Determination of test performance of two contemporary screening tests for Lynch syndrome in endometrial cancer: A clinical trial.

BACKGROUND/PURPOSE: Published data on the performance of the immunohistochemistry (IHC) test for mismatch repair (MMR) protein expression to detect Lynch syndrome (LS) index cases suggests it is highly variable; its performance in our system was unknown. Moreover, a brief family history questionnaire (bFHQ) developed by Eiriksson and colleagues in Canada demonstrated 100% sensitivity for LS case identification thus was of interest to us, but its performance outside of its original setting was unknown. Determination of the performance of these tests requires complete LS case identification in the testing population. METHODS: Two hundred women were recruited during routine care for endometrial cancer (EC) to administer the bFHQ and perform genetic testing for the LS genes. Independently, the IHC test was performed to screen for presumptive LS cases. We determined the sensitivity, specificity, and positive and negative predictive values of the bFHQ and IHC test as well as simulating outcomes of the complete protocols. RESULTS: Genetic testing all participants identified 8 cases of LS out of 200 (4% prevalence), the bFHQ identified 5 of 8 of these cases (62.5%, CI: 31.5%-87.6%), and the IHC test identified 6 or 7 of 8 cases (mean of 75% or 87.5%) depending on interpretation of test results. The specificities of the bFHQ and IHC test were 56.8% (CI: 49.8%-63.7%) and 79.8% (CI: 73.6%-85.1%), respectively. CONCLUSIONS: This study is the first, to our knowledge, to test the effectiveness of the bFHQ in an EC population since its original reporting; our results are consistent with many reports of the challenges of collecting family health history. The performance of the IHC test as a screen falls within ranges reported in the literature but do not provide the confidence to drive a decision for or against continued use of this test as a LS screen.

Economic Evaluation of Universal Lynch Syndrome Screening Protocols among Newly Diagnosed Patients with Colorectal Cancer.

We conducted an updated economic evaluation, from a healthcare system perspective, to compare the relative effectiveness and efficiency of eight Lynch syndrome (LS) screening protocols among newly diagnosed colorectal cancer (CRC) patients. We developed decision analytic models for a hypothetical cohort of 1000 patients. Model assumptions and parameter values were based on literature and expert opinion. All costs were in 2018 USD. For identifying LS cases, the direct germline sequencing (DGS) protocol provided the best performance (sensitivity 99.90%, 99.57-99.93%; specificity 99.50%, 97.28-99.85%), followed by the tumor sequencing to germline sequencing (TSGS) protocol (sensitivity, 99.42%, 96.55-99.63%; specificity, 96.58%, 96.46-96.60%). The immunohistochemistry (IHC) protocol was most efficient at $20,082 per LS case identified, compared to microsatellite instability (MSI) ($22,988), DGS ($31,365), and TSGS ($104,394) protocols. Adding double-somatic testing to IHC and MSI protocols did not change sensitivity and specificity, increased costs by 6% and 3.5%, respectively, but reduced unexplained cases by 70% and 50%, respectively. DGS would be as efficient as the IHC protocol when the cost of germline sequencing declines under $368 indicating DGS could be an efficient option in the near future. Until then, IHC and MSI protocols with double-somatic testing would be the optimal choices.

Model-Based Re-Examination of the Effectiveness of Tumor/Immunohistochemistry and Direct-to-Sequencing Protocols for Lynch Syndrome Case Finding in Endometrial Cancer.

PURPOSE: Despite widespread provision of Lynch syndrome (LS) screening programs, questions remain about the most effective and efficient protocol for LS case finding. The purpose of this study was to explore the performance of the two protocols widely shown to be the most efficient and effective, respectively: immunohistochemical (IHC) staining of tumor and direct-to-sequencing (DtS) in endometrial cancer populations. METHODS: Simulation models were developed to explore performance of the IHC and DtS protocols, updated to reflect current evidence. Analyses explicitly account for protocol complexity and failure points, as well as decreased sequencing costs. Key outcomes are percent of LS cases identified, total protocol costs and efficiency, and break-even analyses of sequencing costs. All costs are in 2020 US dollars (USD). RESULTS: Under plausible conditions, the IHC protocol is expected to identify 40%-78% of LS cases and DtS protocol from 49% to 97%. When the key variable success in proceeding to sequencing is fixed for both protocols at 50%, 75%, and 100%, the DtS protocol is 9%, 12%, and 16% better at case finding, respectively, than the IHC protocol. The break-even cost of sequencing is about $488 USD when the outcome is total direct testing protocol costs; it is about $670 USD when the outcome is cost per LS case detected. CONCLUSION: This study quantifies the plausible differences in the clinical effectiveness and cost-effectiveness of the two LS case-finding protocols. We demonstrate the large influence of success in proceeding to sequencing and potential impact of decreasing sequencing prices.

Targeted gene panel sequencing for the rapid diagnosis of acutely ill infants.

