Thyroidectomy Outcomes in Patients Identified With RET Pathogenic Variants Through a Population Genomic Screening Program.

Importance: Population-based genomic screening can facilitate early detection of medullary thyroid carcinoma (MTC) in patients with pathogenic/likely pathogenic (P/LP) RET variants. Objective: To evaluate the clinical treatment and patient outcomes after identification of P/LP RET proto-oncogene variants associated with the risk of MTC via a population genomic screening program. Design, Setting, Participants: This retrospective cross-sectional study was completed between June 1, 2016, and May 31, 2022, for a mean follow-up period of 22.4 months (range, 2-76 months). The study included patients who were identified as having P/LP RET variants through a population genomic screening program at a rural tertiary care center and who underwent thyroidectomy after results disclosure. Main Outcomes and Measures: The outcomes of interest were preoperative evaluation and treatment-related outcomes. Measures included imaging and laboratory findings, extent of surgery, pathologic diagnosis, and staging. Results: Seventy-five patients were identified as having P/LP RET variants exclusively through genomic screening. Twenty of these patients (27%; 11 women [55%] and 9 men [45%]; median age, 48 years [range, 22-73 years]) underwent total thyroidectomy; 13 of these patients (65%) also had a central neck dissection. No patients had clinically apparent disease at the time of surgery. Pathologic findings indicated MTC for 12 patients and papillary thyroid carcinoma in 2. Of patients with MTC, 10 had stage I disease, 1 had stage II disease, 1 had stage III disease, and none had stage IV disease. Based on postoperative surveillance imaging and laboratory results, no patient had evidence of recalcitrant disease. Conclusions and Relevance: In this cross-sectional study, all malignant neoplasms identified on surgical pathology were clinically occult, with surgical intervention based solely on the identification of the P/LP RET variant via population genomic screening. This finding suggests that genomic screening may provide opportunities for early detection and treatment of MTC, with the potential for improved patient outcomes.

Impact of a Population Genomic Screening Program on Health Behaviors Related to Familial Hypercholesterolemia Risk Reduction.

BACKGROUND: Limited information is available regarding clinician and participant behaviors after disclosure of genomic risk variants for familial hypercholesterolemia (FH) from a population genomic screening program. METHODS: We conducted a retrospective cohort study of MyCode participants with an FH risk variant beginning 2 years before disclosure until January 16, 2019. We analyzed lipid-lowering prescriptions (clinician behavior), medication adherence (participant behavior), and LDL (low-density lipoprotein) cholesterol levels (health outcome impact) pre- and post-disclosure. Data were collected from electronic health records and claims. RESULTS: The cohort included 96 participants of mean age 57 (22-90) years with median follow-up of 14 (range, 3-39) months. Most (90%) had a hypercholesterolemia diagnosis but no specific FH diagnosis before disclosure; 29% had an FH diagnosis post-disclosure. After disclosure, clinicians made 36 prescription changes in 38% of participants, mostly in participants who did not achieve LDL cholesterol goals pre-disclosure (81%). However, clinicians wrote prescriptions for fewer participants post-disclosure (71/96, 74.0%) compared with pre-disclosure (81/96, 84.4%); side effects were documented for most discontinued prescriptions (23/25, 92%). Among the 16 participants with claims data, medication adherence improved (proportion of days covered pre-disclosure of 70% [SD, 24.7%] to post-disclosure of 79.1% [SD, 27.3%]; P=0.05). Among the 52 (54%) participants with LDL cholesterol values both before and after disclosure, average LDL cholesterol decreased from 147 to 132 mg/dL (P=0.003). CONCLUSIONS: Despite disclosure of an FH risk variant, nonprescribing and nonadherence to lipid-lowering therapy remained high. However, when clinicians intensified medication regimens and participants adhered to medications, lipid levels decreased.

Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia: CARE-FH Protocol.

The Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia (CARE-FH) study aims to improve diagnostic evaluation rates for FH at Geisinger, an integrated health delivery system. This clinical trial relies upon implementation science to transition the initial evaluation for FH into primary care, attempting to identify individuals prior to the onset of atherosclerotic cardiovascular disease events. The protocol for the CARE-FH study of this paper is available online. The first phase of the project focuses on trial design, including the development of implementation strategies to deploy evidence-based guidelines. The second phase will study the intervention, rolled out regionally to internal medicine, community medicine, and pediatric care clinicians using a stepped-wedge design, and analyzing data on diagnostic evaluation rates, and implementation, service, and health outcomes.

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.

