Barriers to incorporating pharmacogenetics into routine clinical practice in the United States are well documented. Initial surveys by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2009 and 2010 identified barriers across four key domains that have hindered the widespread adoption of clinical pharmacogenetic testing. These are presented verbatim as: (i) absence of a definition of the processes required to interpret genotype information and to translate genetic information into clinical actions; (ii) need for recommended drug/gene pairs to implement clinically now; (iii) clinician resistance to consider pharmacogenetic information at the bedside; and (iv) concerns about test costs and reimbursement. Over time, many of these challenges have been overcome, and clinical pharmacogenetic testing has subsequently reached broader implementation. Despite this progress, several barriers remain that block further adoption. This narrative review used authors' expertise and experience to identify and describe current barriers to pharmacogenetic implementation across seven domains in the United States: equity and inclusion; guidelines and supporting evidence; regulatory agency oversight; payer coverage and insurance; availability of quality pharmacogenetic tests; electronic health records; and provider and patient education. Within each domain, it revisits past successes and challenges and explores remaining barriers. We also propose solutions to address ongoing challenges across these domains, including further expansion of recommendations beyond pharmacogenetic-specific guidelines, standards for designing clinical decision support tools, and broader pharmacogenetics education. Addressing these remaining obstacles directs work to enable broader adoption of clinical pharmacogenetic implementation to ultimately improve patient outcomes.

[This corrects the article DOI: 10.1371/journal.pone.0278137.].

Background: Sickle cell disease (SCD) and its complications contribute to high rates of morbidity and early mortality and high cost in the United States and African heritage community. Objective: To evaluate the cost-effectiveness of gene therapy for SCD and its value-based prices (VBPs). Design: Comparative modeling analysis across 2 independently developed simulation models (University of Washington Model for Economic Analysis of Sickle Cell Cure [UW-MEASURE] and Fred Hutchinson Institute Sickle Cell Disease Outcomes Research and Economics Model [FH-HISCORE]) using the same databases. Data Sources: Centers for Medicare & Medicaid Services claims data, 2008 to 2016; published literature. Target Population: Persons eligible for gene therapy. Time Horizon: Lifetime. Perspective: U.S. health care sector and societal. Intervention: Gene therapy versus common care. Outcome Measures: Incremental cost-effectiveness ratios (ICERs), equity-informed VBPs, and price acceptability curves. Results of Base-Case Analysis: At an assumed $2 million price for gene therapy, UW-MEASURE and FH-HISCORE estimated ICERs of $193 000 per QALY and $427 000 per QALY, respectively, under the health care sector perspective. Corresponding estimates from the societal perspective were $126 000 per QALY and $281 000 per QALY. The difference in results between models stemmed primarily from considering a slightly different target population and incorporating the quality-of-life (QOL) effects of splenic sequestration, priapism, and acute chest syndrome in the UW model. From a societal perspective, acceptable (>90% confidence) VBPs ranged from $1 million to $2.5 million depending on the use of alternative effective metrics or equity-informed threshold values. Results of Sensitivity Analysis: Results were sensitive to the costs of myeloablative conditioning before gene therapy, effect on caregiver QOL, and effect of gene therapy on long-term survival. Limitation: The short-term effects of gene therapy on vaso-occlusive events were extrapolated from 1 study. Conclusion: Gene therapy for SCD below a $2 million price tag is likely to be cost-effective when applying a societal perspective at an equity-informed threshold for cost-effectiveness analysis. Primary Funding Source: National Heart, Lung, and Blood Institute.

