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PURPOSE: This study compared Lynch syndrome universal tumor screening (UTS) across multiple health systems (some of which had 2 or more distinct UTS programs) to understand multilevel factors that may affect the successful implementation of complex programs. METHODS: Data from 66 stakeholder interviews were used to conduct multivalue coincidence analysis and identify key factors that consistently make a difference in whether UTS programs were implemented and optimized at the system level. RESULTS: The selected coincidence analysis model revealed combinations of conditions that distinguish 4 optimized UTS programs, 10 nonoptimized programs, and 4 systems with no program. Fully optimized UTS programs had both a maintenance champion and a positive inner setting. Two independent paths were unique to nonoptimized programs: (1) positive attitudes and a mixed inner setting or (2) limited planning and engaging among stakeholders. Negative views about UTS evidence or lack of knowledge about UTS led to a lack of planning and engaging, which subsequently prevented program implementation. CONCLUSION: The model improved our understanding of program implementation in health care systems and informed the creation of a toolkit to guide UTS implementation, optimization, and changes. Our findings and toolkit may serve as a use case to increase the successful implementation of other complex precision health programs.
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OBJECTIVE: Women with a fragile X premutation (PM) self-report higher rates of attention difficulties than women without a PM; however, results of studies using objective measures of attention are inconsistent. The present study assessed whether intrasubject variability during a sustained attention task better predicted functional outcomes in women with a PM than the previously published standard reaction time and accuracy variables. METHOD: We analyzed continuous performance test, a computerized measure of sustained attention, and the Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale Report (CAARS) data from 273 women with a PM and 175 women without a PM aged 18-50 years. Separate analyses using Pearson correlations and independent t tests were performed on the full range of coefficient of variation (CV) of reaction time scores and the subset of scores that showed higher variability. RESULTS: Performance variability of sustained attention measured by the continuous performance test was associated with functional outcomes measured by the CAARS in women with a PM but not women without a PM. Specifically, the CV in those with higher variability was correlated with two CAARS subscale scores (p = .006). Independent t tests showed significant differences in CV between CAARS scores dichotomized for the presence of subclinical symptoms for two subscales (p ≤ .001-.007). Correlation between the full range of CV scores and the CAARS Inattention/Memory Problems subscale approached significance (p = .012). CONCLUSIONS: Findings highlight the importance of including intrasubject variability in analyzing attention in clinical populations as a more sensitive objective measure associated with reported symptoms and to assist in predicting functional outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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BACKGROUND: Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal tumor screening (UTS) of newly diagnosed CRC cases is recommended to aid in diagnosis of LS and reduce cancer-related morbidity and mortality. However, not all health systems have adopted UTS processes and implementation may be inconsistent due to system and patient-level complexities. METHODS: To identify barriers, facilitators, and suggestions for improvements of the UTS process from the patient perspective, we conducted in-depth, semi-structured interviews with patients recently diagnosed with CRC, but not screened for or aware of LS. Patients were recruited from eight regionally diverse US health systems. Interviews were conducted by telephone, 60-minutes, audio-recorded, and transcribed. An inductive, constant comparative analysis approach was employed. RESULTS: We completed 75 interviews across the eight systems. Most participants were white (79%), about half (52%) were men, and the mean age was 60 years. Most self-reported either no (60%) or minimal (40%) prior awareness of LS. Overall, 96% of patients stated UTS should be a routine standard of care for CRC tumors, consistently citing four primary motivations for wanting to know their LS status and engage in the process for LS identification: "knowledge is power"; "family knowledge"; "prevention and detection"; and "treatment and surveillance." Common concerns pertaining to the process of screening for and identifying LS included: creating anticipatory worry for patients, the potential cost and the accuracy of the genetic test, and possibly having one's health insurance coverage impacted by the LS diagnosis. Patients suggested health systems communicate LS results in-person or by phone from a trained expert in LS; offer proactive verbal and written education about LS, the screening steps, and any follow-up surveillance recommendations; and support patients in communicating their LS screening to any of their blood relatives. CONCLUSION: Our qualitative findings demonstrate patients with CRC have a strong desire for healthcare systems to regularly implement and offer UTS. Patients offer key insights for health systems to guide future implementation and optimization of UTS and other LS screening programs and maximize diagnosis of individuals with LS and improve cancer-related surveillance and outcomes. TRIAL REGISTRATION: Not available: not a clinical trial.
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The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.
