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PURPOSE: The Risk of Pediatric and Adolescent Cancer Associated with Medical Imaging (RIC) Study is quantifying the association between cumulative radiation exposure from fetal and/or childhood medical imaging and subsequent cancer risk. This manuscript describes the study cohorts and research methods. METHODS: The RIC Study is a longitudinal study of children in two retrospective cohorts from 6 U.S. healthcare systems and from Ontario, Canada over the period 1995–2017. The fetal-exposure cohort includes children whose mothers were enrolled in the healthcare system during their entire pregnancy and followed to age 20. The childhood-exposure cohort includes children born into the system and followed while continuously enrolled. Imaging utilization was determined using administrative data. Computed tomography (CT) parameters were collected to estimate individualized patient organ dosimetry. Organ dose libraries for average exposures were constructed for radiography, fluoroscopy, and angiography, while diagnostic radiopharmaceutical biokinetic models were applied to estimate organ doses received in nuclear medicine procedures. Cancers were ascertained from local and state/provincial cancer registry linkages. RESULTS: The fetal-exposure cohort includes 3,474,000 children among whom 6,606 cancers (2,394 leukemias) were diagnosed over 37,659,582 person-years; 0.5% had in utero exposure to CT, 4.0% radiography, 0.5% fluoroscopy, 0.04% angiography, 0.2% nuclear medicine. The childhood-exposure cohort includes 3,724,632 children in whom 6,358 cancers (2,372 leukemias) were diagnosed over 36,190,027 person-years; 5.9% were exposed to CT, 61.1% radiography, 6.0% fluoroscopy, 0.4% angiography, 1.5% nuclear medicine. CONCLUSION: The RIC Study is poised to be the largest study addressing risk of childhood and adolescent cancer associated with ionizing radiation from medical imaging, estimated with individualized patient organ dosimetry.

Cascade testing (i.e., genetic testing of family members of individuals with disease) among families affected by hereditary cancer disorders, such as Lynch syndrome, is suboptimal and thus represents a missed opportunity in cancer prevention. We aimed to fill a gap in the literature by exploring multilevel barriers and facilitators to the implementation of cascade testing for Lynch syndrome. We conducted semistructured, in-depth interviews guided by the Consolidated Framework for Implementation Research and the Integrated Behavioral Model among key stakeholders (n = 60): Patients with Lynch syndrome and relatives (n = 20), providers (n = 20), and administrators (n = 20). Transcripts were double-coded (20% sample) using template analysis in ATLAS.ti. Barriers identified included (i) low awareness about Lynch syndrome, (ii) psychosocial barriers, (iii) lack of provider follow-up, (iv) accessibility to genetic counseling, and (v) fear of discrimination. Facilitators included (i) motivation to engage in cascade testing and (ii) free genetic testing offered to relatives. Stakeholders also recommended strategies to overcome implementation barriers in the short-term (increasing education, preparing patients for communicating with relatives), medium-term (optimizing clinical workflow and staffing resources), and long-term (nationwide standardization). These findings indicate that modifiable, multilevel barriers to the implementation of cascade testing in Lynch syndrome are experienced across stakeholders. Understanding and targeting implementation barriers is imperative to achieving public health impact of precision health interventions such as cascade testing.

Supplemental Methods: Includes Semi-structured interview guide sample (Appendix A); and COREQ checklist (Appendix B)

Introduction: A traceback genetic testing program for ovarian cancer has the potential to identify individuals with hereditary breast and ovarian cancer and their relatives. Successful implementation depends on understanding and addressing the experiences, barriers, and preferences of the people served. Methods: We conducted a remote, human-centered design research study of people with ovarian, fallopian tube, or peritoneal cancer (probands) and people with a family history of ovarian cancer (relatives) at three integrated health systems between May and September 2021. Participants completed activities to elicit their preferences about ovarian cancer genetic testing messaging, and to design their ideal experience receiving an invitation to participate in genetic testing. Interview data were analyzed using a rapid thematic analysis approach. Results: We interviewed 70 participants and identified five preferred experiences for a traceback program. Participants strongly prefer discussing genetic testing with their doctor but are comfortable discussing with other clinicians. The most highly preferred experience for both probands and relatives was to discuss with a knowledgeable clinician who can answer questions, followed by directed (sent directly to specific people) or passive (shared in a public area) communication. Repeated contact was acceptable for reminders. Discussion/Conclusion: Participants were open to receiving information about traceback genetic testing and recognized its value. Participants preferred discussing genetic testing with a trusted clinician. Directed communication was preferable to passive communication. Other valued information included how genetic tests help their family and the cost of genetic testing. These findings are informing traceback cascade genetic testing programs at all three sites.