BACKGROUND: Exome/genome sequencing (ES/GS) have been recently used in neonatal and pediatric/cardiac intensive care units (NICU and PICU/CICU) to diagnose and care for acutely ill infants, but the effectiveness of targeted gene panels for these purposes remains unknown. METHODS: RapSeq, a newly developed panel targeting 4,503 disease-causing genes, was employed on selected patients in our NICU/PICU/CICU. Twenty trios were sequenced from October 2015 to March 2017. We assessed diagnostic yield, turnaround times, and clinical consequences. RESULTS: A diagnosis was made in 10/20 neonates (50%); eight had de novo variants (ASXL1, CHD, FBN1, KMT2D, FANCB, FLNA, PAX3), one was a compound heterozygote for CHAT, and one had a maternally inherited GNAS variant. Preliminary reports were generated by 9.6 days (mean); final reports after Sanger sequencing at 16.3 days (mean). In all positive infants, the diagnosis changed management. In a case with congenital myasthenia, diagnosis and treatment occurred at 17 days versus 7 months in a historical control. CONCLUSIONS: This study shows that a gene panel that includes the majority of known disease-causing genes can rapidly identify a diagnosis in a large number of tested infants. Due to simpler deployment and interpretation and lower costs, this approach might represent an alternative to ES/GS in the NICU/PICU/CICU.

Is immunohistochemistry-based screening for Lynch syndrome in endometrial cancer effective? The consent's the thing.

PURPOSE: To investigate the plausible failure rate of the immunohistochemistry (IHC)-based screening protocol to identify Lynch syndrome (LS) index cases among endometrial cancer (EC) patients. METHODS: We developed a simulation model of the IHC protocol in this context. The model was populated from systematic and focused reviews, augmented with local data and expert opinion. The virtual cohort represents the number of women expected to be diagnosed with EC in the U.S. in 2018. The outcomes include protocol failure rates and LS cases missed in a variety of hypothetical scenarios. RESULTS: The best estimate of failure rate of the IHC protocol is 58%; minimum and maximum estimates are 33% and 80%, respectively. These failure rates are driven primarily by the high rates of failure to obtain consent from patients for sequencing (25% to 80%). The multiple imperfect tests and potential failure points in this protocol, collectively, make up 7% to 20% of the total failure rate. When consent for sequencing was fixed in the model at 25%, 50%, and 80%; the expected ranges for index case identification failure are 78%-82%, 57%-64%, and 29%-42%, respectively. CONCLUSION: The primary driver of failure to identify index cases remains consent for sequencing. Consent rates have shown little improvement since LS screening programs were instituted in the U.S., leaving us to conclude these high failure rates are resistant to substantial improvement. These missed opportunities will be magnified because cascade screening for carrier status among family members will not be pursued.

Implementing universal Lynch syndrome screening (IMPULSS): protocol for a multi-site study to identify strategies to implement, adapt, and sustain genomic medicine programs in different organizational contexts.

BACKGROUND: Systematic screening of all colorectal tumors for Lynch Syndrome (LS) has been recommended since 2009. Currently, implementation of LS screening in healthcare systems remains variable, likely because LS screening involves the complex coordination of multiple departments and individuals across the healthcare system. Our specific aims are to (1) describe variation in LS screening implementation across multiple healthcare systems; (2) identify conditions associated with both practice variation and optimal implementation; (3) determine the relative effectiveness, efficiency, and costs of different LS screening protocols by healthcare system; and (4) develop and test in a real-world setting an organizational toolkit for LS screening program implementation and improvement. This toolkit will promote effective implementation of LS screening in various complex health systems. METHODS: This study includes eight healthcare systems with 22 clinical sites at varied stages of implementing LS screening programs. Guided by the Consolidated Framework for Implementation Research (CFIR), we will conduct in-depth semi-structured interviews with patients and organizational stakeholders and perform economic evaluation of site-specific implementation costs. These processes will result in a comprehensive cross-case analysis of different organizational contexts. We will utilize qualitative data analysis and configurational comparative methodology to identify facilitators and barriers at the organizational level that are minimally sufficient and necessary for optimal LS screening implementation. DISCUSSION: The overarching goal of this project is to combine our data with theories and tools from implementation science to create an organizational toolkit to facilitate implementation of LS screening in various real-world settings. Our organizational toolkit will account for issues of complex coordination of care involving multiple stakeholders to enhance implementation, sustainability, and ongoing improvement of evidence-based LS screening programs. Successful implementation of such programs will ultimately reduce suffering of patients and their family members from preventable cancers, decrease waste in healthcare system costs, and inform strategies to facilitate the promise of precision medicine. TRIAL REGISTRATION: N/A.

Impact of age cutoffs on a lynch syndrome screening program.