Abstract The EDGE (Early Detection of GEnetic risk) trial compared two population-based engagement strategies for identifying primary care patients with a family or personal history of cancer and offered eligible individuals genetic testing for cancer susceptibility (GT). A total of twelve clinics from two healthcare systems (6 clinics each) participated in Montana, Wyoming and Washington State. Clinics were cluster-randomized to one of two engagement approaches: 1) point of care screening (POC), conducted by clinic staff when a patient came in for their appointment and 2) direct patient engagement (DPE), where letter and email outreach facilitated online home screening. Patients who completed screening and met pre-specified personal and family history criteria were offered GT via a home-delivered saliva kit at no cost. The two primary outcomes of the trial were the fraction of active clinic patients who 1) completed the risk assessment tool and 2) completed GT. Logistic regression models were used to compare POC and DPE, allowing for overdispersion and including clinic as a design factor. Analyses in the screened population were adjusted for age, sex, personal and/or family history of cancer, and healthcare system. Over a 12-month engagement window, 95,623 patients were seen in the 12 clinics (Table 1). The POC approach resulted in a higher proportion screened for hereditary risk (19.1% vs. 8.7%), but a similar proportion completed testing (1.5% vs. 1.6%). Notably, the rate of testing among eligible patients approached via POC was approximately half the rate observed with DPE (24.7% vs. 44.7%). POC screen completers were less likely to have a personal history of cancer (9.1% vs. 10.7%), a significant family history of cancer (9.5% vs. 12.8%), and, if eligible, order a test kit (33.8% vs. 58.1%). Overall, a POC approach resulted in higher screening rates for familial cancer risk but a similar fraction completing GT, with DPE screeners self-selecting due to greater personal and/or family history of cancer. Analyses are ongoing to examine patient, clinic and system-level factors predicting screening and testing uptake, which can inform best practices for population-based hereditary cancer screening efforts. POC % (N) DPE % (N) Unadjusted OR (POC vs DPE) Adjusted OR * (POC vs DPE) p-value Patient Denominator 51,693 43,930 Completed Screening 19.1% (9892) 8.7% (3813) 2.49 - 0.0074 Completed GT 1.5% (757) 1.6% (717) 0.89 - 0.75 Screened Participants 9892 3813 % screened with any personal cancer history 9.1% (902) 10.7% (406) 0.77 <0.0001 % of screened with significant** family history of cancer 9.5% (935) 12.8% (487) - 0.69 <0.0001 % of screened found eligible for GT 31.0% (3070) 42.0% (1603) - 0.65 <0.0001 Participants eligible for GT 3070 1603 % of eligible who ordered test kit 33.8% (1039) 58.1% (932) - 0.43 <0.0001 % of eligible who completed GT 24.7% (757) 44.7% (717) - 0.49 <0.0001 *Adjusted ORs - Adjusted for age, sex, personal cancer history, family cancer history, healthcare system.**Significant family history: 2 or more first degree relatives with a high-risk cancer Citation Format: Elizabeth M. Swisher, Heather M. Harris, Barbara M. Norquist, Jeannine Brant, Brian Shirts, Sarah Knerr, Emerson J. Dusic, Faith Beers, Tesla N. Theoryn, DaLaina Cameron, Howard Cabral, Laurie A. Riemann, Michael Raff, Beth Devine, Deborah J. Bowen, Catharine Wang. Implementation of population-based risk assessment for hereditary cancer in primary care: Results from the Early Detection of Genetic Risk (EDGE) Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB232.

OBJECTIVE:To compare healthcare resource utilization and healthcare costs in patients with migraine with or without a history of misdiagnosis. BACKGROUND:Despite the high prevalence of migraine, migraine is commonly misdiagnosed. The healthcare resource use and cost burden of a misdiagnosis is unknown. METHODS:This retrospective cohort study identified adults with an incident migraine diagnosis from the Merative™ Marketscan® Commercial and Medicare Supplemental Databases between June 2018 and 2019. Patients with a diagnosis of commonly considered misdiagnoses (headache, sinusitis, or cervical pain) before their migraine diagnosis were classified as the "misdiagnosed cohort." Patients in the misdiagnosed cohort were potentially misdiagnosed, then eventually received a correct diagnosis. Patients without a history of commonly considered misdiagnoses prior to their migraine diagnosis were classified as the "correctly diagnosed cohort." Healthcare resource utilization and healthcare costs were assessed in the period before migraine diagnosis and compared between the cohorts. Outcomes were reported as per patient per month and compared with incidence rate ratios. RESULTS:A total of 29,147 patients comprised the correctly diagnosed cohort and 3841 patients comprised the misdiagnosed cohort and met the inclusion criteria. Patients in the misdiagnosed cohort had statistically significantly higher rates of inpatient admissions (0.02 vs. 0.01, incidence rate ratio [IRR] 1.61, 95% confidence interval [CI] 1.47-1.74), emergency department visits (0.10 vs. 0.05; IRR 1.89, 95% CI 1.79-1.99), neurologist visits (0.12 vs. 0.02; IRR 5.95, 95% CI 5.40-6.57), non-neurologist outpatient visits (2.64 vs. 1.58; IRR 1.67, 95% CI 1.62-1.72) and prescription fills (2.82 vs. 1.84; IRR 1.53, 95% CI 1.48-1.58) compared to correctly diagnosed patients. Misdiagnosed patients had statistically significantly higher rates of healthcare cost accrual for inpatient admissions ($1362 vs. $518; IRR 2.62, 95% CI 2.50-2.75), emergency department visits ($222 vs. $98; IRR 2.27, 95% CI 2.18-2.36), neurologist visits ($42 vs. $9; IRR 4.39, 95% CI 4.00-4.79), non-neurologist outpatient visits ($1327 vs. $641; IRR 2.07, 95% CI 1.91-2.24), and prescription fills ($305 vs. $215; IRR 1.41, 95% CI 1.18-1.70) compared to correctly diagnosed patients. CONCLUSION:Patients with migraine who have a history of misdiagnoses have higher rates of healthcare resource utilization and cost accrual versus those without such history.

