Exploring what lies behind public preferences for avoiding health losses caused by lapses in healthcare safety and patient lifestyle choices

© 2013 Singh et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This article has been made available through the Brunel Open Access Publishing Fund.Background: Although many studies have identified public preferences for prioritising health care interventions based on characteristics of recipient or care, very few of them have examined the reasons for the stated preferences. We conducted an on-line person trade-off (PTO) study (N=1030) to investigate whether the public attach a premium to the avoidance of ill health associated with alternative types of responsibilities: lapses in healthcare safety, those caused by individual action or lifestyle choice; or genetic conditions. We found that the public gave higher priority to prevention of harm in a hospital setting such as preventing hospital associated infections than genetic disorder but drug administration errors were valued similar to genetic disorders. Prevention of staff injuries, lifestyle diseases and sports injuries, were given lower priority. In this paper we aim to understand the reasoning behind the responses by analysing comments provided by respondents to the PTO questions. Method: A majority of the respondents who participated in the survey provided brief comments explaining preferences in free text responses following PTO questions. This qualitative data was transformed into explicit codes conveying similar meanings. An overall coding framework was developed and a reliability test was carried out. Recurrent patterns were identified in each preference group. Comments which challenged the assumptions of hypothetical scenarios were also investigated. Results: NHS causation of illness and a duty of care were the most cited reasons to prioritise lapses in healthcare safety. Personal responsibility dominated responses for lifestyle related contexts, and many respondents mentioned that health loss was the result of the individual’s choice to engage in risky behaviour. A small proportion of responses questioned the assumptions underlying the PTO questions. However excluding these from the main analysis did not affect the conclusions. Conclusion: Although some responses indicated misunderstanding or rejection of assumptions we put forward, the results were still robust. The reasons put forward for responses differed between comparisons but responsibility was the most frequently cited. Most preference elicitation studies only focus on eliciting numerical valuations but allowing for qualitative data can augment understanding of preferences as well as verifying results.EPSRC through the MATCH programme(EP/F063822/1 and EP/G012393/1) and HERG within Brunel University

A probable cis-acting genetic modifier of Huntington disease frequent in individuals with African ancestry

Huntington disease (HD)is a dominantly inherited neurodegenerative disorder caused by the expansion of a polyglutamine encoding CAG repeat in the huntingtin gene. Recently, it has been established that disease severity in HD is best predicted by the number of pure CAG repeats rather than total glutamines encoded. Along with uncovering DNA repair gene variants as trans-acting modifiers of HD severity, these data reveal somatic expansion of the CAG repeat as a key driver of HD onset. Using high-throughput DNA sequencing, we have determined the precise sequence and somatic expansion profiles of the HTT repeat tract of 68 HD-affected and 158 HD-unaffected African ancestry individuals. A high level of HTT repeat sequence diversity was observed, with three likely African-specific alleles identified. In the most common disease allele (30 out of 68), the typical proline-encoding CCGCCA sequence was absent. This CCGCCA-loss disease allele was associated with an earlier age of diagnosis of approximately 7.1 years and occurred exclusively on haplotype B2. Although somatic expansion was associated with an earlier age of diagnosis in the study overall, the CCGCCA-loss disease allele displayed reduced somatic expansion relative to the typical HTT expansions in blood DNA. We propose that the CCGCCA loss occurring on haplotype B2 is an African cis-acting modifier that appears to alter disease diagnosis of HD through a mechanism that is not driven by somatic expansion. The assessment of a group of individuals from an understudied population has highlighted population-specific differences that emphasize the importance of studying genetically diverse populations in the context of disease

Implications of direct-to-consumer whole-exome sequencing in South Africa

This editorial examines a number of vitally important ethical, legal and scientific concerns that have to be addressed to ensure proper and ethical implementation of direct-to-consumer whole-exome sequencing in South Africa. Individuals taking part in this endeavour must be fully informed of the positive and negative sequelae

A CIS-acting Modifier of Age at Diagnosis of Huntington Disease in Black South African Patients