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Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Humanos , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Mutação/genética , RNA Mensageiro/metabolismo , Expansão das Repetições de Trinucleotídeos/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/terapiaRESUMO
PURPOSE: With increasing utilization of genetic testing, sharing genetic information can become part of general family health communication while providing biological relatives with important information about their own genetic risk. Importantly, little is known about motivations for and barriers to family communication of genetic information in historically underserved populations. METHODS: Using mixed methods, we explored patient experiences with family communication in a study population of English- and Spanish-speaking adults aged 18 to 49 years, enriched for participants from historically underserved backgrounds. Risk screening for hereditary cancer guided genetic testing for cancer risk genes and other medically actionable findings. RESULTS: Most participants overall (91%), including most with normal findings (89%), shared or planned to share their results with relatives. Common motivations for sharing results were to give relatives information about their genetic risk and because the participant thought the results were interesting. Reasons for not sharing were limited contact with relatives, perceptions of limited clinical utility for relatives, and concern that discussion of genetic information was stigmatized or taboo. CONCLUSION: Results demonstrate high rates of sharing genetic information, indicate motivations for sharing go beyond facilitating genetic testing for relatives, and suggest general willingness to share genetic information as part of family health communication.
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Testes Genéticos , Neoplasias , Adulto , Humanos , Testes Genéticos/métodos , Comunicação , Neoplasias/genética , Família , Inquéritos e Questionários , Predisposição Genética para DoençaRESUMO
BACKGROUND: Identifying key determinants is crucial for improving program implementation and achieving long-term sustainment within healthcare organizations. Organizational-level complexity and heterogeneity across multiple stakeholders can complicate our understanding of program implementation. We describe two data visualization methods used to operationalize implementation success and to consolidate and select implementation factors for further analysis. METHODS: We used a combination of process mapping and matrix heat mapping to systematically synthesize and visualize qualitative data from 66 stakeholder interviews across nine healthcare organizations, to characterize universal tumor screening programs of all newly diagnosed colorectal and endometrial cancers and understand the influence of contextual factors on implementation. We constructed visual representations of protocols to compare processes and score process optimization components. We also used color-coded matrices to systematically code, summarize, and consolidate contextual data using factors from the Consolidated Framework for Implementation Research (CFIR). Combined scores were visualized in a final data matrix heat map. RESULTS: Nineteen process maps were created to visually represent each protocol. Process maps identified the following gaps and inefficiencies: inconsistent execution of the protocol, no routine reflex testing, inconsistent referrals after a positive screen, no evidence of data tracking, and a lack of quality assurance measures. These barriers in patient care helped us define five process optimization components and used these to quantify program optimization on a scale from 0 (no program) to 5 (optimized), representing the degree to which a program is implemented and optimally maintained. Combined scores within the final data matrix heat map revealed patterns of contextual factors across optimized programs, non-optimized programs, and organizations with no program. CONCLUSIONS: Process mapping provided an efficient method to visually compare processes including patient flow, provider interactions, and process gaps and inefficiencies across sites, thereby measuring implementation success via optimization scores. Matrix heat mapping proved useful for data visualization and consolidation, resulting in a summary matrix for cross-site comparisons and selection of relevant CFIR factors. Combining these tools enabled a systematic and transparent approach to understanding complex organizational heterogeneity prior to formal coincidence analysis, introducing a stepwise approach to data consolidation and factor selection.
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Purpose: Genetic information has health implications for patients and their biological relatives. Death of a patient before sharing a genetic diagnosis with at-risk relatives is a missed opportunity to provide important information that could guide interventions to minimize cancer-related morbidity and mortality in relatives. Methods: We performed semi-structured interviews with individuals diagnosed with Lynch syndrome at 1 of 4 health systems to explore their perspectives on whether health systems should share genetic risk information with relatives following a patient's death. An inductive, open-coding approach was used to analyze audio-recorded content, with software-generated code reports undergoing iterative comparative analysis by a qualitative research team to identify broad themes and representative participant quotes. Results: Among 23 participating interviewees, 19 supported health systems informing relatives about their Lynch syndrome risk while the remaining 4 were conflicted about patient privacy. Most (n=22) wanted their Lynch syndrome diagnosis shared with relatives if they were unable to share and to be informed of their own risk if a diagnosed relative was unable to share. The most common issues noted regarding information-sharing with relatives included patient privacy and privacy laws (n=8), potential anxiety (n=5), and lack of contact information for relatives (n=3). Interviewee perspectives on how health systems could communicate genetic findings generated a consensus: When - a few months after but within a year of the patient's death; How - explanatory letter and follow-up phone call; and Who - a knowledgeable professional. Conclusions: Interviews demonstrated strong and consistent perspectives from individuals diagnosed with Lynch syndrome that health systems have a role and responsibility to inform relatives of genetic findings following a patient's death.
