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Diagnostic exome sequencing (ES) can be performed on the proband only (singleton; sES) or with additional samples, often including both biological parents with the proband (trio; tES). In this study we sought to compare the efficiencies of exome sequencing (ES) by trio (tES) versus singleton (sES) approach, determine costs, and identify factors to consider when deciding on optimal implementation strategies for the diagnosis of monogenic disorders. We undertook ES in 30 trios and analysed each proband’s sES and tES data in parallel. Two teams were randomly allocated to either sES or tES analysis for each case and blinded to each other’s work. Each task was timed and cost analyses were based on time taken and diagnostic yield. We modelled three scenarios to determine the factors to consider in the implementation of tES. sES diagnosed 11/30 (36.7%) cases and tES identified one additional diagnosis (12/30 (40.0%)). tES obviated the need for Sanger segregation, reduced the number of variants for curation, and had lower cost-per-diagnosis when considering analysis alone. When sequencing costs were included, tES nearly doubled the cost of sES. Reflexing to tES in those who remain undiagnosed after sES was cost-saving over tES in all as first-line. This approach requires a large differential in diagnostic yield between sES and tES for maximal benefit given current sequencing costs. tES may be preferable when scaling up laboratory throughput due to efficiency gains and opportunity cost considerations. Our findings are relevant to clinicians, laboratories and health services considering tES over sES.

CYP2C19 loss of function (LOF) carriers undergoing percutaneous coronary intervention (PCI) have an increased risk of ischemic events when treated with clopidogrel. PCI patients in TAILOR-PCI were randomized to clopidogrel or genotype-guided (GG) therapy in which LOF carriers received ticagrelor and non-carriers clopidogrel. Direct medical costs associated with a GG approach have not been described before. TAILOR-PCI participants for whom direct medical costs were available for the duration from the date of PCI to one-year post PCI were included. Primary cost estimates were obtained from the Mayo Clinic Cost Data Warehouse. There were no differences in direct medical costs between the GG and clopidogrel groups (mean $20,682 versus $19,747, p  = 0.11) however total costs were greater in the GG group (mean $21,245 versus $19,891, p  = 0.02) which was primarily driven by ticagrelor costs. In conclusion the increased expense of a GG strategy post PCI as compared to clopidogrel for all is primarily driven by the cost of ticagrelor.

Great uncertainty exists about the costs associated with whole-genome sequencing (WGS). One hundred cardiology patients with cardiomyopathy diagnoses and 100 ostensibly healthy primary care patients were randomized to receive a family-history report alone or with a WGS report. Cardiology patients also reviewed prior genetic test results. WGS costs were estimated by tracking resource use and staff time. Downstream costs were estimated by identifying services in administrative data, medical records, and patient surveys for 6 months. The incremental cost per patient of WGS testing was $5,098 in cardiology settings and $5,073 in primary care settings compared with family history alone. Mean 6-month downstream costs did not differ statistically between the control and WGS arms in either setting (cardiology: difference = −$1,560, 95% confidence interval −$7,558 to $3,866, p = 0.36; primary care: difference = $681, 95% confidence interval −$884 to $2,171, p = 0.70). Scenario analyses showed the cost reduction of omitting or limiting the types of secondary findings was less than $69 and $182 per patient in cardiology and primary care, respectively. Short-term costs of WGS were driven by the costs of sequencing and interpretation rather than downstream health care. Disclosing additional types of secondary findings has a limited cost impact following disclosure.

Gastrointestinal stromal tumor (GIST) is frequently driven by oncogenic KIT variations. Imatinib targeting of KIT marked a new era in GIST treatment and ushered in precision oncological treatment for all solid malignant neoplasms. However, studies on the molecular biological traits of GIST have found that tumors respond differentially to imatinib dosage based on the KIT exon with variation. Despite this knowledge, few patients undergo genetic testing at diagnosis, and empirical imatinib therapy remains routine. Barriers to genetic profiling include concerns about the cost and utility of testing. To determine whether targeted gene testing (TGT) is a cost-effective diagnostic for patients with metastatic GIST from the US payer perspective. This economic evaluation developed a Markov model to compare the cost-effectiveness of TGT and tailored first-line therapy compared with empirical imatinib therapy among patients with a new diagnosis of metastatic GIST. The main health outcome, quality-adjusted life years (QALYs), and costs were obtained from the literature, and transitional probabilities were modeled from disease progression and survival estimates from randomized clinical trials of patients with metastatic GIST. Data analyses were conducted October 2019 to January 2020. TGT and tailored first-line therapy. The primary outcome was QALYs and cost. Cost-effectiveness was defined using an incremental cost-effectiveness ratio, with an incremental cost-effectiveness ratio less than $100 000/QALY considered cost-effective. One-way and probabilistic sensitivity analyses were conducted to assess model stability. Therapy directed by TGT was associated with an increase of 0.10 QALYs at a cost of $9513 compared with the empirical imatinib approach, leading to an incremental cost-effectiveness ratio of $92 100. These findings were sensitive to the costs of TGT, drugs, and health utility model inputs. Therapy directed by TGT remained cost-effective for genetic testing costs up to $3730. Probabilistic sensitivity analysis found that TGT-directed therapy was considered cost-effective 70% of the time. These findings suggest that using genetic testing to match treatment of KIT variations to imatinib dosing is a cost-effective approach compared with empirical imatinib.

