Cheryl Erwin

Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study

BACKGROUND Although the association between cytosine-adenine-guanine (CAG) repeat length and age at onset of Huntingtons disease is well known, improved prediction of onset would be advantageous for clinical trial design and prognostic counselling. We compared various measures for tracking progression and predicting conversion to manifest Huntingtons disease. METHODS In this prospective observational study, we assessed the ability of 40 measures in five domains (motor, cognitive, psychiatric, functional, and imaging) to predict time to motor diagnosis of Huntingtons disease, accounting for CAG repeat length, age, and the interaction of CAG repeat length and age. Eligible participants were individuals from the PREDICT-HD study (from 33 centres in six countries [USA, Canada, Germany, Australia, Spain, UK]) with the gene mutation for Huntingtons disease but without a motor diagnosis (a rating below 4 on the diagnostic confidence level from the 15-item motor assessment of the Unified Huntingtons Disease Rating Scale). Participants were followed up between September, 2002, and July, 2014. We used joint modelling of longitudinal and survival data to examine the extent to which baseline and change of measures analysed separately was predictive of CAG-adjusted age at motor diagnosis. FINDINGS 1078 individuals with a CAG expansion were included in this analysis. Participants were followed up for a mean of 5·1 years (SD 3·3, range 0·0-12·0). 225 (21%) of these participants received a motor diagnosis of Huntingtons disease during the study. 37 of 40 cross-sectional and longitudinal clinical and imaging measures were significant predictors of motor diagnosis beyond CAG repeat length and age. The strongest predictors were in the motor, imaging, and cognitive domains: an increase of one SD in total motor score (motor domain) increased the risk of a motor diagnosis by 3·07 times (95% CI 2·26-4·16), a reduction of one SD in putamen volume (imaging domain) increased risk by 3·32 times (2·37-4·65), and a reduction of one SD in Stroop word score (cognitive domain) increased risk by 2·32 times (1·88-2·87). INTERPRETATION Prediction of diagnosis of Huntingtons disease can be improved beyond that obtained by CAG repeat length and age alone. Such knowledge about potential predictors of manifest Huntingtons disease should inform discussions about guidelines for diagnosis, prognosis, and counselling, and might be useful in guiding the selection of participants and outcome measures for clinical trials. FUNDING US National Institutes of Health, US National Institute of Neurological Disorders and Stroke, and CHDI Foundation.

Cognitive domains that predict time to diagnosis in prodromal Huntington disease

Background Prodromal Huntingtons disease (prHD) is associated with a myriad of cognitive changes but the domains that best predict time to clinical diagnosis have not been studied. This is a notable gap because some domains may be more sensitive to cognitive decline, which would inform clinical trials. Objectives The present study sought to characterise cognitive domains underlying a large test battery and for the first time, evaluate their ability to predict time to diagnosis. Methods Participants included gene negative and gene positive prHD participants who were enrolled in the PREDICT-HD study. The CAG–age product (CAP) score was the measure of an individuals genetic signature. A factor analysis of 18 tests was performed to identify sets of measures or latent factors that elucidated core constructs of tests. Factor scores were then fit to a survival model to evaluate their ability to predict time to diagnosis. Results Six factors were identified: (1) speed/inhibition, (2) verbal working memory, (3) motor planning/speed, (4) attention–information integration, (5) sensory–perceptual processing and (6) verbal learning/memory. Factor scores were sensitive to worsening of cognitive functioning in prHD, typically more so than performances on individual tests comprising the factors. Only the motor planning/speed and sensory–perceptual processing factors predicted time to diagnosis, after controlling for CAP scores and motor symptoms. Conclusions The results suggest that motor planning/speed and sensory–perceptual processing are important markers of disease prognosis. The findings also have implications for using composite indices of cognition in preventive Huntingtons disease trials where they may be more sensitive than individual tests.

