Joshua A. Roth

A Formal Risk-Benefit Framework for Genomic Tests: Facilitating the Appropriate Translation of Genomics Into Clinical Practice

Purpose: Evaluation of genomic tests is often challenging because of the lack of direct evidence of clinical benefit compared with usual care and unclear evidence requirements. To address these issues, this study presents a risk-benefit framework for assessing the health-related utility of genomic tests.Methods: We incorporated approaches from a variety of established fields including decision science, outcomes research, and health technology assessment to develop the framework. Additionally, we considered genomic test stakeholder perspectives and case studies.Results: We developed a three-tiered framework: first, we use decision-analytic modeling techniques to synthesize data, project incidence of clinical events, and assess uncertainty. Second, we defined the health-related utility of genomic tests as improvement in health outcomes as measured by clinical event rates, life expectancy, and quality-adjusted life-years. Finally, we displayed results using a risk-benefit policy matrix to facilitate the interpretation and implementation of findings from these analyses.Conclusion: A formal risk-benefit framework may accelerate the utilization and practice-based evidence development of genomic tests that pose low risk and offer plausible clinical benefit, while discouraging premature use of tests that provide little benefit or pose significant health risks compared with usual care.

Prognostic Role of ERCC1 in Advanced Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

UNLABELLED Small observational studies have demonstrated an association between high ERCC1 expression level and poor prognosis in advanced NSCLC treated with platinum-based chemotherapy. This meta-analysis presents pooled estimates of association from 11 studies. High ERCC1 patients had lower response rates and higher risk of death relative to low ERCC1 patients. These results support the prognostic significance of ERCC1 expression level in advanced NSCLC. BACKGROUND Observational studies have demonstrated an association between excision repair cross-complementation group 1 (ERCC1) expression level and health outcomes in patients with advanced non-small-cell lung cancer (NSCLC) treated with platinum-based regimens. This analysis presents pooled estimates of association from these studies to better elucidate the prognostic role of ERCC1 in advanced NSCLC. METHODS A systematic literature search was conducted using the MEDLINE, EMBASE, and American Society of Clinical Oncology (ASCO) annual meeting databases from June 1995 to December 2010. Included studies were evaluated for clinical, methodological, and statistical heterogeneity. Pooled analyses were conducted using fixed and random effects models. RESULTS In high ERCC1 expression versus low ERCC1 expression patients, pooled analysis results demonstrated a significantly lower response (risk ratio [RR], 0.80, 0.66-0.98) and significantly higher risk of death (hazard ratio [HR], 2.04, (1.48-2.80)), respectively. Subgroup analyses demonstrated significant heterogeneity in outcomes by ERCC1 measurement method (I(2): 90.7%, P = 0.001) and patient population ethnicity (I(2): 66%, P = 0.003). CONCLUSION This studys findings support the hypothesis that ERCC1 expression is associated with response rate and overall survival (OS) in patients with advanced NSCLC treated with platinum-based chemotherapy. Heterogeneity in subgroup analyses demonstrates the need for standardized methods to classify ERCC1 expression level, studies evaluating the association between ERCC1 expression and OS in non-Asian populations, and studies evaluating interaction between ERCC1 and other known prognostic factors in advanced NSCLC.

Genetic Risk Factors for Major Bleeding in Patients Treated With Warfarin in a Community Setting

The influence of warfarin pharmacogenomics on major bleeding risk has been little studied in long‐term users and non–specialist care settings. We conducted a case–control study to evaluate associations between CYP2C9*2/*3, VKORC1(1173), and CYP4F2*3 variants and major bleeding among patients treated with warfarin in a community setting. We calculated major bleeding odds ratios, adjusting for race, duration of warfarin use, age, gender, and body mass index. In 265 cases and 305 controls with 3.4 and 3.7 mean years of warfarin use, respectively, CYP4F2*3 was associated with decreased major bleeding risk (odds ratio: 0.62; 95% confidence interval: 0.43–0.91). CYP2C9*2/*3 and VKORC1(1173) had null associations overall, but there was a nonsignificant increase in major bleeding risk in patients with duration <6 months (odds ratio: 1.30; 95% confidence interval: 0.60–2.83; odds ratio: 1.23; 95% confidence interval: 0.57–2.64, respectively). In summary, in the largest study of warfarin pharmacogenomics and major bleeding to date, we found a 38% lower risk in patients with CYP4F2*3, potentially reflecting interaction with warfarin and dietary vitamin K intake and warranting additional evaluation.

Economic Analysis of Prostate-Specific Antigen Screening and Selective Treatment Strategies

IMPORTANCE Prostate-specific antigen (PSA) screening for prostate cancer is controversial. Experts have suggested more personalized or more conservative strategies to improve benefit-risk tradeoffs, but the value of these strategies-particularly when combined with increased conservative management for low-risk cases-is uncertain. OBJECTIVES To evaluate the potential cost-effectiveness of plausible PSA screening strategies and to assess the value added by increased use of conservative management among low-risk, screen-detected cases. DESIGN, SETTING, AND PARTICIPANTS A microsimulation model of prostate cancer incidence and mortality was created. A simulated contemporary cohort of US men beginning at 40 years of age underwent 18 strategies for PSA screening. Treatment strategies included (1) contemporary treatment practices based on age and cancer stage and grade observed in the Surveillance, Epidemiology, and End Results program in 2010 or (2) selective treatment practices whereby cases with a Gleason score lower than 7 and clinical T2a stage cancer or lower are treated only after clinical progression, and all other cases undergo contemporary treatment practices. National and trial data on PSA growth, screening and biopsy patterns, incidence of prostate cancer, treatment distributions, treatment efficacy, mortality, health-related quality of life, and direct medical expenditure were analyzed. Data were collected from March 18, 2009, to August 15, 2014, and analyzed from November 20, 2012, to December 11, 2015. INTERVENTIONS Eighteen screening strategies that vary by start and stop age, screening interval, and criteria for biopsy referral and contemporary or selective treatment practices. MAIN OUTCOMES AND MEASURES Life-years (LYs), quality-adjusted life-years (QALYs), direct medical expenditure, and cost per LY and QALY gained. RESULTS All 18 screening strategies were associated with increased LYs (range, 0.03-0.06) and costs (

Economic return from the Women's Health Initiative estrogen plus progestin clinical trial: a modeling study.

263-

Stakeholder Perspectives on a Risk-Benefit Framework for Genetic Testing

1371) compared with no screening, with the cost ranging from

Projected Clinical, Resource Use, and Fiscal Impacts of Implementing Low-Dose Computed Tomography Lung Cancer Screening in Medicare.

7335 to

Cost-Effectiveness of a Computerized Provider Order Entry System in Improving Medication Safety Ambulatory Care

21 649 per LY. With contemporary treatment, only strategies with biopsy referral for PSA levels higher than 10.0 ng/mL or age-dependent thresholds were associated with increased QALYs (0.002-0.004), and only quadrennial screening of patients aged 55 to 69 years was potentially cost-effective in terms of cost per QALY (incremental cost-effectiveness ratio,

Cost-Effectiveness of Gemcitabine + Cisplatin vs. Gemcitabine Monotherapy in Advanced Biliary Tract Cancer

92 446). With selective treatment, all strategies were associated with increased QALYs (0.002-0.004), and several strategies were potentially cost-effective in terms of cost per QALY (incremental cost-effectiveness ratio,

The short-term cost-effectiveness of once-daily liraglutide versus once-weekly exenatide for the treatment of type 2 diabetes mellitus in the United States.

70 831-