ObjectivesRecruiting large, diverse cohorts efficiently can speed the translation of findings into care across a range of scientific disciplines and medical specialties. Yet, efficient recruitment can be hampered by factors such as financial barriers, logistical concerns, and lack of resources for patients and clinicians. Here we use a case study of a large, prospective trial of a multi-cancer early detection test to describe how the study team tracked enrollment, protocol fidelity, and participant experience and iteratively adapted procedures.MethodsWhile conducting a large, prospective trial of a multi-cancer early detection blood test at Geisinger, an integrated health system in central Pennsylvania, we monitored recruitment progress, fidelity to protocol procedures, and participants’ satisfaction. Tracking mechanisms such as paper records, electronic health records, research databases, dashboards, and electronic files were utilized to measure each outcome. We then reviewed study procedures and timelines to list the implementation strategies that were used to address barriers to recruitment, protocol fidelity and participant satisfaction.ResultsWe enrolled 10,006 women ages 65-75 over 22 months. Adaptations to recruitment and enrollment methods that contributed to achieving the enrollment goal included adopting group consenting, improving visit convenience, increasing electronic capture and tracking of data and source documents, staffing optimization via leveraging resources external to the study team when appropriate, and integrating the disclosure of study results into routine clinical care without adding unfunded work for physicians. We maintained high protocol fidelity and positive participant experience as exhibited by a very low protocol deviation rate and a low number of participant complaints.ConclusionRecruiting rapidly for large studies – and thereby facilitating clinical translation – requires a nimble, creative approach that marshals available resources and changes course according to data. Planning a rigorous assessment of a study’s implementation outcomes prior to study recruitment can further ground study adaptations and facilitate translation into practice. This can be accomplished by proactively and continuously assessing and revising implementation strategies.Strengths and limitations of this studySynthesis and tracking of various dataReal-time identification of necessary adaptationsMapping of adaptations to problems and consequencesAnalysis of results post-hocInability to analyze the value or impact of a single adaptation

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Understanding unselected individuals’ experiences receiving genetic results through population genomic screening is critical to advancing clinical utility and improving population health. We conducted qualitative interviews with individuals who received clinically actionable genetic results via the MyCode© Genomic Screening and Counseling program. We purposively sampled cohorts to seek diversity in result-related disease risk (e.g., cancer or cardiovascular) and in personal or family history of related diseases. Transcripts were analyzed using a two-step inductive coding process of broad thematic analysis followed by in-depth coding of each theme. Four thematic domains identified across all cohorts were examined: process assessment, psychosocial response, behavioral change due to the genetic result, and family communication. Coding of 63 interviews among 60 participants revealed that participants were satisfied with the results disclosure process, initially experienced a range of positive, neutral, and negative psychological reactions to results, adjusted positively to results over time, undertook clinically indicated actions in response to results, and communicated results with relatives to whom they felt emotionally close. Our findings of generally favorable responses to receiving clinically actionable genetic results via a genomic screening program may assuage fear of patient distress in such programs and guide additional biobanks, genomic screening programs, and research studies.

Background Individuals with complex dyslipidemia, or those with medication intolerance, are often difficult to manage in primary care. They require the additional attention, expertise, and adherence counseling that occurs in multidisciplinary lipid clinics (MDLCs). We conducted a program evaluation of the first year of a newly implemented MDLC utilizing the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework to provide empirical data not only on program effectiveness, but also on components important to local sustainability and future generalizability. Methods The purpose of the MDLC is to increase the uptake of guideline-based care for lipid conditions. Established in 2019, the MDLC provides care via a centralized clinic location within the healthcare system. Primary care providers and cardiologists were invited to refer individuals with lipid conditions. Using a pre/post-study design, we evaluated the implementation outcomes from the MDLC using the RE-AIM framework. Results In 2019, 420 referrals were made to the MDLC (reach). Referrals were made by 19% (148) of the 796 active cardiology and primary care providers, with an average of 35 patient referrals per month in 2019 (SD 12) (adoption). The MDLC saw 83 patients in 2019 (reach). Additionally, 50% (41/82) had at least one follow-up MDLC visit, and 12% (10/82) had two or more follow-up visits in 2019 (implementation). In patients seen by the MDLC, we found an improved diagnosis of specific lipid conditions (FH (familial hypercholesterolemia), hypertriglyceridemia, and dyslipidemia), increased prescribing of evidence-based therapies, high rates of medication prior authorization approvals, and significant reductions in lipid levels by lipid condition subgroup (effectiveness). Over time, the operations team decided to transition from in-person follow-up to telehealth appointments to increase capacity and sustain the clinic (maintenance). Conclusions Despite limited reach and adoption of the MDLC, we found a large intervention effect that included improved diagnosis, increased prescribing of guideline-recommended treatments, and clinically significant reduction of lipid levels. Attention to factors including solutions to decrease the large burden of unseen referrals, discussion of the appropriate number and duration of visits, and sustainability of the clinic model could aid in enhancing the success of the MDLC and improving outcomes for more patients throughout the system.

