Australian researcher's perspectives on the Australian industry-led moratorium on genetic tests in life insurance.

Fear of insurance discrimination can inhibit genetic research participation. In 2019, an industry-led partial moratorium on using genetic results in Australian life insurance underwriting was introduced. This mixed-methods study used online surveys (n = 59 participants) and semi-structured interviews (n = 22 participants) to capture researchers' perceptions about the moratorium. 66% (n = 39/59) were aware of the moratorium before the survey. Of researchers returning genetic results, 56% (n = 22/39) reported that insurance implications were mentioned in consent forms, but a minority reported updating consent forms post-moratorium (n = 13/39, 33%). Most researchers reported that concerns regarding life insurers utilizing research results inhibited recruitment (35/59, 59%), and few perceived that the moratorium positively influenced participation (n = 9/39, 23%). These findings were supported by qualitative findings which revealed that genetic discrimination concerns were a major issue for some individuals, though these concerns could be eclipsed by the promise of a diagnosis through research participation. The majority thought a regulatory solution should be permanent (n = 34/51, 67%), have financial limits of at least ≥1,000,000 AUD (37/51, 73%), and involve government oversight/legislation (n = 44/51, 86%). In an era where an increasing number of research studies involve genomics as a primary or secondary objective, it is crucial that we have regulatory solutions to address participants' hesitation.

Public willingness to participate in population DNA screening in Australia.

BACKGROUND: Population-based DNA screening for medically actionable conditions has the potential to improve public health by enabling early detection, treatment and/or prevention; however, public attitudes and willingness to participate in DNA screening have not been well investigated. METHODS: We presented a scenario to members of the Australian public, randomly selected from the electoral roll via the Australian Survey of Societal Attitudes, describing an adult population DNA screening programme currently under development, to detect risk of medically actionable cancers and heart disease. We asked questions regarding willingness to participate and pay, preferred delivery methods and concerns. RESULTS: We received 1060 completed questionnaires (response rate 23%, mean age 58 years). The vast majority (>92%) expressed willingness to undertake DNA screening. When asked about the optimal age of screening, most (56%) favoured early adulthood (aged 18-40 years) rather than at birth or childhood. Many respondents would prefer samples and data be kept for re-screening (36%) or research use (43%); some preferred samples to be destroyed (21%). Issues that decrease likelihood of participation included privacy (75%) and insurance (86%) implications. CONCLUSION: Our study demonstrates public willingness to participate in population DNA screening in Australia, and identifies barriers to participation, to be addressed in the design of screening programmes. Results are informing the development of a pilot national DNA screening programme.

Population-based BRCA1/2 testing programmes are highly acceptable in the Jewish community: results of the JeneScreen Study.

BACKGROUND: Ashkenazi Jewish (AJ) people have a higher incidence of BRCA1/2 pathogenic variants (PVs) than unselected populations. Three BRCA-Jewish founder mutations (B-JFMs) comprise >90% of BRCA1/2 PVs in AJ people. Personal/family cancer history-based testing misses ≥50% of people with B-JFM. METHODS: We compared two population-based B-JFM screening programmes in Australia-using (1) an online tool (Sydney) and (2) in-person group sessions (Melbourne). RESULTS: Of 2167 Jewish people tested (Sydney n=594; Melbourne n=1573), 1.3% (n=28) have a B-JFM, only 2 of whom had a significant cancer family history (Manchester score ≥12). Pretest anxiety scores were normal (mean 9.9±3.5 (6-24)), with no significant post-result change (9.5±3.3). Decisional regret (mean 7.4±13.0 (0-100)), test-related distress (mean 0.8+/2.2 (0-30)) and positive experiences (reverse-scored) (mean 3.4±4.5 (1-20)) scores were low, with no significant differences between Sydney and Melbourne participants. Post-education knowledge was good overall (mean 11.8/15 (±2.9)) and significantly higher in Melbourne than Sydney. Post-result knowledge was the same (mean 11.7 (±2.4) vs 11.2 (±2.4)). Participants with a B-JFM had higher post-result anxiety and test-related distress and lower positive experiences, than those without a B-JFM, but scores were within the normal range. Family cancer history did not significantly affect knowledge or anxiety, or pretest perception of B-JFM or cancer risks. Most participants (93%) were satisfied/very satisfied with the programme. CONCLUSION: Both B-JFM screening programmes are highly acceptable to Australian Jewish communities. The programme enabled identification of several individuals who were previously unaware they have a B-JFM, many of whom would have been ineligible for current criteria-based testing in Australia.

