Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data.

Expanded carrier screening (ECS) for recessive monogenic diseases requires prior knowledge of genomic variation, including DNA variants that cause disease. The composition of pathogenic variants differs greatly among human populations, but historically, research about monogenic diseases has focused mainly on people with European ancestry. By comparison, less is known about pathogenic DNA variants in people from other parts of the world. Consequently, inclusion of currently underrepresented Indigenous and other minority population groups in genomic research is essential to enable equitable outcomes in ECS and other areas of genomic medicine. Here, we discuss this issue in relation to the implementation of ECS in Australia, which is currently being evaluated as part of the national Government's Genomics Health Futures Mission. We argue that significant effort is required to build an evidence base and genomic reference data so that ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. These efforts are essential steps to achieving the Australian Government's objectives and its commitment "to leveraging the benefits of genomics in the health system for all Australians." They require culturally safe, community-led research and community involvement embedded within national health and medical genomics programs to ensure that new knowledge is integrated into medicine and health services in ways that address the specific and articulated cultural and health needs of Indigenous people. Until this occurs, people who do not have European ancestry are at risk of being, in relative terms, further disadvantaged.

They Can Have Our Cake - But Can We Eat It? Access to Raw Genomic Data under Australian Privacy Law.

There is an increasing demand for the return of raw genomic data by research participants in translational genomic research. This article discusses the scope and application of privacy and freedom of information legislative provisions in Australia. Whether there is a right to access a copy of such data under Australian privacy legislation is contingent on whether raw genomic data can identify an individual and this article explores the opportunities for genomic data to be linked to individuals. We conclude that despite the complexity and overlapping nature of privacy laws in Australia, there is a clear right on the part of research participants to access their raw genomic data.

Provenance and risk in transfer of biological materials.

Whereas biological materials were once transferred freely, there has been a marked shift in the formalisation of exchanges involving these materials, primarily through the use of Material Transfer Agreements (MTAs). This paper considers how risk aversion dominates MTA negotiations and the impact it may have on scientific progress. Risk aversion is often based on unwarranted fears of incurring liability through the use of a material or loss of control or missing out on commercialisation opportunities. Evidence to date has suggested that complexity tends to permeate even straightforward transactions despite extensive efforts to implement simple, standard MTAs. We argue that in most cases, MTAs need do little more than establish provenance, and any attempt to extend MTAs beyond this simple function constitutes stifling behaviour. Drawing on available examples of favourable practice, we point to a number of strategies that may usefully be employed to reduce risk-averse tendencies, including the promotion of simplicity, education of those engaged in the MTA process, and achieving a cultural shift in the way in which technology transfer office (TTO) success is measured in institutions employing MTAs.

General practitioner perceptions of assessment and reporting of absolute cardiovascular disease risk via pathology services: a qualitative study.

BACKGROUND: Guidelines for cardiovascular disease (CVD) prevention recommend assessment of absolute CVD risk to guide clinical management. Despite this, use among general practitioners (GPs) remains limited. OBJECTIVE: Pathology services may provide an appropriate setting to assess and report absolute CVD risk in patients attending for cholesterol measurement. This study aimed to explore GPs perceptions of such a service. METHODS: A focus group and semi-structured interviews were conducted with GPs (n = 18) in Tasmania, Australia, to identify perceptions of assessment and reporting of absolute CVD risk via pathology services. An example pathology report including absolute CVD risk was provided and discussed. Audio-recordings were transcribed and thematically coded by two researchers. RESULTS: Almost all GPs identified that absolute CVD risk assessed and reported via pathology services could address deficits in practice. First, by reducing the number of appointments required to collect risk factors. Second, by providing a systematic (rather than opportunistic) approach for assessment of absolute CVD risk. Third, by reducing misclassification of patient CVD risk caused by overreliance on clinical intuition. All GPs reported they would order absolute CVD risk when issuing a cholesterol referral if such a service was offered. GPs recommended improving the service by providing information on methods used to measure risk factors on the pathology report. CONCLUSIONS: Absolute CVD risk assessed and reported via pathology services may address challenges of screening CVD risk experienced by GPs in practice and encourage dedicated follow-up care for CVD prevention.

Integration of absolute cardiovascular disease risk assessment into routine blood cholesterol testing at pathology services.