Feasibility and Assessment of a Cascade Traceback Screening Program (FACTS): Protocol for a Multisite Study to Implement and Assess an Ovarian Cancer Traceback Cascade Testing Program.

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. "Traceback" cascade testing -outreach to potential probands and relatives-is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking to determine a Traceback program's feasibility, acceptability, effectiveness, and costs. This is a multisite prospective observational feasibility study across three integrated health systems. Informed by the Conceptual Model for Implementation Research, we will outline, implement, and evaluate the outcomes of an OVCA Traceback program. We will use standard legal research methodology to review genetic privacy statutes; engage key stakeholders in qualitative interviews to design communication strategies; employ descriptive statistics and regression analyses to evaluate the site differences in genetic testing and the OVCA Traceback testing; and assess program outcomes at the proband, family member, provider, system, and population levels. This study aims to determine a Traceback program's feasibility and acceptability in a real-world context. It will account for the myriad factors affecting implementation, including legal issues, organizational- and individual-level barriers and facilitators, communication issues, and program costs. Project results will inform how health care providers and systems can develop effective, practical, and sustainable Traceback programs.

Cost-effectiveness of Population-Wide Genomic Screening for Hereditary Breast and Ovarian Cancer in the United States.

Importance: Genomic screening for hereditary breast and ovarian cancer (HBOC) in unselected women offers an opportunity to prevent cancer morbidity and mortality, but the potential clinical impact and cost-effectiveness of such screening have not been well studied. Objective: To estimate the lifetime incremental incidence of HBOC and the quality-adjusted life-years (QALYs), costs, and cost-effectiveness of HBOC genomic screening in an unselected population vs family history-based testing. Design, Setting, and Participants: In this study conducted from October 27, 2017, to May 3, 2020, a decision analytic Markov model was developed that included health states for precancer, for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), for earlier- and later-stage HBOC, after cancer, and for death. A complimentary cascade testing module was also developed to estimate outcomes in first-degree relatives. Age-specific RRM and RRSO uptake probabilities were estimated from the Geisinger MyCode Community Health Initiative and published sources. Parameters including RRM and RRSO effectiveness, variant-specific cancer risk, costs, and utilities were derived from published sources. Sensitivity and scenario analyses were conducted to evaluate model assumptions and uncertainty. Main Outcomes and Measures: Lifetime cancer incidence, QALYs, life-years, and direct medical costs for genomic screening in an unselected population vs family history-based testing only were calculated. The incremental cost-effectiveness ratio (ICER) was calculated as the difference in cost between strategies divided by the difference in QALYs between strategies. Earlier-stage and later-stage cancer cases prevented and total cancer cases prevented were also calculated. Results: The model found that population screening of 30-year-old women was associated with 75 (95% credible range [CR], 60-90) fewer overall cancer cases and 288 QALYs (95% CR, 212-373 QALYs) gained per 100 000 women screened, at an incremental cost of $25 million (95% CR, $21 millon to $30 million) vs family history-based testing; the ICER was $87 700 (78% probability of being cost-effective at a threshold of $100 000 per QALY). In contrast, population screening of 45-year-old women was associated with 24 (95% CR, 18-29) fewer cancer cases and 97 QALYs (95% CR, 66-130 QALYs) gained per 100 000 women screened, at an incremental cost of $26 million (95% CR, $22 million to $30 million); the ICER was $268 200 (0% probability of being cost-effective at a threshold of $100 000 per QALY). A scenario analysis without cascade testing increased the ICER to $92 600 for 30-year-old women and $354 500 for 45-year-old women. A scenario analysis assuming a 5% absolute decrease in mammography screening in women without a variant was associated with the potential for net harm (-90 QALYs per 100 000 women screened; 95% CR, -180 to 10 QALYs). Conclusions and Relevance: The results of this study suggest that population HBOC screening may be cost-effective among younger women but not among older women. Cascade testing of first-degree relatives added a modest improvement in clinical and economic value. The potential for harm conferred by inappropriate reduction in mammography among noncarriers should be quantified.

Healthcare Utilization and Costs after Receiving a Positive BRCA1/2 Result from a Genomic Screening Program.