Perceptions of discrimination among persons who have undergone predictive testing for Huntington's disease†

Potential discrimination from genetic testing may undermine technological advances for health care. Researching long‐term consequences of testing for genetic conditions that may lead to discrimination is a public health priority. The consequences of genetic discrimination generate social, health, and economic burdens for society by diminishing opportunities for at‐risk individuals in a range of contexts. The current study objective was to investigate perceptions of genetic stigmatization and discrimination among persons who completed predictive testing for Huntingtons disease (HD). Using semi‐structured interviews and computerized qualitative analysis, the perceptions of 15 presymptomatic persons with a positive gene test predicting HD were examined with regard to differential treatment following testing. The sample comprised 11 women and 4 men, mostly married (73%), aged between 22 and 62 years, with an average education of 14.6 years (SD ± 2.57) and residing in urban, rural and suburban settings of eight U.S. States. Participants reported perceptions of consequences following disclosure of genetic test results in three areas: employment, insurance, and social relationships. Although most employed participants (90%) revealed their test results to their employers, nearly all reported they would not disclose this information to future employers. Most (87%) participants disclosed test results to their physician, but a similar majority (83%) did not tell their genetic status to insurers. Most participants (87%) disclosed test results to family and peers; patterns of disclosure varied widely. Discrimination concerns remain high in this sample and point to the need for more information to determine the extent and scope of the problem.

A pilot examination of the genome-wide DNA methylation signatures of subjects entering and exiting short-term alcohol dependence treatment programs

Alcoholism has a profound impact on millions of people throughout the world. However, the ability to determine if a patient needs treatment is hindered by reliance on self-reporting and the clinician’s capability to monitor the patient’s response to treatment is challenged by the lack of reliable biomarkers. Using a genome-wide approach, we have previously shown that chronic alcohol use is associated with methylation changes in DNA from human cell lines. In this pilot study, we now examine DNA methylation in peripheral mononuclear cell DNA gathered from subjects as they enter and leave short-term alcohol treatment. When compared with abstinent controls, subjects with heavy alcohol use show widespread changes in DNA methylation that have a tendency to reverse with abstinence. Pathway analysis demonstrates that these changes map to gene networks involved in apoptosis. There is no significant overlap of the alcohol signature with the methylation signature previously derived for smoking. We conclude that DNA methylation may have future clinical utility in assessing acute alcohol use status and monitoring treatment response.

Perception, experience, and response to genetic discrimination in Huntington disease: the international RESPOND-HD study

Genetic discrimination—defined as the denial of rights, privileges, or opportunities or other adverse treatment based solely on genetic information (including family history)—is an important concern to patients, healthcare professionals, lawmakers, and family members at risk for carrying a deleterious gene. Data from the United States, Canada, and Australia were collected from 433 individuals at risk for Huntington disease (HD) who have tested either positive or negative for the gene that causes HD and family members of affected individuals who have a 50% risk for developing the disorder but remain untested. Across all three countries, a total of 46.2% of respondents report genetic discrimination or stigma based on either their family history of HD or genetic testing for the HD gene mutation. We report on the overall incidence of discrimination and stigma in the domains of insurance (25.9%), employment (6.5%), relationships (32.9%), and other transactions (4.6%) in the United States, Canada, and Australia combined. The incidence of self‐reported discrimination is less than the overall worry about the risk of discrimination, which is more prevalent in each domain. Despite a relatively low rate of perceived genetic discrimination in the areas of health insurance and employment, compared to the perception of discrimination and stigma in personal relationships, the cumulative burden of genetic discrimination across all domains of experience represents a challenge to those at risk for HD. The effect of this cumulative burden on daily life decisions remains unknown.

Personal factors associated with reported benefits of Huntington disease family history or genetic testing.

AIMS A family history of Huntington disease (HD) or receiving results of HD predictive genetic testing can influence individual well-being, family relationships, and social interactions in positive and negative ways. The aim of this study was to examine benefits reported by people with an HD family history or those who have undergone predictive HD testing, as well as the personal variables associated with perceived benefits. METHODS Seventy-four of 433 people completing the International Response of a Sample Population to HD risk (I-RESPOND-HD) survey reported benefits. Knowledge and understanding was perceived as the most common benefit from participants in both groups. The next most frequent perceived benefits from a family history were connecting with others and achieving life meaning and insights. The next most common perceived benefits from genetic testing were life planning and social support. The least common perceived benefit for both groups was renewed hope and optimism. Older age and spirituality were significantly associated with benefits in both groups. CONCLUSIONS Perceptions of benefit may not be as likely until later years in people with prodromal HD. A developed sense of spirituality is identified as a personal resource associated with the perception of benefit from genetic testing for HD. Associations among spirituality, perceived benefits, and other indicators of personal and family well-being may be useful in genetic counseling and health care of people with prodromal HD.