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PURPOSE: Effective approaches to communicate genomic information are needed to ensure equitable care. In a randomized controlled superiority trial, we tested a novel practice model that aims to make genetic counseling inclusive, by making the communication accessible, relational, and actionable (ARIA). METHODS: In total, 696 English- and Spanish-speaking patients aged 18 to 49 years, enriched for individuals from historically underserved backgrounds, were randomized in 1:1 ratio to ARIA or usual care. Primary outcomes were accuracy of recall, communication satisfaction, and perceived understanding. In total, 33 participants completed qualitative interviews. RESULTS: Recall and understanding were high for all participants. ARIA participants scored higher on the relationship scale of communication satisfaction (mean difference = 0.09, 95% CI = <0.01 to 0.17). Moderator analyses of communication satisfaction showed that those with lower health literacy reported less communication difficulty in ARIA and those using medical interpreters reported greater communication ease in ARIA. No significant difference was found on other primary and secondary outcomes. Qualitative data enhanced understanding of how and why ARIA can be effective. CONCLUSION: This study provides evidence that a genetic counseling intervention that focuses on specific communication skills to enhance relationship-building, patient engagement, and comprehension can be effective with all patients and may be especially valuable for patients of lower health literacy and Spanish-speakers who use a medical interpreter.
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Comunicação , Aconselhamento Genético , Letramento em Saúde , Humanos , Coleta de Dados , Aconselhamento Genético/métodos , Hispânico ou LatinoRESUMO
INTRODUCTION: Lynch syndrome (LS) is associated with an increased risk of colorectal (CRC) and endometrial (EC) cancers. Universal tumor screening (UTS) of all individuals diagnosed with CRC and EC is recommended to increase identification of LS. Kaiser Permanente Northwest (KPNW) implemented a UTS program for LS among individuals newly diagnosed with CRC in January 2016 and EC in November 2016. UTS at KPNW begins with immunohistochemistry (IHC) of tumor tissue to determine loss of mismatch repair proteins associated with LS (MLH1, MSH2, MSH6, and PMS2)., IHC showing loss of MLH1 is followed by reflex testing (automatic testing) to detect the presence of the BRAF V600E variant (in cases of CRC) and MLH1 promoter hypermethylation to rule out likely sporadic cases. MATERIALS AND METHODS: Individuals newly diagnosed with CRC and EC were identified between the initiation of the respective UTS programs and July 2018. Electronic medical records were reviewed to extract patient data related to UTS, including IHC and reflex testing results, date of referrals to the genetics department, and results of germline genetic testing for LS. RESULTS: 313 out of 362 individuals diagnosed with CRC and 61 out of 64 individuals diagnosed with EC who were eligible were screened by IHC for LS. Most (47/52 or 90%, including 46/49 CRC and 1/3 EC) individuals that were not screened by IHC only had a biopsy sample available. Fourteen individuals (3.7% overall, including 13/313 CRC and 1/61 EC) received an abnormal result after reflex testing and were referred for genetic counseling. Of these, 10 individuals (71% overall, including 9/13 CRC and 1/1 EC) underwent germline genetic testing for LS. Five individuals diagnosed with CRC were found to have pathogenic variants. in PMS2 (n = 3), MLH1 (n = 1), and MSH6 (n = 1). No pathogenic variants were identified in individuals diagnosed with EC. CONCLUSIONS: UTS identified individuals at risk for LS. Most individuals who screened positive for LS had follow-up germline genetic testing for LS. The consistent use of biopsy samples is an opportunity to improve UTS.
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Actionability is an important concept in medicine that does not have a well-accepted standard definition, nor is there a general consensus on how to establish it. Medical actionability is often conflated with clinical utility, a related but distinct concept. This lack of clarity contributes to practice variation and inconsistent coverage decisions in genomic medicine, leading to the potential for systematic bias in the use of evidence-based interventions. We clarify how medical actionability and clinical utility are distinct and then discuss the spectrum of actionability, including benefits for the person, the family, and society. We also describe applications across the life course, including prediction, diagnosis, and treatment. Current challenges in assessing the medical actionability of identified genomic variants include gaps in the evidence, limited contexts with practice guidelines, and subjective aspects of medical actionability. A standardized and authoritative assessment of medical actionability is critical to implementing genomic medicine in a fashion that improves population health outcomes and reduces health disparities.