A step forward, but still inadequate: Australian health professionals' views on the genetics and life insurance moratorium.

BACKGROUND: In 2019, the Australian life insurance industry introduced a partial moratorium (ban) limiting the use of genetic test results in life insurance underwriting. The moratorium is industry self-regulated and applies only to policies below certain financial limits (eg, $500 000 of death cover). METHODS: We surveyed Australian health professionals (HPs) who discuss genetic testing with patients, to assess knowledge of the moratorium; reported patient experiences since its commencement; and HP views regarding regulation of genetic discrimination (GD) in Australia. RESULTS: Between April and June 2020, 166 eligible HPs responded to the online survey. Of these, 86% were aware of the moratorium, but <50% had attended related training/information sessions. Only 16% answered all knowledge questions correctly, yet 69% believed they had sufficient knowledge to advise patients. Genetics HPs' awareness and knowledge were better than non-genetics HPs' (p<0.05). There was some reported decrease in patients delaying/declining testing after the moratorium's introduction, however, 42% of HPs disagreed that patients were more willing to have testing post-moratorium. Although many (76%) felt the moratorium resolved some GD concerns, most (88%) still have concerns, primarily around self-regulation, financial limits and the moratorium's temporary nature. Almost half (49%) of HPs reported being dissatisfied with the moratorium as a solution to GD. The majority (95%) felt government oversight is required, and 93% felt specific Australian legislation regarding GD is required. CONCLUSION: While the current Australian moratorium is considered a step forward, most HPs believe it falls short of an adequate long-term regulatory solution to GD in life insurance.

Population genomic screening of young adults for familial hypercholesterolaemia: a cost-effectiveness analysis.

AIMS: The aim of this study was to assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolaemia (FH). METHODS AND RESULTS: We designed a decision analytic Markov model to compare the current standard of care for heterozygous FH diagnosis in Australia (opportunistic cholesterol screening and genetic cascade testing) with the alternate strategy of population genomic screening of adults aged 18-40 years to detect pathogenic variants in the LDLR/APOB/PCSK9 genes. We used a validated cost-adaptation method to adapt findings to eight high-income countries. The model captured coronary heart disease (CHD) morbidity/mortality over a lifetime horizon, from healthcare and societal perspectives. Risk of CHD, treatment effects, prevalence, and healthcare costs were estimated from published studies. Outcomes included quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER), discounted 5% annually. Sensitivity analyses were undertaken to explore the impact of key input parameters on the robustness of the model. Over the lifetime of the population (4 167 768 men; 4 129 961 women), the model estimated a gain of 33 488years of life lived and 51 790 QALYs due to CHD prevention. Population genomic screening for FH would be cost-effective from a healthcare perspective if the per-test cost was ≤AU$250, yielding an ICER of

Knowledge, views and expectations for cancer polygenic risk testing in clinical practice: A cross-sectional survey of health professionals.