An assessment of the validity of studies is an essential component of most evidence syntheses (systematic reviews) to understand the risk of bias (ROB) and applicability of the evidence. A formal validity assessment requires a structured and comprehensive approach, which can be implemented using an assessment tool, specifically developed for this purpose. Many different tools are available, marking it difficult for researchers to choose the best tool for their evidence synthesis. We have established the LATITUDES Network to assist researchers in identifying the most appropriate tool to use in their evidence synthesis and to support researchers using these tools. The LATITUDES website (www.latitudes-network.org) includes a searchable library of validity assessment tools designed for use in evidence syntheses, bringing tools together in one place and providing researchers with clear information on suitable tools, categorized by study design. The website also provides links to training on the process of validity assessment and a list of tools currently under development. To be included in the LATITUDES library, tools must meet the following criteria: be designed for use in evidence syntheses; assess multidimensional aspects of validity of individual studies or reviews; and be developed for use by the wider research community rather than for a single research group. We highlight 'key' tools, those that are considered to be the most robust and reliable tools based on prespecified criteria agreed in conjunction with our advisory board, an international group of experts in the area of evidence synthesis and ROB tools.

BACKGROUND:Patients with chronic limb threatening ischemia may require a transmetatarsal amputation (TMA) or a transtibial amputation. When making an amputation-level decision, these patients face a tradeoff-a TMA preserves more limb and may provide better mobility but has a lower probability of primary wound healing and may therefore result in additional same or higher level amputation surgeries with an associated negative impact on function. Understanding differences in how patients and providers prioritize these tradeoffs and other outcomes may enhance shared decision-making. OBJECTIVES:Compare patient priorities with provider perceptions of patient priorities using Multiple Criteria Decision Analysis (MCDA). METHODS:The MCDA Analytic Hierarchy Process was chosen due to its low cognitive burden and ease of implementation. We included 5 criteria (outcomes): ability to walk, healing after amputation surgery, rehabilitation program intensity, limb length, and ease of use of prosthetic/orthotic device. A national sample of dysvascular lower-limb amputees and providers were recruited from the Veterans Health Administration with the MCDA administered online to providers and telephonically to patients. RESULTS:Twenty-six dysvascular amputees and 38 providers participated. Fifty percent of patients had undergone a TMA; 50%, a transtibial amputation. When compared to providers, patients placed higher value on TMA (72% vs. 63%). Patient versus provider priorities were ability to walk (47% vs. 42%), healing (18% vs. 28%), ease of prosthesis use (17% vs. 13%), limb length (11% vs. 13%), and then rehabilitation intensity (7% vs. 6%). LIMITATIONS:Our sample may not generalize to other populations. CONCLUSIONS:Provider perceptions aligned with patient values on amputation level but varied around the importance of each outcome. IMPLICATIONS:These findings illuminate some differences between patients' values and provider perceptions of patient values, suggesting a role for shared decision-making. Embedding this MCDA framework into a future decision aid may facilitate these discussions.

