores in the diagnosed group. Possible explanations and implications are discussed.

Relationships among stress measures, risk factors, and inflammatory biomarkers in law enforcement officers.

Law enforcement officers suffer higher morbidity and mortality rates from all causes than the general population. Cardiovascular disease (CVD) accounts for a significant portion of the excess illness, with a reported prevalence as high as 1.7 times that of the general population. To determine which occupational hazards cause this increased risk and morbidity, it is imperative to study law enforcement officers before they retire. The long-range goal of our research is to reduce the incidence of CVD-related illness and death among aging law enforcement officers. The purpose of the present study was to measure pro- and anti-atherogenic inflammatory markers in blood samples from law enforcement officers (n = 71) and determine what types of occupation-related stress correlate with differences in these markers. For each outcome variable of interest, we developed separate regression models. Two groups of potential predictors were examined for inclusion in the models. Selected measures of stress were examined for inclusion in the models, in addition to general covariates, such as gender, ethnicity, years in law enforcement, and body mass index. Our results revealed statistically significant relationships between several physiologic variables and measures of stress.

New measures to capture end of life concerns in Huntington disease: Meaning and Purpose and Concern with Death and Dying from HDQLIFE (a patient-reported outcomes measurement system).

PurposeHuntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD.MethodsAn EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items.ResultsEFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying.ConclusionThe HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.