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Genoma Humano , Genômica , HumanosRESUMO
PURPOSE: Synthesis and curation of evidence regarding the clinical actionability of secondary findings (SFs) from genome-scale sequencing are needed to support decision-making on reporting of these findings. To assess actionability of SFs in children and adolescents, the Clinical Genome Resource established the Pediatric Actionability Working Group (AWG). METHODS: The Pediatric AWG modified the framework of the existing Adult AWG, which included production of summary reports of actionability for genes and associated conditions and consensus actionability scores for specific outcome-intervention pairs. Modification of the adult framework for the pediatric setting included accounting for special considerations for reporting presymptomatic or predictive genetic findings in the pediatric context, such as maintaining future autonomy by not disclosing conditions not actionable until adulthood. The Pediatric AWG then applied this new framework to genes and associated conditions with putative actionability. RESULTS: As of September 2021, the Pediatric AWG applied the new framework to 70 actionability topics representing 143 genes. Reports and scores are publicly available at www.clinicalgenome.org. CONCLUSION: The Pediatric AWG continues to curate gene-condition topics and build an evidence-based resource, supporting clinical communities and decision-makers with policy development on the return of SFs in pediatric populations.
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Testes Genéticos , Relatório de Pesquisa , Adolescente , Adulto , Criança , Mapeamento Cromossômico , HumanosRESUMO
BACKGROUND: A critical step in access to genetic testing for hereditary cancer syndromes is referral for genetic counseling to assess personal and family risk. Individuals meeting testing guidelines have the greatest need to be evaluated. However, referrals to genetics are underutilized in US patients with hereditary cancer syndromes, especially within traditionally underserved populations, including racial and ethnic minorities, low-income, and non-English speaking patients. METHODS: We studied existing processes for referral to genetic evaluation and testing for hereditary cancer risk to identify areas of potential improvement in delivering these services, especially for traditionally underserved patients. We conducted a retrospective review of 820 referrals to the Kaiser Permanente Northwest (KPNW) genetics department containing diagnosis codes for hereditary cancer risk. We classified referrals as high- or low-quality based on whether sufficient information was provided to determine if patients met national practice guidelines for testing. Through chart abstraction, we also assessed consistency with practice guidelines, whether the referral resulted in a visit to the genetics department for evaluation, and clinical characteristics of patients receiving genetic testing. RESULTS: Most referrals (n = 514, 63%) contained sufficient information to assess the appropriateness of referral; of those, 92% met practice guidelines for genetic testing. Half of referred patients (50%) were not offered genetic evaluation; only 31% received genetic testing. We identified several barriers to receiving genetic evaluation and testing, the biggest barrier being completion of a family history form sent to patients following the referral. Those with a referral consistent with testing guidelines, were more likely to receive genetic testing than those without (39% vs. 29%, respectively; p = 0.0058). Traditionally underserved patients were underrepresented in those receiving genetic evaluation and testing relative to the overall adult KPNW population. CONCLUSIONS: Process improvements are needed to increase access to genetic services to diagnose hereditary cancer syndromes prior to development of cancer.
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PURPOSE: Understanding the motivations and concerns of patients from diverse populations regarding participation in implementation research provides the needed evidence about how to design and conduct studies for facilitating access to genetics services. Within a hereditary cancer screening study assessing a multifaceted intervention, we examined primary care patients' motivations and concerns about participation. METHODS: We surveyed and interviewed study participants after they enrolled, surveyed those who did not complete enrollment, and used descriptive qualitative and quantitative methods to identify motivations and concerns regarding participation. RESULTS: Survey respondents' most common motivations included a desire to learn about their future risk (81%), receiving information that may help family (58%), and a desire to advance research (34%). Interviews revealed 3 additional important factors: affordability of testing, convenience of participation, and clinical relationships supporting research decision-making. Survey data of those who declined enrollment showed that the reasons for declining included concerns about privacy (38%), burdens of the research (19%), and their fear of not being able to cope with the genetic information (19%). CONCLUSION: Understanding the facilitating factors and concerns that contribute to decisions about research may reveal ways to improve equity in access to care and research that could lead to greater uptake of genomic medicine across diverse primary care patient populations.