Curative regimens, such as stem cell transplant, employ cytotoxic agents to facilitate acceptance of novel progenitor cells, though the risk associated with malignancy post-treatment remains a concern. In anticipation of the widespread introduction of gene therapies, our aim was to conduct a systematic review to characterize the baseline risk of cancer in SCD patients regardless of types of therapy.

Background Imaging tests are one of the most frequently used diagnostic modalities in healthcare, but the benefits of their direct impacts on clinical decision-making have been countered by concerns that they can be overused. Assessing the relative value of imaging tests has largely focused on measures of test accuracy, which overlooks more comprehensive benefits and risks of imaging tests, particularly their impact on patient-centred outcomes (PCOs). We present the findings of the Patient Reported Outcomes of Diagnostics (PROD) research study in response to a methodological gap in the area of diagnostic test comparative effectiveness research. Methods Over a 3-year period, the PROD Study engaged with multiple stakeholders to identify existing conceptual models related to PCOs for imaging testing, conducted primary research and evidence synthesis, and developed consensus recommendations to describe and categorise PCOs related to imaging testing. Results The PROD framework categorises PCOs from imaging studies within four main domains: information or knowledge yielded, physical impact, emotional outcomes and test burden. PCOs interact with each other and influence effects across domains, and can be modified by factors related to the patient, clinical situation, healthcare team and the testing environment. Conclusions Using PCOs to inform healthcare decision-making will require ways of collating and presenting information on PCOs in ways that can inform patient–provider decision-making, and developing methods to determine the relative importance of outcomes (including test accuracy) to one another.

To our knowledge, we report the first population-based period life table, the expected lifetime survival for Medicare and Medicaid beneficiaries with sickle cell disease (SCD), and the disparities in survival by insurance types in the United States. We constructed a retrospective cohort of individuals with diagnosed SCD receiving common care (any real-world patterns of care except transplant) based on nationwide Medicare and Medicaid claim data (2008-2016), covering beneficiaries in all 50 states. We analyzed lifetime survival probabilities using Kaplan-Meier curves and projected life expectancies at various ages for all, stratified by sex and insurance types. Our analysis included 94 616 individuals with SCD that have not undergone any transplant. Life expectancy at birth was 52.6 years (95% confidence interval: 51.9-53.4). Compared with the adults covered by Medicaid only, those covered by Medicare for disabilities or end-stage renal disease and those dually insured by Medicare and Medicaid had significantly worse life expectancy. Similarly, for beneficiaries aged ≥65 years, these 2 insurance types were associated with significantly shorter life expectancy than those enrolled in Medicare old age and survivor's insurance. Our study underscores the persistent life expectancy shortfall for patients with SCD, the burden of premature mortality during adulthood, and survival disparities by insurance status.

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001-September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator's choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population.

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BACKGROUND:Misinformation hampers vaccine uptake. The European Union (EU) employed a coordinated effort to curb misinformation during the Covid-19 pandemic. In this context, we investigated relationships between sources of information, vaccine safety/effectiveness, satisfaction with government vaccination strategy, and vaccination intent. METHODS:We used cross-sectional survey data (May 2021) from Flash Eurobarometer 494, a population-adjusted dataset comprised of a representative sample of those ≥15 years from 27 EU nations. We employed a latent class analysis to create clusters of information sources as the independent variable and beliefs in vaccine safety/efficacy, satisfaction with government vaccination strategy, and vaccine intent as four outcome variables. We first estimated the association between source clusters and each of the first three outcomes separately. Then, using these three as intermediate variables, we employed structural equation modeling to estimate the relationship between sources and vaccine intent. We adjusted for individual and country-level variables. RESULTS:Among 23 012 respondents, four clusters of information sources emerged: (1) national authorities/health professionals (n = 9602; 42%), (2) mostly health professionals (6184; 27%), (3) mixed (n = 1705; 17%) and (4) social media/family/friends (n = 5524; 24%). Using cluster (3) as the referent, we found decreasing odds of beliefs in vaccine safety/effectiveness, satisfaction and vaccine intent across clusters (1), (2) and (4), respectively. Demographics played a role. CONCLUSION:In the context of the Covid pandemic, these results provide the first EU-wide estimates of the association between sources of information about vaccine safety/effectiveness, satisfaction and vaccine intent. The coordinated approach promulgated by the EU to minimize misinformation provides a model for managing future pandemics.