Polygenic risk scores (PRS) are becoming increasingly available in clinical practice to evaluate cancer risk. However, little is known about health professionals' knowledge, attitudes, and expectations of PRS. An online questionnaire was distributed by relevant health professional organisations predominately in Australia, Canada and the US to evaluate health professionals' knowledge, views and expectations of PRS. Eligible participants were health professionals who provide cancer risk assessments. Results from the questionnaire were analysed descriptively and content analysis was undertaken of free-text responses. In total, 105 health professionals completed the questionnaire (genetic counsellors 84%; oncologists 6%; clinical geneticists 4%; other 7%). Although responses differed between countries, most participants (61%) had discussed PRS with patients, 20% had ordered a test and 14% had returned test results to a patient. Confidence and knowledge around interpreting PRS were low. Although 69% reported that polygenic testing will certainly or likely influence patient care in the future, most felt unprepared for this. If scaled up to the population, 49% expect that general practitioners would have a primary role in the provision of PRS, supported by genetic health professionals. These findings will inform the development of resources to support health professionals offering polygenic testing, currently and in the future.

Study protocol: the Australian genetics and life insurance moratorium-monitoring the effectiveness and response (A-GLIMMER) project.

BACKGROUND: The use of genetic test results in risk-rated insurance is a significant concern internationally, with many countries banning or restricting the use of genetic test results in underwriting. In Australia, life insurers' use of genetic test results is legal and self-regulated by the insurance industry (Financial Services Council (FSC)). In 2018, an Australian Parliamentary Inquiry recommended that insurers' use of genetic test results in underwriting should be prohibited. In 2019, the FSC introduced an industry self-regulated moratorium on the use of genetic test results. In the absence of government oversight, it is critical that the impact, effectiveness and appropriateness of the moratorium is monitored. Here we describe the protocol of our government-funded research project, which will serve that critical function between 2020 and 2023. METHODS: A realist evaluation framework was developed for the project, using a context-mechanism-outcome (CMO) approach, to systematically assess the impact of the moratorium for a range of stakeholders. Outcomes which need to be achieved for the moratorium to accomplish its intended aims were identified, and specific data collection measures methods were developed to gather the evidence from relevant stakeholder groups (consumers, health professionals, financial industry and genetic research community) to determine if aims are achieved. Results from each arm of the study will be analysed and published in peer-reviewed journals as they become available. DISCUSSION: The A-GLIMMER project will provide essential monitoring of the impact and effectiveness of the self-regulated insurance moratorium. On completion of the study (3 years) a Stakeholder Report will be compiled. The Stakeholder Report will synthesise the evidence gathered in each arm of the study and use the CMO framework to evaluate the extent to which each of the outcomes have been achieved, and make evidence-based recommendations to the Australian federal government, life insurance industry and other stakeholders.

Explainable AI enables clinical trial patient selection to retrospectively improve treatment effects in schizophrenia.

BACKGROUND: Heterogeneity among patients' responses to treatment is prevalent in psychiatric disorders. Personalized medicine approaches-which involve parsing patients into subgroups better indicated for a particular treatment-could therefore improve patient outcomes and serve as a powerful tool in patient selection within clinical trials. Machine learning approaches can identify patient subgroups but are often not "explainable" due to the use of complex algorithms that do not mirror clinicians' natural decision-making processes. METHODS: Here we combine two analytical approaches-Personalized Advantage Index and Bayesian Rule Lists-to identify paliperidone-indicated schizophrenia patients in a way that emphasizes model explainability. We apply these approaches retrospectively to randomized, placebo-controlled clinical trial data to identify a paliperidone-indicated subgroup of schizophrenia patients who demonstrate a larger treatment effect (outcome on treatment superior than on placebo) than that of the full randomized sample as assessed with Cohen's d. For this study, the outcome corresponded to a reduction in the Positive and Negative Syndrome Scale (PANSS) total score which measures positive (e.g., hallucinations, delusions), negative (e.g., blunted affect, emotional withdrawal), and general psychopathological (e.g., disturbance of volition, uncooperativeness) symptoms in schizophrenia. RESULTS: Using our combined explainable AI approach to identify a subgroup more responsive to paliperidone than placebo, the treatment effect increased significantly over that of the full sample (p < 0.0001 for a one-sample t-test comparing the full sample Cohen's d = 0.82 and a generated distribution of subgroup Cohen's d's with mean d = 1.22, std d = 0.09). In addition, our modeling approach produces simple logical statements (if-then-else), termed a "rule list", to ease interpretability for clinicians. A majority of the rule lists generated from cross-validation found two general psychopathology symptoms, disturbance of volition and uncooperativeness, to predict membership in the paliperidone-indicated subgroup. CONCLUSIONS: These results help to technically validate our explainable AI approach to patient selection for a clinical trial by identifying a subgroup with an improved treatment effect. With these data, the explainable rule lists also suggest that paliperidone may provide an improved therapeutic benefit for the treatment of schizophrenia patients with either of the symptoms of high disturbance of volition or high uncooperativeness. TRIAL REGISTRATION: clincialtrials.gov identifier: NCT 00,083,668; prospectively registered May 28, 2004.