Background Therapies may be more efficacious when targeting a patient subpopulation with specific attributes, thereby enhancing the cost-effectiveness of treatment. In the CRYSTAL study, patients with metastatic colorectal cancer (mCRC) were treated with cetuximab plus FOLFIRI or FOLFIRI alone until disease progression, unacceptable toxic effects or withdrawal of consent. Objective To determine if stratified use of cetuximab based on genetic biomarker detection improves cost-effectiveness. Methods We used individual patient data from CRYSTAL to compare the cost-effectiveness, cost per life-year (LY) and cost per quality-adjusted LY (QALY) gained of cetuximab plus FOLFIRI versus FOLFIRI alone in three cohorts of patients with mCRC: all randomised patients (intent-to-treat; ITT), tumours with no detectable mutations in codons 12 and 13 of exon 2 of the KRAS protein (‘KRAS wt’) and no detectable mutations in exons 2, 3 and 4 of KRAS and exons 2, 3 and 4 of NRAS (‘RAS wt’). Survival analysis was conducted using RStudio, and a cost-utility model was modified to allow comparison of the three cohorts. Results The deterministic base-case ICER (cost per QALY gained) was £130,929 in the ITT, £72,053 in the KRAS wt and £44,185 in the RAS wt cohorts for cetuximab plus FOLFIRI compared with FOLFIRI alone. At a £50,000 willingness-to-pay threshold, cetuximab plus FOLFIRI has a 2.8, 20 and 63% probability of being cost-effective for the ITT, KRAS wt and RAS wt cohorts, respectively, versus FOLFIRI alone. Conclusion Screening for mutations in both KRAS and NRAS may provide the most cost-effective approach to patient selection.

Background The Melanoma Genomics Managing Your Risk Study is a randomised controlled trial that aims to evaluate the efficacy of providing information on personal genomic risk of melanoma in reducing ultraviolet radiation (UV) exposure, stratified by traditional risk group (low or high phenotypic risk) in the general population. The primary outcome is objectively measured total daily Standard Erythemal Doses at 12 months. Secondary outcomes include UV exposure at specific time periods, self-reported sun protection and skin-examination behaviours, psychosocial outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the cost-effectiveness of the intervention. Objective To publish the pre-determined statistical analysis plan (SAP) before database lock and the start of analysis. Methods This SAP describes the data synthesis, analysis principles and statistical procedures for analysing the outcomes from this trial. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid potential analysis bias that may arise from knowledge of the outcome data. Results This SAP is consistent with best practice and should enable transparent reporting. Conclusion This SAP has been developed for the Melanoma Genomics Managing Your Risk Study and will be followed to ensure high-quality standards of internal validity and to minimise analysis bias. Trial registration Prospectively registered with the Australian New Zealand Clinical Trials Registry, ID: ACTR N12617000691347 . Registered on 15 May 2017.