In Their Own Words: Reports of Stigma and Genetic Discrimination by People at Risk for Huntington Disease in the International RESPOND-HD Study

Genetic discrimination may be experienced in the day‐to‐day lives of people at risk for Huntington disease (HD), encompassing occurrences in the workplace, when seeking insurance, within social relationships, and during other daily encounters. At‐risk individuals who have tested either positive or negative for the genetic expansion that causes HD, as well as at‐risk persons with a 50% chance for developing the disorder but have not had DNA testing completed the International RESPOND‐HD (I‐RESPOND‐HD) survey. One of the studys purposes was to examine perceptions of genetic stigmatization and discrimination. A total of 412 out of 433 participants provided narrative comments, and 191 provided related codable narrative data. The core theme, Information Control, refers to organizational policies and interpersonal actions. This theme was found in narrative comments describing genetic discrimination perceptions across employment, insurance, social, and other situations. These reports were elaborated with five themes: What They Encountered, What They Felt, What Others Did, What They Did, and What Happened. Although many perceptions were coded as hurtful, this was not true in all instances. Findings document that reports of genetic discrimination are highly individual, and both policy as well as interpersonal factors contribute to the outcome of potentially discriminating events.

Methylation array data can simultaneously identify individuals and convey protected health information: an unrecognized ethical concern

BackgroundGenome-wide methylation arrays are increasingly used tools in studies of complex medical disorders. Because of their expense and potential utility to the scientific community, current federal policy dictates that data from these arrays, like those from genome-wide genotyping arrays, be deposited in publicly available databases. Unlike the genotyping information, access to the expression data is not restricted. An underlying supposition in the current nonrestricted access to methylation data is the belief that protected health and personal identifying information cannot be simultaneously extracted from these arrays.ResultsIn this communication, we analyze methylation data from the Illumina HumanMethylation450 array and show that genotype at 1,069 highly informative loci, and both alcohol and smoking consumption information, can be derived from the array data.ConclusionsWe conclude that both potentially personally identifying information and substance-use histories can be simultaneously derived from methylation array data. Because access to genetic information about a database subject or one of their relatives is critical to the de-identification process, this risk of de-identification is limited at the current time. We propose that access to genome-wide methylation data be restricted to institutionally approved investigators who accede to data use agreements prohibiting re-identification.

Development of a medical humanities and ethics certificate program in Texas.

Education in the medical humanities and ethics is an integral part of the formation of future physicians. This article reports on an innovative approach to incorporating the medical humanities and ethics into the four-year curriculum in a Certificate Program spanning all four years of the medical school experience. The faculty of the McGovern Center for Humanities and Ethics at the University of Texas Medical School at Houston conceived and implemented this program to teach medical students a range of scholarly topics in the medical humanities and to engage the full human experience into the process of becoming a physician. This study follows six years of experience, and we report student experiences and learning in their own words.

A Review of Epigenetic Markers of Tobacco and Alcohol Consumption.

Over the past two decades, advances in genetic technologies have posed unexpected challenges to the ethical and legal framework guiding the application of the most recent advances in healthcare technologies. By and large, these challenges have been successfully met by the introduction by statutes such as the Genetic Information Nondiscrimination Act (GINA). However, over the past several years, these advances in the ability to measure genetic (or heritable) contributions to medical illness have been joined by advances in epigenetic (or acquired) contributions to common medical illnesses. Unfortunately, the moral and legal framework for the use of these epigenetic technologies, which can objectively determine the presence of medical illnesses such as diabetes or the consumption of substances of abuse, is not as well developed. This communication provides an introduction to the fundamentals of epigenetics and then reviews how some of the latest advances in this technology can now be used to assess the consumption of alcohol and tobacco. Next, the possible mechanisms through which these tools could be employed clinically are discussed. Finally, the authors outline the potential for misuse of this technology and suggest that well-informed policy could play a critical role in shaping the optimal implementation of epigenetic technologies.