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

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

A systematic framework for selecting gene-condition pairs for inclusion in newborn sequencing panels: Early Check implementation

Purpose Research is underway worldwide to investigate the feasibility, acceptability, and utility of sequencing-based newborn screening. Different methods have been used to select gene-condition pairs for screening, leading to highly inconsistent gene lists across studies. Methods Early Check developed and utilized actionability-based frameworks for evaluating gene-condition pairs for inclusion in newborn panels (Panel 1 - high actionability, Panel 2 - possible actionability). A previously developed framework, the Age-based Semi Quantitative Metric (ASQM), was adapted. Increasing ASQM scores, with a maximum of 15, suggest greater actionability. Wilcoxon tests were performed to compare Panel 1 gene-condition pairs on the Recommended Uniform Screening Panel (RUSP) to non-RUSP pairs. Results In our first round of assessment, Early Check identified 178 gene-condition pairs for inclusion in Panel 1 and 29 for Panel 2. Median ASQM scores of RUSP conditions on Panel 1 was 12 (range 4 to 15) and non-RUSP was 13 (range 9 to 15). Median scores for Panel 2 was 10 (range 6 to 14). Conclusion The Early Check frameworks provide a transparent, semiquantitative, and reproducible methodology for selecting gene-condition pairs for NBS sequencing pilot studies that may inform future integration of genomic sequencing into population-level NBS. Collaborative efforts among newborn sequencing studies to establish shared criteria is needed to enhance cross-study comparisons

Should Health Systems Share Genetic Findings With At-Risk Relatives When the Proband Is Deceased? Interviews With Individuals Diagnosed With Lynch Syndrome

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

Evaluating gene expression in C57BL/6J and DBA/2J mouse striatum using RNA-Seq and microarrays.

C57BL/6J (B6) and DBA/2J (D2) are two of the most commonly used inbred mouse strains in neuroscience research. However, the only currently available mouse genome is based entirely on the B6 strain sequence. Subsequently, oligonucleotide microarray probes are based solely on this B6 reference sequence, making their application for gene expression profiling comparisons across mouse strains dubious due to their allelic sequence differences, including single nucleotide polymorphisms (SNPs). The emergence of next-generation sequencing (NGS) and the RNA-Seq application provides a clear alternative to oligonucleotide arrays for detecting differential gene expression without the problems inherent to hybridization-based technologies. Using RNA-Seq, an average of 22 million short sequencing reads were generated per sample for 21 samples (10 B6 and 11 D2), and these reads were aligned to the mouse reference genome, allowing 16,183 Ensembl genes to be queried in striatum for both strains. To determine differential expression, 'digital mRNA counting' is applied based on reads that map to exons. The current study compares RNA-Seq (Illumina GA IIx) with two microarray platforms (Illumina MouseRef-8 v2.0 and Affymetrix MOE 430 2.0) to detect differential striatal gene expression between the B6 and D2 inbred mouse strains. We show that by using stringent data processing requirements differential expression as determined by RNA-Seq is concordant with both the Affymetrix and Illumina platforms in more instances than it is concordant with only a single platform, and that instances of discordance with respect to direction of fold change were rare. Finally, we show that additional information is gained from RNA-Seq compared to hybridization-based techniques as RNA-Seq detects more genes than either microarray platform. The majority of genes differentially expressed in RNA-Seq were only detected as present in RNA-Seq, which is important for studies with smaller effect sizes where the sensitivity of hybridization-based techniques could bias interpretation

The Healthcare Systems Research Network (HCSRN) as an Environment for Dissemination and Implementation Research: A Case Study of Developing a Multi-Site Research Study in Precision Medicine

