Kristin R. Muessig

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.

Purpose:Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research.Methods:We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability.Results:We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders.Conclusion:The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258–1268.

Genome sequencing and carrier testing: decisions on categorization and whether to disclose results of carrier testing

Purpose:We investigated the use of genome sequencing for preconception carrier testing. Genome sequencing could identify one or more of thousands of X-linked or autosomal recessive conditions that could be disclosed during preconception or prenatal counseling. Therefore, a framework that helps both clinicians and patients understand the possible range of findings is needed to respect patient preferences by ensuring that information about only the desired types of genetic conditions are provided to a given patient.Methods:We categorized gene–condition pairs into groups using a previously developed taxonomy of genetic conditions. Patients could elect to receive results from these categories. A Return of Results Committee (RORC) developed inclusion and exclusion criteria for each category.Results:To date, the RORC has categorized 728 gene–condition pairs: 177 are categorized as life span–limiting, 406 are categorized as serious, 93 are categorized as mild, 41 are categorized as unpredictable, and 11 are categorized as adult-onset. An additional 64 gene–condition pairs were excluded from reporting to patients or put on a watch list, generally because evidence that a gene and condition were associated was limited.Conclusion:Categorization of gene–condition pairs using our taxonomy simplifies communication regarding patient preferences for carrier information from a genomic test.Genet Med advance online publication 12 January 2017

Stakeholder perspectives on implementing a universal Lynch syndrome screening program: a qualitative study of early barriers and facilitators

Purpose:Evidence-based guidelines recommend that all newly diagnosed colon cancer be screened for Lynch syndrome (LS), but best practices for implementing universal tumor screening have not been extensively studied. We interviewed a range of stakeholders in an integrated health-care system to identify initial factors that might promote or hinder the successful implementation of a universal LS screening program.Methods:We conducted interviews with health-plan leaders, managers, and staff. Interviews were audio-recorded and transcribed. Thematic analysis began with a grounded approach and was also guided by the Practical Robust Implementation and Sustainability Model (PRISM).Results:We completed 14 interviews with leaders/managers and staff representing involved clinical and health-plan departments. Although stakeholders supported the concept of universal screening, they identified several internal (organizational) and external (environment) factors that promote or hinder implementation. Facilitating factors included perceived benefits of screening for patients and organization, collaboration between departments, and availability of organizational resources. Barriers were also identified, including: lack of awareness of guidelines, lack of guideline clarity, staffing and program “ownership” concerns, and cost uncertainties. Analysis also revealed nine important infrastructure-type considerations for successful implementation.Conclusion:We found that clinical, laboratory, and administrative departments supported universal tumor screening for LS. Requirements for successful implementation may include interdepartmental collaboration and communication, patient and provider/staff education, and significant infrastructure and resource support related to laboratory processing and systems for electronic ordering and tracking.Genet Med 18 2, 152–161.

Universal tumor screening for Lynch syndrome

Universal tumor screening for Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria.

Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers

Universal tumor screening for Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria.

Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen's Actionability Working Group

The use of genome‐scale sequencing allows for identification of genetic findings beyond the original indication for testing (secondary findings). The ClinGen Actionability Working Groups (AWG) protocol for evidence synthesis and semi‐quantitative metric scoring evaluates four domains of clinical actionability for potential secondary findings: severity and likelihood of the outcome, and effectiveness and nature of the intervention. As of February 2018, the AWG has scored 127 genes associated with 78 disorders (up‐to‐date topics/scores are available at www.clinicalgenome.org). Scores across these disorders were assessed to compare genes/disorders recommended for return as secondary findings by the American College of Medical Genetics and Genomics (ACMG) with those not currently recommended. Disorders recommended by the ACMG scored higher on outcome‐related domains (severity and likelihood), but not on intervention‐related domains (effectiveness and nature of the intervention). Current practices indicate that return of secondary findings will expand beyond those currently recommended by the ACMG. The ClinGen AWG evidence reports and summary scores are not intended as classifications of actionability, rather they provide a resource to aid decision makers as they determine best practices regarding secondary findings. The ClinGen AWG is working with the ACMG Secondary Findings Committee to update future iterations of their secondary findings list.