Background: A recent clinical trial has demonstrated that patients with acute coronary syndromes (ACS) and the reduced function allele CYP2C19 *2 (*2 allele), who are treated with thienopyridines, have an increased risk of adverse cardiac events with clopidogrel, but not with prasugrel. The frequency of the *2 allele varies by ethnicity and the Maoris, Asians and Pacific Islanders of New Zealand have a relatively high incidence. Objective: Our objective was to evaluate, from a New Zealand health system perspective, the cost effectiveness of treating all ACS patients with generic clopidogrel compared with prasugrel, and also compared with the genetically guided strategy that *2 allele carriers receive prasugrel and non-carriers receive clopidogrel. Methods: A decision-tree model consisting of five health states (myocardial infarction, stroke, bleeding, stent thrombosis and cardiovascular death) was developed. Clinical outcome data (two TRITON-TIMI 38 genetic sub-studies) comparing clopidogrel and prasugrel for both *2 allele carriers and non-carriers were combined with the prevalence of the heterozygosity for the *2 allele in New Zealand Europeans (15%), Maoris (24%), Asians (29%) and Pacific Islanders (45%) to determine the predicted adverse event rate for the New Zealand population. National hospital diagnosis-related group (DRG) discharge codes were used to determine alternative adverse event rates, along with the costs of hospitalizations during the 15 months after patients presented with an ACS. The primary outcome measure was the incremental cost per QALY (calculated using literature-reported weights). Monte Carlo simulations and alternative scenario analysis based on both clinical trial and national hospital incidence were used. Additional analysis considered the overall TRITON-TIMI 38 rates. Costs (in New Zealand dollars [$NZ], year 2009 values) and benefits were discounted at 3% per annum. Results: Actual hospital-based adverse event rates were higher than those reported in the TRITON-TIMI 38 randomized controlled trial and the genetic sub-studies, especially for myocardial infarction and cardiovascular death, and for Maoris and Pacific Islanders. For both sources of adverse event rates, treating the population with prasugrel was associated with worse outcomes (QALYs) than clopidogrel. However, prasugrel became cost effective ($NZ31 751/QALY) when the overall TRITON-TIMI 38 rates were used. A genetic test to guide the selected use of prasugrel was cost effective ($NZ8702/QALY versus $NZ24617/QALY) for hospital and clinical trial incidence, respectively. Based on the hospital rates, the genetically guided strategy was especially cost effective for Maoris ($NZ7312/QALY) and Pacific Islanders ($NZ7041/QALY). These results were robust to the sensitivity analysis, except the genetically guided strategy under the 15-month clinical trial event rate scenario ($NZ168 748/QALY) did not remain cost effective under a $NZ50 000 threshold. Conclusions: Use of a genetic test to guide thienopyridine treatment in patients with ACS is a potentially cost-effective treatment strategy, especially for Maoris and Pacific Islanders. This treatment strategy also has the potential to reduce ethnic health disparities that exist in New Zealand. However, the results comparing clopidogrel and prasugrel are sensitive to whether the genetic sub-studies or the overall TRITON-TIMI 38 rates are used. While the national hospital event rates may be more appropriate for the New Zealand population, many assumptions are required when they are used to adjust the genetic sub-studies rates.

New genetic tests for adult-onset diseases raise concerns about possible adverse selection in insurance markets. To test for this behavior, we followed 148 cognitively normal people participating in a randomized clinical trial of genetic testing for Alzheimer's disease for one year after risk assessment and Apolipoprotein E (APOE) genotype disclosure. Although no significant differences were found in health, life, or disability insurance purchases, those who tested positive were 5.76 times more likely to have altered their long-term care insurance than those who did not receive APOE genotype disclosure. If genetic testing for Alzheimer's risk assessment becomes common, it could trigger adverse selection in long-term care insurance. [PUBLICATION ABSTRACT]

Increasingly, women are offered genetic testing shortly after diagnosis of breast cancer to facilitate decision-making about treatment, often referred to as ‘treatment-focused genetic testing’ (TFGT). As understanding the attitudes of health professionals is likely to inform its integration into clinical care we surveyed professionals who participated in our TFGT randomized control study. Thirty-six completed surveys were received (response rate 59 %), 15 (42 %) health professionals classified as genetic and 21 (58 %) as non-genetic. Mainly positive experiences with participating in the TFGT trial were reported. The high cost of testing and who could best deliver information about TGFT to the patient were raised as key constraints to implementation of TFGT in usual care. More non-genetic than genetic health professionals (44 vs 8 %) preferred that the surgeon provide the information for decision-making about TFGT. While costs of TFGT itself and the time and effort of staff involved were perceived barriers, as testing costs become lower, it is expected that TFGT will become a routine part of standard clinical care for patients at high genetic risk in the near future.

- Next-generation sequencing (NGS) is a technology being used by many laboratories to test for inherited disorders and tumor mutations. This technology is new for many practicing pathologists, who may not be familiar with the uses, methodology, and limitations of NGS. - To familiarize pathologists with several aspects of NGS, including current and expanding uses; methodology including wet bench aspects, bioinformatics, and interpretation; validation and proficiency; limitations; and issues related to the integration of NGS data into patient care. - The review is based on peer-reviewed literature and personal experience using NGS in a clinical setting at a major academic center. - The clinical applications of NGS will increase as the technology, bioinformatics, and resources evolve to address the limitations and improve quality of results. The challenge for clinical laboratories is to ensure testing is clinically relevant, cost-effective, and can be integrated into clinical care.