Cascade testing (i.e., genetic testing of family members of individuals with disease) among families affected by hereditary cancer disorders, such as Lynch syndrome, is suboptimal and thus represents a missed opportunity in cancer prevention. We aimed to fill a gap in the literature by exploring multilevel barriers and facilitators to the implementation of cascade testing for Lynch syndrome. We conducted semistructured, in-depth interviews guided by the Consolidated Framework for Implementation Research and the Integrated Behavioral Model among key stakeholders (n = 60): Patients with Lynch syndrome and relatives (n = 20), providers (n = 20), and administrators (n = 20). Transcripts were double-coded (20% sample) using template analysis in ATLAS.ti. Barriers identified included (i) low awareness about Lynch syndrome, (ii) psychosocial barriers, (iii) lack of provider follow-up, (iv) accessibility to genetic counseling, and (v) fear of discrimination. Facilitators included (i) motivation to engage in cascade testing and (ii) free genetic testing offered to relatives. Stakeholders also recommended strategies to overcome implementation barriers in the short-term (increasing education, preparing patients for communicating with relatives), medium-term (optimizing clinical workflow and staffing resources), and long-term (nationwide standardization). These findings indicate that modifiable, multilevel barriers to the implementation of cascade testing in Lynch syndrome are experienced across stakeholders. Understanding and targeting implementation barriers is imperative to achieving public health impact of precision health interventions such as cascade testing.

Cancer genetics clinics have seen increasing demand, challenging genetic counselors (GCs) to increase efficiency and prompting some clinics to implement genetic counseling assistants (GCAs). To evaluate the impact of GCAs on Geisinger’s cancer genetics clinic, we tracked GC time utilization, new patient volume, and clinic cost per patient before and after implementing a GCA program. GCs used time-tracking software while completing preappointment activities. Electronic health records were reviewed for appointment length and number of patients per week. Internal salary data for GCs and GCAs were used to calculate clinic costs per patient. Time spent by GCs completing each preappointment activity (21.8 vs. 15.1 minutes) and appointment length (51.6 vs. 44.5 minutes) significantly decreased after GCA program implementation (p values < 0.001). New patients per week per GC significantly increased (7.9 vs. 11.4, p

Background Familial hypercholesterolemia (FH) affects more than one million Americans, and most individuals have not been formally diagnosed with the condition. Individuals with FH have markedly elevated serum low-density lipoprotein cholesterol (LDL-C) levels from birth that substantially increase their risk for early-onset cardiovascular (CV) events. Guideline-recommended treatments exist to lower LDL-C and reduce the risk of CV events in individuals with FH and hypercholesterolemia. This study seeks to address a significant gap in the care of individuals with FH by systematically developing an effective approach to increase the adoption of guideline-recommended treatments for FH. Methods This developmental study will consist of three aims: 1) determine the barriers to and facilitators of treatment of FH; 2) develop a list of potential implementation strategies to promote the adoption of guideline-recommended treatment of individuals with FH, and 3) pilot one implementation strategy from Aim 2 in one health care system to evaluate implementation outcomes of the strategy. The Practical, Robust Implementation and Sustainability Model will guide this project, including the development of interview questions, implementation strategies, and evaluation of the implementation strategy. The implementation outcomes include: of individuals targeted by the implementation strategy, how many are impacted by it (reach), measure the change in knowledge, attitude, and behavior that is impacted by the implementation strategy (effectiveness), in settings targeted by the implementation strategy, how many adopt it (adoption), and fidelity and cost of the implementation strategy (implementation). Data sources will include electronic health records, administrative databases, surveys, and semi-structured interviews. Discussion The inclusion of patient and organizational stakeholder experiences is a critically important step in developing efficient and effective implementation strategies. Additionally, perspectives from a variety of geographic areas and cultural perspectives should increase feasibility and fidelity of the interventional approach to improve adoption of guideline-recommended practices for FH care.