Returning negative results to individuals in a genomic screening program: lessons learned

PurposeIn genomics, the return of negative screening results for rare, medically actionable conditions in large unselected populations with low prior risk of disease is novel and may involve important and nuanced concerns for communicating their meaning. Recruitment may result in self-selection because of participants’ personal or family history, changing the characteristics of the screened population and interpretation of both positive and negative findings; prior motivations may also affect responses to results.MethodsUsing data from GeneScreen, an exploratory adult screening project that targets 17 genes related to 11 medically actionable conditions, we address four questions: (1) Do participants self-select based on actual or perceived risk for one of the conditions? (2) Do participants understand negative results? (3) What are their psychosocial responses? (4) Are negative results related to changes in reported health-related behaviors?ResultsWe found disproportionate enrollment of individuals at elevated prior risk for conditions being screened, and a need to improve communication about the nature of screening and meaning of negative screening results. Participants expressed no decision regret and did not report intention to change health-related behaviors.ConclusionThis study illuminates critical challenges to overcome if genomic screening is to benefit the general population.

Patient and provider perspectives on adherence to and care coordination of lynch syndrome surveillance recommendations: findings from qualitative interviews

BackgroundPatients with a genetic variant associated with Lynch syndrome (LS) are recommended to undergo frequent and repeated cancer surveillance activities to minimize cancer-related morbidity and mortality. Little is known about how patients and primary care providers (PCPs) track and manage these recommendations. We conducted a small exploratory study of patient and PCP experiences with recommended LS surveillance activities and communication with family members in an integrated health care system.MethodsWe used in-depth interviews with patients and providers to understand how surveillance is coordinated and monitored following confirmation of LS. We recruited patients with a range of ages/gender, and providers with at least at least one patient with a molecular diagnosis of LS. All interviews were recorded, transcribed, and content analyzed by a trained qualitative methodologist.ResultsTwenty-two interviews were completed with 12 patients and 10 providers. Most patients (10) had detailed knowledge of surveillance recommendations, but were less sure of time intervals. While all patients reported receiving initial education about their surveillance recommendations from a genetic counselor, seven did not follow-up with a genetic counselor in subsequent years. A third of patients described taking sole responsibility for managing their LS surveillance care. Lack of routine communication from the health system (e.g., prompts for surveillance activities), and provider engagement were surveillance barriers. PCPs were generally aware of LS, but had limited familiarity with surveillance recommendations. Most PCPs (7) viewed LS as rare and relied on patient and specialist expertise and support. Providers typically had 1 patient with LS in a panel of 1800 patients overall. Providers felt strongly that management of LS should be coordinated by a dedicated team of specialists. Most patients (92%) had at least one family member that sought LS testing, and common barriers for family members included lack of insurance, affordability, and fear of result.ConclusionThe maximal benefits of screening for confirmation of LS will only be realized with adherence to recommended preventive care. Important factors to ensure patients receive recommended LS care include a comprehensive and coordinated monitoring program that includes reminder prompts, and increased PCP education of LS and associated surveillance recommendations.

Universal screening for Lynch syndrome among patients with colorectal cancer: patient perspectives on screening and sharing results with at-risk relatives

Universal screening for Lynch syndrome (LS) among all cases of colorectal cancer (CRC) could increase the diagnosis of LS and reduce morbidity and mortality of LS-associated cancers. Given universal screening includes all patients, irrespective of high risk factors such early age at onset or family history of CRC, it is important to understand perspectives of all patients and not just those at high risk. As part of a study to assess the feasibility and implementation of universal screening, 189 patients newly diagnosed with CRC were surveyed about their interest in screening for LS and communication of results with at-risk family members. Overall, participants responded positively regarding screening for LS, with most wanting to know their genetic risks in general (86%) and risk of hereditary CRC (93%). Prior to receiving screening results, most participants stated they intended to share their screening results with parents (89%), siblings (96%), and children (96%). Of the 28 participants who received a positive LS screening result, 26 (93%) reported sharing their result with at least one first-degree family member. Interest in screening for LS and communication of screening results with family members was not associated with high risk factors. This study indicates that patients are interested in being screened for LS and that sharing information on the risk of LS with at-risk family members is not a significant barrier. These findings provide novel insight into patient perspectives about screening for LS and can guide successful implementation of universal screening programs.