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals.

PURPOSE: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals. METHODS: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards. RESULTS: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders. CONCLUSION: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.

Correction: Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.

In the original version of this Article, the affiliation details for Lei Zhang were given as Monash University. While working on the Article Dr. Zhang was also affiliated with the Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China. This has now been corrected in both the PDF and HTML versions of the Article.

Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.

PURPOSE: To consider the impact and cost-effectiveness of offering preventive population genomic screening to all young adults in a single-payer health-care system. METHODS: We modeled screening of 2,688,192 individuals, all adults aged 18-25 years in Australia, for pathogenic variants in BRCA1/BRCA2/MLH1/MSH2 genes, and carrier screening for cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS), at 71% testing uptake using per-test costs ranging from AUD$200 to $1200 (~USD$140 to $850). Investment costs included genetic counseling, surveillance, and interventions (reimbursed only) for at-risk individuals/couples. Cost-effectiveness was defined below AUD$50,000/DALY (disability-adjusted life year) prevented, using an incremental cost-effectiveness ratio (ICER), compared with current targeted testing. Outcomes were cancer incidence/mortality, disease cases, and treatment costs reduced. RESULTS: Population screening would reduce variant-attributable cancers by 28.8%, cancer deaths by 31.2%, and CF/SMA/FXS cases by 24.8%, compared with targeted testing. Assuming AUD$400 per test, investment required would be between 4 and 5 times higher than current expenditure. However, screening would lead to substantial savings in medical costs and DALYs prevented, at a highly cost-effective ICER of AUD$4038/DALY. At AUD$200 per test, screening would approach cost-saving for the health system (ICER = AUD$22/DALY). CONCLUSION: Preventive genomic screening in early adulthood would be highly cost-effective in a single-payer health-care system, but ethical issues must be considered.

Direct notification by health professionals of relatives at-risk of genetic conditions (with patient consent): views of the Australian public.

Genetic risk information for medically actionable conditions has relevance for patients' blood relatives. However, cascade testing uptake in at-risk families is <50%, and the burden of contacting relatives is a significant barrier to dissemination of risk information. Health professionals (HPs) could notify at-risk relatives directly, with patients' consent. This practice is supported by international literature, including strong public support. However, there is little exploration of the Australian public's views about this issue. We surveyed Australian adults using a consumer research company. Respondents were provided a hypothetical scenario and asked about views and preferences regarding direct contact by HPs. 1030 members of the public responded, with median age 45 y and 51% female. The majority would want to be told about genetic risk for conditions that can be prevented/treated early (85%) and contacted directly by a HP (68%). Most preferred a letter that included specific information about the genetic condition in the family (67%) and had no privacy concerns about HPs sending a letter using contact details provided by a relative (85%). A minority (< 5%) had significant privacy concerns, mostly about use of personal contact information. Concerns included ensuring information was not shared with third parties. Almost 50% would prefer that a family member contacted them before the letter was sent, while about half did not prefer this or were unsure. The Australian public supports (and prefers) direct notification of relatives at risk of medically actionable genetic conditions. Guidelines would assist with clarifying clinicians' discretion in this area.