BACKGROUND: Absolute cardiovascular disease (CVD) risk assessment is recommended for primary prevention of CVD, yet uptake in general practice is limited. Cholesterol requests at pathology services provide an opportunity to improve uptake by integrating absolute CVD risk assessment with this service. OBJECTIVE: This study aimed to assess the feasibility of such an additional service. METHODS: Two-hundred and ninety-nine patients (45-74 years) referred to pathology services for blood cholesterol had measurement of all variables required to determine absolute CVD risk according to Framingham calculator (blood pressure, age, sex, smoking and diabetes status via self-report). Data were recorded via computer-based application. The absolute risk score was communicated via the report sent to the referring medical practitioner as per usual practice. Evaluation questionnaires were completed immediately post visit and at 1-, 3- and 6-month follow-up via telephone (n = 262). RESULTS: Absolute CVD risk reports were issued for 90% of patients. Most patients (95%) reported that the length of time for the pathology service assessment was acceptable, and 91% that the self-directed computer-based application was easy to use. Seventy-eight per cent reported a preference for pathology services to conduct absolute CVD risk assessment. Only 2% preferred a medical practitioner. Of follow-up patients, 202 (75%) had a consultation with a medical practitioner, during which, aspects of CVD risk prevention were discussed (cholesterol and blood pressure 74% and 69% of the time, respectively). CONCLUSIONS: Measurement of absolute CVD risk in pathology services is feasible, highly acceptable among middle-to-older adults and may increase uptake of guideline-directed care in general practice.

Recurrence patterns identify aggressive form of human papillomavirus-dependent vulvar cancer.

BACKGROUND: Vulvar cancer is rare and, as a result, is understudied. Treatment is predominantly surgery, irrespective of the type of vulvar cancer, and is associated with physical, emotional and sexual complications. A cluster of human papillomavirus (HPV)-dependent vulvar cancer patients was identified in Arnhem Land Northern Territory (NT), Australia, in which young Indigenous women were diagnosed at 70 times the national incidence rate. AIMS: To assess whether women from the Arnhem Land cluster differ from women with vulvar squamous cell carcinoma (VSCC) and vulvar intraepithelial neoplasia (VIN) resident elsewhere in the NT in recurrence after treatment, disease progression and mortality. MATERIALS AND METHODS: A retrospective cohort study of NT-resident women diagnosed with VIN or invasive vulvar cancer (VSCC) between 1 January 1993 and 30 June 2015 was undertaken. Time to recurrence was assessed using cumulative incidence plots and Fine and Gray competing risk regression models. Mean cumulative count was used to estimate the burden of recurrent events. RESULTS: Indigenous women from Arnhem Land experienced more recurrences after treatment than non-Indigenous women, the cancers recurred faster, and Indigenous women have worse survival at five years. CONCLUSIONS: In characterising the epidemiological features of this cluster, we have identified a particularly aggressive form of vulvar cancer. This provides a unique opportunity for elucidating the aetiopathological pathways driving vulvar cancer development that may ultimately lead to preventive and therapeutic targets for this neglected malignancy. Further, these findings have important implications for clinical practice and HPV vaccination policy in the affected population.

Disclosure of Genetic Results to At-risk Relatives without Consent: Issues for Health Care Professionals in Australia.

Disclosure of genetic information without consent of the patient (proband) challenges the legal frameworks of privacy and confidentiality. Changes to privacy legislation enable and provide guidelines for undertaking disclosure, with the purpose of reducing the harm to genetic relatives who, armed with such information, may seek predictive testing themselves. Nevertheless, significant uncertainty remains for health care professionals in the application of the discretion to disclose genetic information to at-risk relatives. First, jurisdictional inconsistencies in privacy legislation present challenges for the provision of genetic services across the country. Second, the current guidelines provide insufficient clarity regarding the justification for disclosure of genetic information to reduce psychological harm to relatives. Third, the implications of a potential expansion of a legal duty of care to inform genetic relatives in some circumstances indicates that such a duty would be unduly burdensome for health care professionals, and suggests that revision of the threshold for use - rather than disclosure - of depersonalised genetic information may represent a pragmatic way forward.

Australia: regulating genomic data sharing to promote public trust.

The regulation of genomic data sharing in Australia is a confusing mix of common law, legislation, ethical guidelines, and codes of practice. Beyond privacy laws, which only apply to genomic data that meets the definition of personal information, the key regulatory lever is the National Health and Medical Research Council (NHMRC) National Statement for Ethical Conduct in Human Research ("National Statement") (2007). Compliance with the National Statement is a requirement for institutions to apply to the NHMRC for funding, and includes-among other things-requirements for review of most genomic research by Human Research Ethics Committees. The sections of the National Statement specifying requirements for research with human genomic data are currently under review, including proposed new requirements addressing the return of genetic research findings and oversight of transfer agreements. Ensuring the willingness of Australians to donate their genomic information and participate in medical research will require clarification and harmonisation of the applicable regulatory framework, along with reforms to ensure that these regulations reflect the conditions necessary to promote ongoing public trust in researchers and institutions.

Correction to: Australia: regulating genomic data sharing to promote public trust.

This article was inadvertently published under a draft title.

Regulation of Non-consensual Genetic Testing in Australia: Use of Samples from Deceased Persons.