PURPOSE: To determine the impact of applying an age cutoff to tumor-based Lynch syndrome (LS) screening, specifically focusing on changes in relative effectiveness, efficiency, and cost. The project was undertaken to answer questions about implementation of the LS screening program in an integrated health care delivery system. PATIENTS AND METHODS: Clinical data extracted from an internal cancer registry, previous modeling efforts, published literature, and gray data were used to populate decision models designed to answer questions about the impact of age cutoffs in LS screening. Patients with colorectal cancer (CRC) were stratified at 10-year intervals from ages 50 to 80 years and compared with no age cutoff. Outcomes are reported for a cohort of 325 patients screened and includes total cost to screen, LS cases present in the cutoff category, number of LS cases expected to be identified by screening, cost per LS case detected, and total number and percentage of LS cases missed. CONCLUSION: Applying an age cutoff to an LS screening program has considerable potential for decreasing total screening costs and increasing efficiency, but at a loss of effectiveness. Imposing an age cutoff of 50 years reduces the cost of the screening program to 16% of a program with no age cutoff, but at the expense of missing more than half of the cases. Failure to identify LS cases is magnified by a cascade effect in family members. The results of this analysis influenced the final policy in our system.

Lynch syndrome screening implementation: business analysis by a healthcare system.

OBJECTIVE: To characterize the current state of evidence and apply simulation modeling to support decision making about provision and coverage of a Lynch syndrome (LS) screening program among colorectal cancer (CRC) patients in our integrated healthcare delivery system. STUDY DESIGN: Application of multiple methods for synthesizing evidence guided by needs of our clinical and administrative decision makers. METHODS: Narrative and focused reviews, computerized simulation models of multiple screening options, queries of our electronic data warehouse, and extensive communication with decision makers. RESULTS: Review of published evidence at the time of the study period revealed that screening unselected CRC patients for LS would likely cost less than $25,000 per life-year saved (compared with no screening) and that screening with immunohistochemistry is substantially more efficient than other options. Our simulation models suggest that not only does including BRAF mutation testing substantially improve efficiency but that adding methylation testing improves it further. We characterized a variety of other metrics that contributed not only to local decisions but to the broader evidence base on this topic. CONCLUSION: The current state of evidence at the time of the study period suggests an LS screening program can be both effective in reducing mortality from CRC and cost-effective. However, direct evidence remains limited and multiple factors could threaten success of such a program. We have identified opportunities for optimizing the efficiency of available screening protocols. While there was enough evidence for our system to proceed with an LS screening program, we recognize the threats to program success and will prospectively collect outcome data supporting empirical examination of the program.

A policy model to evaluate the benefits, risks and costs of warfarin pharmacogenomic testing.

BACKGROUND: In 2007, the US FDA added information about pharmacogenomics to the warfarin label based on the influence of the CYP2C9 and VKORC1 genes on anticoagulation-related outcomes. Payers will be facing increasing demand for coverage decisions regarding this technology, but the potential clinical and economic impacts of testing are not clear. OBJECTIVE: To develop a policy model to evaluate the potential outcomes of warfarin pharmacogenomic testing based on the most recently available data. METHODS: A decision-analytic Markov model was developed to assess the addition of genetic testing to anticoagulation clinic standard care for a hypothetical cohort of warfarin patients. The model was based on anticoagulation status (international normalized ratio), a common outcome measure in clinical trials that captures both the benefits and risks of warfarin therapy. Initial estimates of testing effects were derived from a recently completed randomized controlled trial (n = 200). Healthcare cost ($US, year 2007 values) and health-state utility data were obtained from the literature. The perspective was that of a US third-party payer. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results. RESULTS: The policy model included thromboembolic events (TEs) and bleeding events and was populated by data from the COUMAGEN trial. The rate of bleeding calculated for standard care approximated bleeding rates found in an independent cohort of warfarin patients. According to our model, pharmacogenomic testing provided an absolute reduction in the incidence of bleeds of 0.17%, but an absolute increase in the incidence of TEs of 0.03%. The improvement in QALYs was small, 0.003, with an increase in total cost of $US162 (year 2007 values). The incremental cost-effectiveness ratio (ICER) ranged from testing dominating to standard care dominating, and the ICER was <$US50,000 per QALY in 46% of simulations. Results were most sensitive to the cost of genotyping and the effect of genotyping. CONCLUSION: Our model, based on initial clinical studies to date, suggests that warfarin pharmacogenomic testing may provide a small clinical benefit with significant uncertainty in economic value. Given the uncertainty in the analysis, further updates will be important as additional clinical data become available.

Rapid ACCE: experience with a rapid and structured approach for evaluating gene-based testing.

PURPOSE: To present the rapid-ACCE model and report our early experience of using the ACCE structure to guide systematic reviews for the rapid evaluation of emerging genetic tests. METHODS: A rapid-ACCE review uses the same 44 questions that were developed for the full-ACCE model to guide the conduct of systematic review. We combined published literature with unpublished data to estimate test performance and input from experts to help clarify qualitative issues. As questions were answered, gaps in knowledge were identified and articulated. The draft review was then sent to outside reviewers whose comments were incorporated into the final document. RESULTS: We conducted two reviews, both of which were completed in 6 months or less (averaging about 100 hours of primary analyst time), within modest budgets. In addition to defining the current state of knowledge about the tests, the identified gaps are expected to help define the research agendas. Both collaborating experts and study sponsors valued both the process and outcomes from the reviews. CONCLUSIONS: Based on our early experiences, it is possible to conduct rapid systematic reviews within the ACCE structure of some emerging genetic tests to produce summaries of available evidence and identification of gaps.