BackgroundTo facilitate community-based epidemiologic studies of pediatric leukemia, we validated use of ICD-9-CM diagnosis codes to identify pediatric leukemia cases in electronic medical records of six U.S. integrated health plans from 1996-2015 and evaluated the additional contributions of procedure codes for diagnosis/treatment.ProceduresSubjects (N=408) were children and adolescents born in the health systems and enrolled for at least 120 days after the date of the first leukemia ICD-9-CM code or tumor registry diagnosis. The gold standard was the health system tumor registry and/or medical record review. We calculated positive predictive value (PPV) and sensitivity by number of ICD-9-CM codes received in the 120-day period following and including the first code. We evaluated whether adding chemotherapy and/or bone marrow biopsy/aspiration procedure codes improved PPV and/or sensitivity.ResultsRequiring receipt of one or more codes resulted in 99% sensitivity (95% confidence interval [CI]: 98-100%) but poor PPV (70%; 95% CI: 66-75%). Receipt of two or more codes improved PPV to 90% (95% CI: 86-93%) with 96% sensitivity (95% CI: 93-98%). Requiring at least four codes maximized PPV (95%; 95% CI: 92-98%) without sacrificing sensitivity (93%; 95% CI: 89-95%). Across health plans, PPV for four codes ranged from 84-100% and sensitivity ranged from 83-95%. Including at least one code for a bone marrow procedure or chemotherapy treatment had minimal impact on PPV or sensitivity.ConclusionsThe use of diagnosis codes from the electronic health record has high PPV and sensitivity for identifying leukemia in children and adolescents if more than one code is required.

PURPOSE: The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants. METHODS: RoR processes were developed and approved by each eMERGE institution’s internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant’s disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed. RESULTS: Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052). CONCLUSION: The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.

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.

Introduction: Familial hypercholesterolemia (FH) is an inherited disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. The 2020 FH Global Call to Action, produced by international FH global advocacy organizations, individuals with FH, and scientific experts, provides nine recommendations to reduce premature death and the public health burden of FH. We explored alignment of patient and family member perspectives with these recommendations. Methods: Interviews and focus groups were conducted with individuals with FH and their family members from multiple U.S. health systems and members of the FH Foundation community to identify barriers to identification, cascade testing, and treatment. Patient-centered perspectives were sought to develop solutions that can be implemented. These perspectives were then examined and classified, according to their alignment to recommendations within the FH Global Call to Action. Results: Stories from 75 individuals with FH and family members, who participated in at least one of the qualitative assessments, were analyzed. The table lists the FH Global Call to Action recommendations with patient-centric perspectives abstracted from individuals’ stories. The most common stories and perspectives linked to the recommendations for awareness, screening, diagnosis, testing, and treatment, and family-based care. Conclusions: The Global Call to Action recommendations resonate highly with U.S. FH individuals and their family members. Patient-centric perspectives further address the need to prioritize FH as a global public health concern and support FH education and advocacy efforts.

Importance Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown. Objective To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry. Design, Setting, and Participants This cohort study using the Electronic Medical Records and Genomics (eMERGE) network data set included 39 591 women from 9 contributing medical centers in the US that had electronic medical records (EMR) linked to genotype data. Breast cancer cases and controls were identified through a validated EMR phenotyping algorithm. Main Outcomes and Measures Multivariable logistic regression was used to assess the association between breast cancer risk and 7 previously developed PRSs, adjusting for age, study site, breast cancer family history, and first 3 ancestry informative principal components. Results This study included 39 591 women: 33 594 with European, 3801 with African, and 2196 with Latinx ancestry. The mean (SD) age at breast cancer diagnosis was 60.7 (13.0), 58.8 (12.5), and 60.1 (13.0) years for women with European, African, and Latinx ancestry, respectively. PRSs derived from women with European ancestry were associated with breast cancer risk in women with European ancestry (highest odds ratio [OR] per 1-SD increase, 1.46; 95% CI, 1.41-1.51), women with Latinx ancestry (highest OR, 1.31; 95% CI, 1.09-1.58), and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35). For women with European ancestry, this association with breast cancer risk was largest in the extremes of the PRS distribution, with ORs ranging from 2.19 (95% CI, 1.84-2.53) to 2.48 (95% CI, 1.89-3.25) for the 3 different PRSs examined for those in the highest 1% of the PRS compared with those in the middle quantile. Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations. Conclusions and Relevance This cohort study found that PRS models derived from women with European ancestry for breast cancer risk generalized well for women with European, Latinx, and African ancestries across different clinical settings, although the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