The creation of a criminal offence for non-consensual genetic testing in Australia has been recommended repeatedly in recent years, but has not yet resulted in reform. The increasing affordability and accessibility of genome-wide analysis amplifies the potential harm that unauthorised testing could cause to individuals. The familial nature of genomic information means that there is also potential for serious harm to an individual's relatives or community, such that harm can result even when the individual whose sample is being tested is deceased. In preventing such harms, it is important not to unduly restrict clinical, research and forensic applications that will result in considerable benefits and can better be regulated through alternative means. For these reasons, an offence of non-consensual genetic testing should be introduced and expanded to include samples from deceased persons, subject to appropriate exceptions.

Genomics in research and health care with Aboriginal and Torres Strait Islander peoples.

Genomics is increasingly becoming an integral component of health research and clinical care. The perceived difficulties associated with genetic research involving Aboriginal and Torres Strait Islander people mean that they have largely been excluded as research participants. This limits the applicability of research findings for Aboriginal and Torres Strait Islander patients. Emergent use of genomic technologies and personalised medicine therefore risk contributing to an increase in existing health disparities unless urgent action is taken. To allow the potential benefits of genomics to be more equitably distributed, and minimise potential harms, we recommend five actions: (1) ensure diversity of participants by implementing appropriate protocols at the study design stage; (2) target diseases that disproportionately affect disadvantaged groups; (3) prioritise capacity building to promote Indigenous leadership across research professions; (4) develop resources for consenting patients or participants from different cultural and linguistic backgrounds; and (5) integrate awareness of issues relating to Indigenous people into the governance structures, formal reviews, data collection protocols and analytical pipelines of health services and research projects.

Runs of homozygosity and a cluster of vulvar cancer in young Australian Aboriginal women.

OBJECTIVE: A cluster of vulvar cancer exists in young Aboriginal women living in remote communities in Arnhem Land, Australia. A genetic case-control study was undertaken involving 30 cases of invasive vulvar cancer and its precursor lesion, high-grade vulvar intraepithelial neoplasia (VIN), and 61 controls, matched for age and community of residence. It was hypothesized that this small, isolated population may exhibit increased autozygosity, implicating recessive effects as a possible mechanism for increased susceptibility to vulvar cancer. METHODS: Genotyping data from saliva samples were used to identify runs of homozygosity (ROH) in order to calculate estimates of genome-wide homozygosity. RESULTS: No evidence of an effect of genome-wide homozygosity on vulvar cancer and VIN in East Arnhem women was found, nor was any individual ROH found to be significantly associated with case status. This study found further evidence supporting an association between previous diagnosis of CIN and diagnosis of vulvar cancer or VIN, but found no association with any other medical history variable. CONCLUSIONS: These findings do not eliminate the possibility of genetic risk factors being involved in this cancer cluster, but rather suggest that alternative analytical strategies and genetic models should be explored.

Genetic and epigenetic variation in vulvar cancer: current research and future clinical practice.

Vulvar cancer is a relatively rare gynaecological malignancy, the treatment of which is associated with significant patient morbidity. With reports that the incidence of vulvar cancer is increasing, there is a rising need for improved preventive, diagnostic and therapeutic tools. Recent advances within genetics and epigenetics present possible approaches for addressing this need, by contributing to the clarification of the aetiology of this disease, identifying screening and drug targets and introducing the potential for personalised treatments. This paper reviews the genetic and epigenetic research undertaken to date within vulvar cancer, evaluates its potential for clinical application and identifies directions for future research.

Body ownership and research.

This article questions whether recognition of property rights in human tissue .would enhance protection of the interests of donors of tissue used for research purposes. Best practice already obliges researchers to comply with a range of legal and ethical obligations, with particular focus on informed consent and research transparency. A number of lawsuits relating to research use of human tissue emphasise the central importance of informed consent to donors. Informed consent of communities, as well as individuals, becomes essential when engaging in research with indigenous peoples. Increasingly genetic researchers are adopting participatory governance as a model for working with communities to develop culturally appropriate genetic studies that address health problems that are priorities for the communities involved. The transparency of the participatory governance model means that participants feel that their autonomy is respected and that their interests are being represented throughout the research process. The question of ownership of samples becomes irrelevant as control is codified through alternative mechanisms.

Context matters in genomic data sharing: a qualitative investigation into responses from the Australian public.