Current guidelines recommend the use of dual or triple antithrombotic therapy for patients with atrial fibrillation (AF) undergoing a percutaneous coronary intervention (PCI). Dual therapy has demonstrated favorable safety outcomes without compromising efficacy endpoints compared to triple therapy in four major clinical trials. In this study, we created a Markov model to evaluate the cost-effectiveness of dual versus triple antithrombotic therapy using data from the RE-DUAL PCI clinical trial.

Background: Postoperative atrial fibrillation (POAF) is one of the most common complications following cardiac surgery. POAF is associated with increased hospitalization costs, but its long-term economic burden is not well defined.Objective: To assess 30-day and 1-year incremental healthcare resource utilization (HRU) and costs associated with POAF in the United States (US).Methods: This retrospective cohort study used claims data from the IBM Watson MarketScan database. A cohort of US adults aged 55--90 years who underwent open-heart surgery between 1 January 2017 and 31 December 2018 was used to compare patients who experienced POAF versus patients who did not (controls). The outcomes of interest were incremental HRU and costs, which were assessed during the index hospitalization and 30-day and 1-year postdischarge time periods. Inverse probability weighting was used to adjust for differences in baseline characteristics.Results: A total of 8,020 patients met the study inclusion criteria with 5,765 patients in the control cohort (mean age, 63.4 years) and 2,255 patients in the POAF cohort (mean age, 65.8 years). After adjustment, patients with POAF had an index hospitalization that was 1.9 days longer (99% CI, 1.3-2.4 days; p < 0.001) and cost $13,919 more (99% CI, $2,828-$25,011; p < 0.001) than for patients without POAF. POAF patients also had significantly higher HRU at 30 days and 1-year postdischarge with incremental costs of $4,649 (99% CI, $1,479-$7,819; p < 0.001) and $10,671 (99% CI, $2,407-$18,935; p < 0.001), respectively.Conclusion: POAF following open-heart surgery poses a significant economic burden up to 1 year postdischarge.

Screening with mammography and breast magnetic resonance imaging (MRI) is an important risk management strategy for individuals with inherited pathogenic variants (PVs) in genes associated with increased breast cancer risk. We describe longitudinal screening adherence in individuals who underwent cancer genetic testing as part of usual care in a vertically integrated health system. We determined the proportion time covered (PTC) by annual mammography and breast MRI for individuals with PVs in TP53, BRCA1, BRCA2, PALB2, NF1, CHEK2, and ATM. We determined time covered by biennial mammography beginning at age 50 years for individuals who received negative results, uncertain results, or with PVs in genes without specific breast cancer screening recommendations. One hundred and forty individuals had PVs in TP53, BRCA1, BRCA2, PALB2, NF1, CHEK2, or ATM. Among these individuals, average PTC was 48

Abstract Background/Objective: The goal of the Patient-Centered Outcomes Research Partnership was to prepare health care professionals and researchers to conduct patient-centered outcomes and comparative effectiveness research (CER). Substantial evidence gaps, heterogeneous health care systems, and decision-making challenges in the USA underscore the need for evidence-based strategies. Methods: We engaged five community-based health care organizations that serve diverse and underrepresented patient populations from Hawai’i to Minnesota. Each partner nominated two in-house scholars to participate in the 2-year program. The program focused on seven competencies pertinent to patient-centered outcomes and CER. It combined in-person and experiential learning with asynchronous, online education, and created adaptive, pragmatic learning opportunities and a Summer Institute. Metrics included the Clinical Research Appraisal Inventory (CRAI), a tool designed to assess research self-efficacy and clinical research skills across 10 domains. Results: We trained 31 scholars in 3 cohorts. Mean scores in nine domains of the CRAI improved; greater improvement was observed from the beginning to the midpoint than from the midpoint to conclusion of the program. Across all three cohorts, mean scores on 52 items (100%) increased (p ≤ 0.01), and 91% of scholars reported the program improved their skills moderately/significantly. Satisfaction with the program was high (91%). Conclusions: Investigators that conduct patient-centered outcomes and CER must know how to collaborate with regional health care systems to identify priorities; pose questions; design, conduct, and disseminate observational and experimental research; and transform knowledge into practical clinical applications. Training programs such as ours can facilitate such collaborations.