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.

There is a need for multimodal strategies to keep research participants informed about study results. Our aim was to characterize preferences of genomic research participants from two institutions along four dimensions of general research result updates: content, timing, mechanism, and frequency. Methods: We conducted a web-based cross-sectional survey that was administered from 25 June 2018 to 5 December 2018. Results: 397 participants completed the survey, most of whom (96%) expressed a desire to receive research updates. Preferences with high endorsement included: update content (brief descriptions of major findings, descriptions of purpose and goals, and educational material), update timing (when the research is completed, when findings are reviewed, when findings are published, and when the study status changes), update mechanism (email with updates, and email newsletter), and update frequency (every three months). Hierarchical cluster analyses based on the four update preferences identified four profiles of participants with similar preference patterns. Very few participants in the largest profile were comfortable with budgeting less money for research activities so that researchers have money to set up services to send research result updates to study participants. Conclusion: Future studies may benefit from exploring preferences for research result updates, as we have in our study. In addition, this work provides evidence of a need for funders to incentivize researchers to communicate results to participants.

Background Numerous implementation strategies to improve utilization of statins in patients with hypercholesterolemia have been utilized, with varying degrees of success. The aim of this systematic review is to determine the state of evidence of implementation strategies on the uptake of statins. Methods and results This systematic review identified and categorized implementation strategies, according to the Expert Recommendations for Implementing Change (ERIC) compilation, used in studies to improve statin use. We searched Ovid MEDLINE, Embase, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov from inception to October 2018. All included studies were reported in English and had at least one strategy to promote statin uptake that could be categorized using the ERIC compilation. Data extraction was completed independently, in duplicate, and disagreements were resolved by consensus. We extracted LDL-C (concentration and target achievement), statin prescribing, and statin adherence (percentage and target achievement). A total of 258 strategies were used across 86 trials. The median number of strategies used was 3 (SD 2.2, range 1–13). Implementation strategy descriptions often did not include key defining characteristics: temporality was reported in 59%, dose in 52%, affected outcome in 9%, and justification in 6%. Thirty-one trials reported at least 1 of the 3 outcomes of interest: significantly reduced LDL-C (standardized mean difference [SMD] − 0.17, 95% CI − 0.27 to − 0.07, p = 0.0006; odds ratio [OR] 1.33, 95% CI 1.13 to 1.58, p = 0.0008), increased rates of statin prescribing (OR 2.21, 95% CI 1.60 to 3.06, p < 0.0001), and improved statin adherence (SMD 0.13, 95% CI 0.06 to 0.19; p = 0.0002; OR 1.30, 95% CI 1.04 to 1.63, p = 0.023). The number of implementation strategies used per study positively influenced the efficacy outcomes. Conclusion Although studies demonstrated improved statin prescribing, statin adherence, and reduced LDL-C, no single strategy or group of strategies consistently improved outcomes. Trial registration PROSPERO CRD42018114952.

Despite efficacious treatments, evidence-based guidelines, and increased availability of integrated behavioral health care, youth coping with attention-deficit/hyperactivity disorder (ADHD) receive suboptimal care. More research is needed to understand and address care gaps, particularly within rural health systems that face unique challenges. We conducted a qualitative study within a predominantly rural health system with a pediatric-integrated behavioral health care program to address research gaps and prepare for quality improvement initiatives, including primary care clinician (PCC) trainings and clinical decision support tools in the electronic health record (EHR).Semistructured interviews were conducted with 26 PCCs representing clinics within the health system. Interview guides were based on the Practical Robust Implementation and Sustainability Model to elicit PCC views regarding determinants of current practices and suggestions to guide quality improvement efforts. We used thematic analysis to identify patterns of responding that were common across participants.PCCs identified several internal and external contextual factors as determinants of current practices. Of note, PCCs recommended increased access to continuing education trainings held in clinic over lunch and delivered in less than 30 minutes. Suggested improvements to the EHR included incorporating parent and teacher versions of the Vanderbilt Rating Scale into the EHR, documentation templates aligned with evidence-based guidelines, and alerts and suggestions to aid medication management during appointments.Future research to identify implementation strategies to help rural PCCs adopt innovations are needed given the increased responsibility for managing ADHD care and intractable gaps in access to behavioral health care in rural regions.