Context: In existence for nearly 25 years, the Healthcare Systems Research Network (HCSRN) is an established and sustainable network of health care systems that serves as a “real world” laboratory to enable the integration of research findings into practice. The objective of this paper is to demonstrate how the HCSRN serves as an ideal environment for studying dissemination and implementation of evidence-based practices into health care systems through the example of developing a multi-site study on the implementation of evidence-based precision medicine practices. Case description: The “Implementing Universal Lynch Syndrome Screening (IMPULSS)” study (NIH R01CA211723) involves seven HCSRN health care systems and two external health care systems. The IMPULSS study will describe and explain organizational variability around Lynch syndrome (LS) screening to identify which factors in different organizational contexts are important for successful implementation of LS screening programs and will create a toolkit to facilitate organizational decision making around implementation and improvement of precision medicine programs in health care systems. Major Themes: The strengths of the HCSRN that facilitate D&I research include: 1) a culture of collaboration, 2) standardization of data and processes across systems, and 3) researchers embedded in diverse health care systems. We describe how these strengths contributed to developing the IMPULSS study. Conclusion: Given the importance of conducting research in real world settings to improve patient outcomes, the unique strengths of the HCSRN are of vital importance. The IMPULSS study is one case example of how the strengths of the HCSRN make it an excellent environment for research on implementing evidence-based precision medicine practices in health care systems

Universal Screen for Lynch Syndrome in an Integrated Health Care System: Assessment of Patient Perspectives and Sharing Results With At-Risk Relatives

Background/Aims: Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC). Evidence-based recommendations promote universal tumor screening for LS among all new cases of CRC over selective screening based on family history or age of diagnosis. Maximal reduction in morbidity and mortality from universal tumor screening depends on patients with a positive screen following up with genetic counseling and testing to confirm a diagnosis of LS and sharing results with at-risk relatives. Methods: Participants included 165 Kaiser Permanente Northwest members aged 39 to 91 years who had undergone surgery for CRC. Tumor samples were screened for microsatellite instability and participants surveyed before and after receiving screening results to assess perspectives on screening and sharing results with at-risk relatives. Results: Most patients reported no family history of CRC; 14.1% had a first-degree relative and 7.4% had a second- or third-degree relative with CRC. However, most (93%) wanted to know their risk for hereditary CRC. Overall, most patients endorsed potential benefits and few barriers to screening, though 62% indicated a worry about the cost of additional testing and surveillance. Before receiving screening results, most patients indicated they would likely share their result with their parents (90%), siblings (96%) and children (97%), where applicable. Of the 25 patients with a positive microsatellite instability screen, 96.0% reported they shared their results with at least one relative. Most patients endorsed motivations to share results, namely: so family members could act to reduce their risk of CRC (76%) and it was their responsibility to let family members know they might be at higher risk of CRC (68%). None of the patients indicated that strained family relationships would prevent them from sharing results, and few indicated that they would not share their results because it would worry relative(s) (8%) or because discussing their results could hurt relationship(s) (4%). Conclusion: Given universal tumor screening will target all new cases of CRC, it is important to understand motivations among patients not identified via high-risk factors such as family history or age of diagnosis. These findings provide insight into patient attitudes and perspectives toward LS screening to guide successful implementation of screening programs

Feasibility of a Traceback Approach for Using Pathology Specimens to Facilitate Genetic Testing in the Genetic Risk Analysis in Ovarian Cancer (GRACE) Study Protocol

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

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

BACKGROUND 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. METHODS A total of 145 patients aged 39 to 87 years were administered surveys assessing perceived risk, patient perspectives, and potential benefits of and barriers to tumor screening for Lynch syndrome. Associations between patient‐specific and cancer‐specific factors and survey responses were analyzed. RESULTS The majority of participants perceived their risk of developing Lynch syndrome as being low, with 9 participants (6.2%) anticipating an abnormal screening result. However, most participants endorsed the potential benefits of screening for themselves and their families, with 84.8% endorsing ≥6 benefits and 50.3% endorsing all 8 benefits. Participants also endorsed few potential barriers to screening, with 89.4% endorsing ≤4 of 9 potential barriers. A common barrier was worry about the cost of additional testing and surveillance, which was endorsed by 54.5% of participants. The level of distress associated with tumor screening for Lynch syndrome, which was very low, was not associated with age or CRC stage. CONCLUSIONS The results of the current study indicate that patients with CRC overall have a positive attitude toward tumor screening for Lynch syndrome, endorse the benefits of screening, and experience low levels of distress. These findings provide insight into patient attitudes toward tumor screening for Lynch syndrome among unselected patients with CRC to inform educational approaches that assist in patient decision‐making and guide the successful implementation of screening programs. Cancer 2015;121:3281–3289. © 2015 American Cancer Society