Background: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder, presenting with a movement disorder, cognitive decline and psychiatric complications. HD is caused by the expansion of a CAG repeat tract in exon 1 of the huntingtin gene (HTT). In other repeat expansion disorders, variants within the associated repeat tracts may affect stability, which in turn modifies disease severity. Although sequence variation has been reported within the sequence encoding the HTT polyglutamine and polyproline tract, little is known about its effect on disease. Aim: To determine the sequence diversity precisely within the HTT exon 1 trinucleotide repeat in black South African individuals and assess the effect of sequence variation in modifying disease. Methods/techniques: A sample of black South African individuals (59 patients and 153 controls) was analysed using a specialised high-throughput DNA sequencing assay and data analysis pipeline, specific for the HTT exon 1 repeat. Results/outcomes: Significant diversity was observed in comparison to a European sample of patients, with novel African alleles defined by the description of allele sub-structures. The most common disease allele structure in our patients was associated with the absence of the CCGCCA cassette that precedes the polyproline CCG repeat in typical HD-causing alleles. Regression analysis determined that age at diagnosis was approximately 6 to 13 years earlier in patients carrying HD-causing alleles lacking the CCGCCA cassette. Conclusion: This is the first study to describe allele sequence diversity within the HTT exon 1 repeat in an African population. The absence of the CCGCCA cassette, which appears to be African-specific and associated with an earlier age at diagnosis in African HD patients, is a potential cis-acting modifier of HD onset

A CIS-acting Modifier of Age at Diagnosis of Huntington Disease in Black South African Patients

Background: Huntington disease (HD) is a dominantly inherited neurodegenerative disorder, presenting with a movement disorder, cognitive decline and psychiatric complications. HD is caused by the expansion of a CAG repeat tract in exon 1 of the huntingtin gene (HTT). In other repeat expansion disorders, variants within the associated repeat tracts may affect stability, which in turn modifies disease severity. Although sequence variation has been reported within the sequence encoding the HTT polyglutamine and polyproline tract, little is known about its effect on disease. Aim: To determine the sequence diversity precisely within the HTT exon 1 trinucleotide repeat in black South African individuals and assess the effect of sequence variation in modifying disease. Methods/techniques: A sample of black South African individuals (59 patients and 153 controls) was analysed using a specialised high-throughput DNA sequencing assay and data analysis pipeline, specific for the HTT exon 1 repeat. Results/outcomes: Significant diversity was observed in comparison to a European sample of patients, with novel African alleles defined by the description of allele sub-structures. The most common disease allele structure in our patients was associated with the absence of the CCGCCA cassette that precedes the polyproline CCG repeat in typical HD-causing alleles. Regression analysis determined that age at diagnosis was approximately 6 to 13 years earlier in patients carrying HD-causing alleles lacking the CCGCCA cassette. Conclusion: This is the first study to describe allele sequence diversity within the HTT exon 1 repeat in an African population. The absence of the CCGCCA cassette, which appears to be African-specific and associated with an earlier age at diagnosis in African HD patients, is a potential cis-acting modifier of HD onset

Implications of direct-to-consumer whole-exome sequencing in South Africa

Next-generation sequencing (NGS) has truly transformed human genetics and is now an integral discovery tool in the field. Whole-exome sequencing (WES) – an NGS application focused on the proteincoding regions of the human genome – has already bridged the bench-to-bedside divide internationally and is offered as a clinical test by several accredited laboratories. Clinical WES is not currently offered in South Africa (SA) for a number of reasons, including technological constraints, insufficient storage for the resulting large datasets, ethical considerations and limitations of our understanding of the impact of human genetic variants on health and in terms of clinical utility. The historical under-representation of individuals of black African descent in genomics research further complicates the interpretation of results obtained from WES data in black Africans. Concurrently, the application of WES for preventive healthcare in seemingly healthy individuals is progressing rapidly. WES offered as a direct-to-consumer (DTC) genetic test to healthy individuals in aid of wellness and future disease risk prediction raises many critical considerations, some of which were highlighted previously in the SAMJ by the Southern African Society for Human Genetics. This topic is currently back in the headlines as local health insurance company Discovery Health launched their suite of personalised medicine products, which includes WES.[5-7] This offering is presented in partnership with US-based company Human Longevity, Inc. (HLI) under the leadership of J Craig Venter.http://www.samj.org.zaam2017Immunolog

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

<p>Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.</p>