Background Children with central nervous system (CNS) tumors undergo frequent imaging for diagnosis and follow-up, but few studies have characterized longitudinal imaging patterns. We described medical imaging in children before and after malignant CNS tumor diagnosis. Procedure We conducted a retrospective cohort study of children aged 0–20 years diagnosed with CNS tumors between 1996–2016 at six U.S. integrated healthcare systems and Ontario, Canada. We collected computed topography (CT), magnetic resonance imaging (MRI), radiography, ultrasound, nuclear medicine examinations from 12 months before through 10 years after CNS diagnosis censoring six months before death or a subsequent cancer diagnosis, disenrollment from the health system, age 21 years, or December 31, 2016. We calculated imaging rates per child per month stratified by modality, country, diagnosis age, calendar year, time since diagnosis, and tumor grade. Results We observed 1,879 children with median four years follow-up post-diagnosis in the U.S. and seven years in Ontario, Canada. During the diagnosis period (±15 days of diagnosis), children averaged 1.10 CTs (95% confidence interval [CI] 1.09–1.13) and 2.14 MRIs (95%CI 2.12–2.16) in the U.S., and 1.67 CTs (95%CI 1.65–1.68) and 1.86 MRIs (95%CI 1.85–1.88) in Ontario. Within one year after diagnosis, 19% of children had ≥5 CTs and 45% had ≥5 MRIs. By nine years after diagnosis, children averaged one MRI and one radiograph per year with little use of other imaging modalities. Conclusions MRI and CT are commonly used for CNS tumor diagnosis, whereas MRI is the primary modality used during surveillance of children with CNS tumors.

Introduction: Despite familial hypercholesterolemia (FH) being a common cardiovascular genetic disorder, it is vastly underdiagnosed and undertreated. This is partly due to the lack of systematic screening methods to identify possible FH and little to no implementation of cascade screening approaches in the US. Screening models, such as machine learning algorithms, and family communication methods for cascade screening, such as chatbot technology and direct contact of at-risk relatives by a clinician, may help close the gap in FH identification. Methods: Focus groups were conducted with individuals with FH and clinicians. Focus groups were audio-recorded, transcribed, and coded for acceptability and feasibility of implementing screening models and family communication methods. Results: Individuals with FH and clinicians felt that models analyzing different data sources, including electronic health records, to screen for FH have the potential to activate patients and stimulate patient-clinician conversations about FH. While some expressed privacy and confidentiality concerns, individuals with FH found screening models acceptable, stating that these could have led to an earlier diagnosis and treatment and expressing their frustration with the status quo. Most had a strong desire to be notified of screening models’ outcomes at the same time as their clinician. Clinicians felt strongly that automated models would be helpful in identifying FH. Many with FH felt responsible for notifying their family about FH first; however, some indicated comfort with their clinician, healthcare system, or other professionals helping to communicate FH risk to their relatives via direct contact methods. Further, they indicated a strong willingness to use chatbots to share FH risk information with their relatives. Clinicians felt the need to support their patients and offer their services when sharing FH risk information with relatives, while individuals with FH expressed doubt that their clinicians would have time and resources to provide active support. Conclusions: Individuals with FH and clinicians agreed that FH screening models and enhanced family communication methods would be beneficial, acceptable, and feasible to implement in US healthcare systems.