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Motivação , Neoplasias , Predisposição Genética para Doença , Humanos , Atenção Primária à Saúde , Medição de Risco , Inquéritos e QuestionáriosRESUMO
This paper examines the legal and ethical aspects of traceback testing, a process in which patients who have been previously diagnosed with ovarian cancer are identified and offered genetic testing so that their family members can be informed of their genetic risk and can also choose to undergo testing. Specifically, this analysis examines the ethical and legal limits in implementing traceback testing in cases when the patient is deceased and can no longer consent to genetic testing.
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Família , Testes Genéticos , Humanos , PacientesRESUMO
Lynch syndrome (LS) is the most common inherited cause of colorectal and endometrial cancers. Identifying individuals at risk for LS without personal cancer history requires detailed collection and assessment of family health history. However, barriers exist to family health history collection, especially in historically underserved populations. To improve LS risk assessment in historically underserved populations, we adapted the provider-facing PREdiction Model for gene Mutations (PREMM5™ model), a validated LS risk assessment model, into a patient-facing electronic application through an iterative development process involving expert and patient stakeholders. We report on preliminary findings based on the first 500 individuals exposed to the adapted application in a primary care population enriched for low-literacy and low-resource patients. Major adaptations to the PREMM5™ provider module included reduction in reading level, addition of interactive literacy aids, incorporation of family history assessment for both maternal and paternal sides of the family, and inclusion of questions about individual relatives or small groups of relatives to reduce cognitive burden. In the first 500 individuals, 90% completed the PREMM5™ independently; of those, 94% did so in 5 min or less (ranged from 0.2 to 48.8 min). The patient-facing application was able to accurately classify 84% of patients as having clinically significant or not clinically significant LS risk. Our preliminary results suggest that in this diverse study population, most participants were able to rapidly, accurately, and independently complete an interactive application collecting family health history assessment that accurately assessed for Lynch syndrome risk.
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Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias do Endométrio , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/genética , Feminino , Humanos , Instabilidade de Microssatélites , Mutação , Medição de RiscoRESUMO
Guidelines currently state that genetic testing is clinically indicated for all individuals diagnosed with ovarian cancer. Individuals with a prior diagnosis of ovarian cancer who have not received genetic testing represent missed opportunities to identify individuals with inherited high-risk cancer variants. For deceased individuals, post-mortem genetic testing of pathology specimens allows surviving family members to receive important genetic risk information. The Genetic Risk Assessment in Ovarian Cancer (GRACE) study aims to address this significant healthcare gap using a "traceback testing" approach to identify individuals with a prior diagnosis of ovarian cancer and offer genetic risk information to them and their family members. This study will assess the potential ethical and privacy concerns related to an ovarian cancer traceback testing approach in the context of patients who are deceased, followed by implementation and evaluation of the feasibility of an ovarian cancer traceback testing approach using tumor registries and archived pathology tissue. Descriptive and statistical analyses will assess health system and patient characteristics associated with the availability of pathology tissue and compare the ability to contact and uptake of genetic testing between patients who are living and deceased. The results of this study will inform the implementation of future traceback programs.
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Disparidades nos Níveis de Saúde , Síndromes Neoplásicas Hereditárias/prevenção & controle , Comportamento de Redução do Risco , Comportamento Social , Letramento em Saúde , Humanos , Síndromes Neoplásicas Hereditárias/psicologia , Relações Profissional-Paciente , Racismo Sistêmico/psicologiaRESUMO
Purpose: Women who carry an FMR1 premutation (PM) can experience two well-established PM-associated disorders: fragile X-associated primary ovarian insufficiency (FXPOI, affects ~20-30% carriers) and fragile X-associated tremor-ataxia syndrome (FXTAS, affects ~6-15% carriers); however, emerging evidence indicates that some of these women experience complex health profiles beyond FXPOI and FXTAS. Methods: In an effort to better understand predictors for these comorbid conditions, we collected self-reported medical histories on 413 women who carry an FMR1 PM. Results: There were 22 health conditions reported by at least 9% of women. In an exploratory analysis, 12 variables were tested in logistic regression models for each comorbid condition, including demographic variables, environmental variables, PM-associated factors, and endorsement of depression and/or anxiety. More than half of the comorbid conditions studied were associated with women who self-reported having anxiety. Age, smoking, body mass index (BMI), and depression were also significant predictor variables for specific comorbid conditions. Conclusions: Age, smoking, and BMI were significantly associated with a subset of the comorbid conditions analyzed. Importantly, depression or anxiety were also significantly associated with many of the comorbid health conditions. This work highlights some of the modifiable factors associated with complex health profiles among women with an FMR1 PM.