BACKGROUND: Understanding public attitudes to genomic data sharing is widely seen as key in shaping effective governance. However, empirical research in this area often fails to capture the contextual nuances of diverse sharing practices and regulatory concerns encountered in real-world genomic data sharing. This study aimed to investigate factors affecting public attitudes to data sharing through responses to diverse genomic data sharing scenarios. METHODS: A set of seven empirically validated genomic data sharing scenarios reflecting a range of current practices in Australia was used in an open-ended survey of a diverse sample of the Australian public (n = 243). Qualitative responses were obtained for each of the scenarios. Respondents were each allocated one scenario and asked five questions on: whether (and why/not) they would share data; what sharing would depend on; benefits and risks of sharing; risks they were willing to accept if sharing was certain to result in benefits; and what could increase their comfort about sharing and any potential risk. A thematic analysis was used to examine responses, coded and validated by two blinded coders. RESULTS: Participants indicated an overall high willingness to share genomic information, although this willingness varied considerably between different scenarios. A strong perception of benefits was reported as the foremost explanation for willingness to share across all scenarios. The high degree of convergence in the perception of benefits and the types of benefits identified by participants across all the scenarios suggests that the differentiation in intention to share may lie in perceptions of risk, which showed distinct patterns within and between the different scenarios. Some concerns were shared strongly across all scenarios, particularly benefit sharing, future use, and privacy. CONCLUSIONS: Qualitative responses provide insight into popular assumptions regarding existing protections, conceptions of privacy, and which trade-offs are generally acceptable. Our results indicate that public attitudes and concerns are heterogeneous and influenced by the context in which sharing takes place. The convergence of key themes such as benefits and future uses point to core concerns that must be centred in regulatory responses to genomic data sharing.

Better Mechanisms Are Needed to Oversee HREC Reviews.

Hawe et al. raise concerns about Human Research Ethics Committees (HRECs) taking a risk-averse and litigation-sensitive approach to ethical review of research proposals. HRECs are tasked with reviewing proposals for compliance with the National Statement on Ethical Conduct in Human Research for the purpose of promoting the welfare of participants. While these guidelines intentionally include a significant degree of discretion in HREC decision making, there is also evidence that HRECs sometimes request changes that go beyond the guidance provided by the National Statement. When HRECs request changes outside their remit, inconsistencies between individual HRECs become more common, contributing to delays in ethical review and reducing the quality of HREC decision making. Improvements to the HREC regulatory system are needed to promote transparency and accountability.

General practitioners maintain a focus on blood pressure management rather than absolute cardiovascular disease risk management.

BACKGROUND: Absolute cardiovascular disease (aCVD) risk assessment is recommended in CVD prevention guidelines. Yet, General Practitioners (GPs) often focus on single risk factors, including blood pressure (BP). Pathology services may be suitable to undertake high-quality automated unobserved BP (AOBP) measurement and aCVD risk assessment. This study explored GP attitudes towards AOBP measurement via pathology services and the role of BP in aCVD risk management. METHODS: A brief survey was completed, after which a focus group (n = 8 GPs) and interviews (n = 10 GPs) explored attitudes to AOBP and aCVD risk via pathology services with an example pathology report discussed. Verbatim transcripts were thematically coded. RESULTS: GPs predominantly used doctor-measured BP despite low levels of confidence. High BP measured by AOBP reported with aCVD risk via pathology services, would prompt a follow-up response. However, GPs focused on BP management. GPs were concerned about AOBP equivalency to routine BP measurements. After protocol explanation, GPs reported AOBP could value-add to care delivery. CONCLUSION: GPs lacked familiarity of AOBP and maintained a focus on BP management in the context of absolute CVD risk. Targeted education on AOBP and BP management as part of absolute CVD risk is needed to support guideline-directed care in practice.

Australian human research ethics committee members' confidence in reviewing genomic research applications.

Human research ethics committees (HRECs) are evaluating increasing quantities of genomic research applications with complex ethical considerations. Genomic confidence is reportedly low amongst many non-genetics-experts; however, no studies have evaluated genomic confidence levels in HREC members specifically. This study used online surveys to explore genomic confidence levels, predictors of confidence, and genomics resource needs of members from 185 HRECs across Australia. Surveys were fully or partially completed by 145 members. All reported having postgraduate 94 (86%) and/or bachelor 15 (14%) degrees. Participants consisted mainly of researchers (n = 45, 33%) and lay members (n = 41, 30%), affiliated with either public health services (n = 73, 51%) or public universities (n = 31, 22%). Over half had served their HREC [Formula: see text]3 years. Fifty (44%) reviewed genomic studies [Formula: see text]3 times annually. Seventy (60%) had undertaken some form of genomic education. While most (94/103, 91%) had high genomic literacy based on familiarity with genomic terms, average genomic confidence scores (GCS) were moderate (5.7/10, n = 119). Simple linear regression showed that GCS was positively associated with years of HREC service, frequency of reviewing genomic applications, undertaking self-reported genomic education, and familiarity with genomic terms (p < 0.05 for all). Conversely, lay members and/or those relying on others when reviewing genomic studies had lower GCSs (p < 0.05 for both). Most members (n = 83, 76%) agreed further resources would be valuable when reviewing genomic research applications, and online courses and printed materials were preferred. In conclusion, even well-educated HREC members familiar with genomic terms lack genomic confidence, which could be enhanced with additional genomic education and/or resources.