Author(s): Reuben, David B; Gill, Thomas M; Stevens, Alan; Williamson, Jeff; Volpi, Elena; Lichtenstein, Maya; Jennings, Lee A; Tan, Zaldy; Evertson, Leslie; Bass, David; Weitzman, Lisa; Carnie, Martie; Wilson, Nancy; Araujo, Katy; Charpentier, Peter; Meng, Can; Greene, Erich J; Dziura, James; Liu, Jodi; Unger, Erin; Yang, Mia; Currie, Katherine; Lenoir, Kristin M; Green, Aval-NaʼRee S; Abraham, Sitara; Vernon, Ashley; Samper-Ternent, Rafael; Raji, Mukaila; Hirst, Roxana M; Galloway, Rebecca; Finney, Glen R; Ladd, Ilene; Rahm, Alanna Kulchak; Borek, Pamela; Peduzzi, Peter | Abstract: Background/objectivesAlthough several approaches have been developed to provide comprehensive care for persons living with dementia (PWD) and their family or friend caregivers, the relative effectiveness and cost effectiveness of community-based dementia care (CBDC) versus health system-based dementia care (CBDC) and the effectiveness of both approaches compared with usual care (UC) are unknown.DesignPragmatic randomized three-arm superiority trial. The unit of randomization is the PWD/caregiver dyad.SettingFour clinical trial sites (CTSs) based in academic and clinical health systems.ParticipantsA total of 2,150 English- or Spanish-speaking PWD who are not receiving hospice or residing in a nursing home and their caregivers.InterventionsEighteen months of (1) HSDC provided by a nurse practitioner or physician's assistant dementia care specialist who works within the health system, or (2) CBDC provided by a social worker or nurse care consultant who works at a community-based organization, or (3) UC with as needed referral to the Alzheimer's Association Helpline.MeasurementsPrimary outcomes: PWD behavioral symptoms and caregiver distress as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity and Modified Caregiver Strain Index scales.Secondary outcomesNPI-Q Distress, caregiver unmet needs and confidence, and caregiver depressive symptoms. Tertiary outcomes: PWD long-term nursing home placement rates, caregiver-reported PWD functional status, cognition, goal attainment, "time spent at home," Dementia Burden Scale-Caregiver, a composite measure of clinical benefit, Quality of Life of persons with dementia, Positive Aspects of Caregiving, and cost effectiveness using intervention costs and Medicare claims.ResultsThe results will be reported in the spring of 2024.ConclusionD-CARE will address whether emphasis on clinical support and tighter integration with other medical services has greater benefit than emphasis on social support that is tied more closely to community resources. It will also assess the effectiveness of both interventions compared with UC and will evaluate the cost effectiveness of each intervention.

Background and Objectives: Despite efficacious treatments and evidence-based guidelines, youth coping with attention deficit hyperactivity disorder (ADHD) receive suboptimal care. Primary care clinicians (PCCs) are frontline providers of ADHD care; however, little is known about PCC perspectives regarding this care gap and how to effectively address it within health systems. We investigated PCC perspectives on determinants of pediatric ADHD care and considerations for improving adherence to evidence-based guidelines. Methods: Semi-structured qualitative interviews were conducted with 26 PCCs representing clinics within a health system on improving adherence to treatment guidelines for pediatric ADHD. Interview guides were based on the Pragmatic Robust Implementation and Sustainability Model (PRISM) to elicit PCC views regarding determinants of current practices and suggestions to guide improvement efforts. We used thematic analysis to identify patterns of responding that were common across participants.Results: We identified 12 themes categorized into two broad domains: Status Quo of Pediatric ADHD Care and Supporting and Constraining Factors for Improvement Initiatives. PCCs identified several internal and external contextual factors as determinants of current practices. Of note, PCCs reported they face challenges at multiple steps in the care process, including mental health stigma, coordinating care across settings, clinical productivity pressures, access to behavioral health care, and insurance mandates regarding medications. PCCs recommended efficient continuing education trainings accompanied by improvements to the electronic health record to include validated screening tools and documentation templates.Conclusions: Future research triangulating these findings may help to more efficiently improve the quality of pediatric ADHD care in health systems.