Community concerns about genetic discrimination in life insurance persist in Australia: A survey of consumers offered genetic testing.

Fears of genetic discrimination in life insurance continue to deter some Australians from genetic testing. In July 2019, the life insurance industry introduced a partial, self-regulated moratorium restricting the use of genetic results in underwriting, applicable to policies up to certain limits (eg AUD$500,000 for death cover).We administered an online survey to consumers who had taken, or been offered, clinical genetic testing for adult-onset conditions, to gather views and experiences about the moratorium and the use of genetic results in life insurance, including its regulation.Most respondents (n = 367) had undertaken a genetic test (89%), and had a positive test result (76%; n = 243/321). Almost 30% (n = 94/326) reported testing after 1 July 2019. Relatively few respondents reported knowing about the moratorium (16%; n = 54/340) or that use of genetic results in life insurance underwriting is legal (17%; n = 60/348). Only 4% (n = 14/350) consider this practice should be allowed. Some respondents reported ongoing difficulties accessing life insurance products, even after the moratorium. Further, discrimination concerns continue to affect some consumers' decision-making about having clinical testing and applying for life insurance products, despite the Moratorium being in place. Most respondents (88%; n = 298/340) support the introduction of legislation by the Australian government to regulate this issue.Despite the introduction of a partial moratorium in Australia, fears of genetic discrimination persist, and continue to deter people from genetic testing. Consumers overwhelmingly consider life insurers should not be allowed to use genetic results in underwriting, and that federal legislation is required to regulate this area.

A proposal for an inclusive working definition of genetic discrimination to promote a more coherent debate.

Genetic discrimination is an evolving phenomenon that impacts fundamental human rights such as dignity, justice and equity. Although, in the past, various definitions to better conceptualize genetic discrimination have been proposed, these have been unable to capture several key facets of the phenomenon. In this Perspective, we explore definitions of genetic discrimination across disciplines, consider criticisms of such definitions and show how other forms of discrimination and stigmatization can compound genetic discrimination in a way that affects individuals, groups and systems. We propose a nuanced and inclusive definition of genetic discrimination, which reflects its multifaceted impact that should remain relevant in the face of an evolving social context and advancing science. We argue that our definition should be adopted as a guiding academic framework to facilitate scientific and policy discussions about genetic discrimination and support the development of laws and industry policies seeking to address the phenomenon.

"Uninsurable because of a genetic test": a qualitative study of consumer views about the use of genetic test results in Australian life insurance.

Genetic testing can provide valuable information to mitigate personal disease risk, but the use of genetic results in life insurance underwriting is known to deter many consumers from pursuing genetic testing. In 2019, following Australian Federal Parliamentary Inquiry recommendations, the Financial Services Council (FSC) introduced an industry-led partial moratorium, prohibiting life insurance companies from using genetic test results for policies up to $AUD500,000. We used semi-structured interviews to explore genetic test consumers' experiences and views about the FSC moratorium and the use of genetic results by life insurers. Individuals who participated in an online survey and agreed to be re-contacted to discuss the issue further were invited. Interviews were 20-30-min long, conducted via video conference, transcribed verbatim and analysed using inductive content analysis. Twenty-seven participants were interviewed. Despite the moratorium, concerns about genetic discrimination in life insurance were prevalent. Participants reported instances where life insurers did not consider risk mitigation when assessing risk for policies based on genetic results, contrary to legal requirements. Most participants felt that the moratorium provided inadequate protection against discrimination, and that government legislation regulating life insurers' use of genetic results is necessary. Many participants perceived the financial limits to be inadequate, given the cost-of-living in Australia. Our findings indicate that from the perspective of participants, the moratorium has not been effective in allaying fears about genetic discrimination or ensuring adequate access to life insurance products. Concern about genetic discrimination in life insurance remains prevalent in Australia.