Population genomic screening has been demonstrated to detect at-risk individuals who would not be clinically identified otherwise. However, there are concerns about the increased utilization of unnecessary services and the associated increase in costs. The objectives of this study are twofold: (1) determine whether there is a difference in healthcare utilization and costs following disclosure of a pathogenic/likely pathogenic (P/LP) BRCA1/2 variant via a genomic screening program, and (2) measure the post-disclosure uptake of National Comprehensive Cancer Network (NCCN) guideline-recommended risk management. We retrospectively reviewed electronic health record (EHR) and billing data from a female population of BRCA1/2 P/LP variant carriers without a personal history of breast or ovarian cancer enrolled in Geisinger's MyCode genomic screening program with at least a one-year post-disclosure observation period. We identified 59 women for the study cohort out of 50,726 MyCode participants. We found no statistically significant differences in inpatient and outpatient utilization and average total costs between one-year pre- and one-year post-disclosure periods ($18,821 vs. $19,359, p = 0.76). During the first year post-disclosure, 49.2% of women had a genetic counseling visit, 45.8% had a mammography and 32.2% had an MRI. The uptake of mastectomy and oophorectomy was 3.5% and 11.8%, respectively, and 5% of patients received chemoprevention.

Upstream and downstream revenue of upper gastrointestinal endoscopic ultrasound determined with an episode-of-care approach.

Background and study aims Upper gastrointestinal endoscopic ultrasound (EUS) has clinical advantages that can lead to improved patient outcome. This study seeks to characterize and quantify the upstream and downstream healthcare utilizations and revenues. Patients and methods A retrospective claims data analysis of upper gastrointestinal EUS procedures was conducted at a large health system. Types of care and total revenues associated with each episode of care were characterized by descriptive statistics. Comparisons were made between patients who had Medicare Advantage and commercial plans as well as those with and without cancer diagnoses during the downstream period. Results A total of 436 cases were identified. The most frequent downstream healthcare utilizations consisted of radiology (31 %), pathology services (28 %), and high-revenue services including chemotherapy and inpatient admissions. The most common upstream utilizations included radiology (18 %) and lab services (22 %). Average total downstream revenue was $ 34 231 (95 %CI: $ 28 561 - $ 39 901) per case, and average total upstream revenue was $4373 (95 %CI: $3227 - $ 5519). Average total revenue per case did not differ significantly between Medicare Advantage and commercial plan members. However, patients who were diagnosed with cancer at or immediately following EUS (20 %) were associated with significantly higher total revenue compared to those without cancer diagnosis ( P  < 0.0001). Conclusions This episode-of-care approach to quantifying the revenue impact of upper gastrointestinal EUS to the providers suggests there are substantial downstream as well as upstream revenues associated with upper gastrointestinal EUS procedures, driven by patients who are diagnosed with cancer by the EUS procedures and subsequently require oncologic care.

Maternal and Infant Health Care Costs Related to Preeclampsia.

OBJECTIVE: To provide U.S. case-based preeclampsia health care cost estimates for mothers and infants from a U.S. payer perspective, with comparisons with both uncomplicated and hypertensive pregnancies. METHODS: Electronic health record and billing data from a large regional integrated health care system in Pennsylvania were used to identify mother-singleton infant pairs with deliveries between 2010 and 2015. Data on clinical care and costs using actual payment amounts were compiled from 20 weeks of gestation to 6 weeks postdelivery for mothers and birth to 12 months for infants. Three defined pregnancy study cohorts, uncomplicated, hypertension and preeclampsia, were matched using a 1:1:1 ratio on the basis of maternal age, parity, body mass index, and comorbidities. Costs per pregnancy were calculated in 2015 dollars and preeclampsia incremental costs estimated by subtracting the average cost of the matched cohorts. RESULTS: The final study population included 712 matched mother-infant pairs in each cohort. The mean combined maternal and infant medical care costs in the preeclampsia cohort of $41,790 were significantly higher than those for the uncomplicated cohort of $13,187 (P<.001) and hypertension cohort of $24,182 (P<.001), and were largely driven by differences in the infant costs. The mean infant cost in the preeclampsia cohort were $28,898, in the uncomplicated cohort $3,669 and $12,648 in the hypertension cohort (P<.001). Mothers with preeclampsia delivered 3 weeks earlier (median 36.5 weeks of gestation) than women in the uncomplicated cohort and more than 2 weeks earlier than women in the hypertension cohort. A significantly larger percentage of women with preeclampsia and their infants experienced adverse events (13.9% for mothers and 14.6% for infants) compared with unaffected women (4.1% and 0.7%) and those with hypertension (9.4% and 4.8%), respectively (P<.001). CONCLUSION: The economic burden of preeclampsia health care is significant with the main cost drivers being infant health care costs associated with lower gestational age at birth and greater adverse outcomes. FUNDING SOURCE: This study is funded by Progenity, Inc.