BackgroundThe majority of polygenic risk scores (PRS) for breast cancer have been developed and validated using cohorts of European ancestry (EA). Less is known about the generalizability of these PRS in other ancestral groups.MethodsThe Electronic Medical Records and Genomics (eMERGE) network cohort dataset was used to evaluate the performance of seven previously developed PRS (three EA-based PRSs, and four non-EA based PRSs) in three major ancestral groups. Each PRS was separately evaluated in EA (cases: 3939; controls: 28840), African ancestry (AA) (cases: 121; controls: 1173) and self-reported LatinX ancestry (LA) (cases: 92; controls: 1363) women. We assessed the association between breast cancer risk and each PRS, adjusting forage, study site, breast cancer family history, and first three ancestry informative principal components.ResultsEA-based PRSs were significantly associated with breast cancer risk in EA women per one SD increase (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.40–1.51), and LA women (OR = 1.41, 95% CI = 1.13–1.77), but not AA women (OR = 1.13, 95% CI = 0.92–1.40). There was no statistically significant association for the non-EA PRSs in all ancestry groups, LA including an LA-based PRS and an AA-based PRS.ConclusionWe evaluated EA-derived PRS for estimating breast cancer risk using the eMERGE dataset and found they generalized well in LA women but not in AA women. For non-EA based PRSs, we did not replicate previously reported associations for the respective ancestries in the eMERGE cohort. Our results highlight the need to improve representation of diverse population groups, particularly AA women, in research cohorts.

PURPOSE Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing—initial testing of priority genes followed by expanded testing—was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

Background Familial hypercholesterolemia (FH) is an inherited lipid disorder that confers high risk for premature cardiovascular disease but remains undertreated. Causes are multifactorial and multilevel, ranging from underprescribing (at the clinician-level) to medication nonadherence (at the patient-level). We evaluated patient and clinician stakeholder barriers and facilitators for treatment of FH to explore possible solutions to the problem. Methods and results Semi-structured interviews and focus groups guided by the Practical, Robust, Implementation and Sustainability Model (PRISM), were conducted with 33 patients and 17 clinician stakeholders across three healthcare systems. A total of14 patients and 9 clinician stakeholders participated in on-site focus groups and the remainder were individual interviews. Transcripts were coded using an iterative process to create a static codebook. We characterized patient and clinician stakeholder barriers into three categories: medical care-, medication-, and life-related. Feasibility of brainstormed solutions varied and was not always representative of the needs of all stakeholders. Patients suggested a need for childhood screening for FH and doctors being persistent about the importance of treating FH, creation of a patient peer group, data transparency, advocacy, and policy changes that would enable patients to receive better treatment. Clinician stakeholders suggested the need for clinical champions. Both groups of stakeholders discussed the need for education about FH. Conclusions Proposed solutions to improve treatment of FH proffered by participants in this study included resources for both patients and clinician stakeholders that clarify cardiovascular disease risks from FH, develop programs to screen for and identify FH at younger ages, and foster open conversations between patients and clinicians about treatment.

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&rsquo, 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.

Purpose The clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility. Methods Whole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient–participants and their clinicians. We queried patient–participants’ electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient–participants of eligible age who had begun risk management. Results Thirty-seven MyCode patient–participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer—including a stage 1C fallopian tube cancer—via these procedures. Conclusion Screening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.

Health care delivery is increasingly influenced by the emerging concepts of precision health and the learning health care system. Although not synonymous with precision health, genomics is a key enabler of individualized care. Delivering patient-centered, genomics-informed care based on individual-level data in the current national landscape of health care delivery is a daunting challenge. Problems to overcome include data generation, analysis, storage, and transfer; knowledge management and representation for patients and providers at the point of care; process management; and outcomes definition, collection, and analysis. Development, testing, and implementation of a genomics-informed program requires multidisciplinary collaboration and building the concepts of precision health into a multilevel implementation framework. Using the principles of a learning health care system provides a promising solution. This article describes the implementation of population-based genomic medicine in an integrated learning health care system-a working example of a precision health program.

Cascade testing, or screening, is the process of stepwise, systematic genetic testing of at-risk relatives for a genetic variant originally identified in a proband. Cascade testing effectively identifies at-risk relatives who would benefit from early screening and/or medical intervention, and can potentially lead to early diagnoses and disease prevention. However, recent studies highlight the need for additional resources to enhance family communication and improve the cascade testing process. In this mini-review of cascade testing, we discuss various factors that influence the effectiveness of communicating genetic risk information among families, including barriers, provision of additional resources, direct contact, and the role of technology and healthcare providers. Patients desire and value involvement of healthcare providers in the cascade testing process. Uptake of cascade testing increases when patients are provided with educational materials and technological resources, and when healthcare providers assist with communicating risk to their at-risk relatives. Through achievable adjustments in patient care, healthcare providers can facilitate family communication and uptake of cascade testing. This can be done by asserting the importance of genetic testing results to at-risk family members when reviewing results with patients and leveraging technological tools and other options for direct contact to maximize the benefits of earlier diagnosis and prevention.