Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research.

Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.

Cancer screening with multicancer detection tests: A translational science review.

Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test.

BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2.

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

A Clinical Service to Support the Return of Secondary Genomic Findings in Human Research.

Human genome and exome sequencing are powerful research tools that can generate secondary findings beyond the scope of the research. Most secondary genomic findings are of low importance, but some (for a current estimate of 1%-3% of individuals) confer high risk of a serious disease that could be mitigated by timely medical intervention. The impact and scope of secondary findings in genome and exome sequencing will only increase in the future. There is considerable agreement that high-impact findings should be returned to participants, but many researchers performing genomic research studies do not have the background, skills, or resources to identify, verify, interpret, and return such variants. Here, we introduce a proposal for the formation of a secondary-genomic-findings service (SGFS) that would support researchers by enabling the return of clinically actionable sequencing results to research participants in a standardized manner. We describe a proposed structure for such a centralized service and evaluate the advantages and challenges of the approach. We suggest that such a service would be of greater benefit to all parties involved than present practice, which is highly variable. We encourage research centers to consider the adoption of a centralized SGFS.

ClinVar: public archive of relationships among sequence variation and human phenotype.

ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) provides a freely available archive of reports of relationships among medically important variants and phenotypes. ClinVar accessions submissions reporting human variation, interpretations of the relationship of that variation to human health and the evidence supporting each interpretation. The database is tightly coupled with dbSNP and dbVar, which maintain information about the location of variation on human assemblies. ClinVar is also based on the phenotypic descriptions maintained in MedGen (http://www.ncbi.nlm.nih.gov/medgen). Each ClinVar record represents the submitter, the variation and the phenotype, i.e. the unit that is assigned an accession of the format SCV000000000.0. The submitter can update the submission at any time, in which case a new version is assigned. To facilitate evaluation of the medical importance of each variant, ClinVar aggregates submissions with the same variation/phenotype combination, adds value from other NCBI databases, assigns a distinct accession of the format RCV000000000.0 and reports if there are conflicting clinical interpretations. Data in ClinVar are available in multiple formats, including html, download as XML, VCF or tab-delimited subsets. Data from ClinVar are provided as annotation tracks on genomic RefSeqs and are used in tools such as Variation Reporter (http://www.ncbi.nlm.nih.gov/variation/tools/reporter), which reports what is known about variation based on user-supplied locations.

Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.

Genome- and exome-sequencing costs are continuing to fall, and many individuals are undergoing these assessments as research participants and patients. The issue of secondary (so-called incidental) findings in exome analysis is controversial, and data are needed on methods of detection and their frequency. We piloted secondary variant detection by analyzing exomes for mutations in cancer-susceptibility syndromes in subjects ascertained for atherosclerosis phenotypes. We performed exome sequencing on 572 ClinSeq participants, and in 37 genes, we interpreted variants that cause high-penetrance cancer syndromes by using an algorithm that filtered results on the basis of mutation type, quality, and frequency and that filtered mutation-database entries on the basis of defined categories of causation. We identified 454 sequence variants that differed from the human reference. Exclusions were made on the basis of sequence quality (26 variants) and high frequency in the cohort (77 variants) or dbSNP (17 variants), leaving 334 variants of potential clinical importance. These were further filtered on the basis of curation of literature reports. Seven participants, four of whom were of Ashkenazi Jewish descent and three of whom did not meet family-history-based referral criteria, had deleterious BRCA1 or BRCA2 mutations. One participant had a deleterious SDHC mutation, which causes paragangliomas. Exome sequencing, coupled with multidisciplinary interpretation, detected clinically important mutations in cancer-susceptibility genes; four of such mutations were in individuals without a significant family history of disease. We conclude that secondary variants of high clinical importance will be detected at an appreciable frequency in exomes, and we suggest that priority be given to the development of more efficient modes of interpretation with trials in larger patient groups.

Evidence synthesis and guideline development in genomic medicine: current status and future prospects.

PURPOSE: With the accelerated implementation of genomic medicine, health-care providers will depend heavily on professional guidelines and recommendations. Because genomics affects many diseases across the life span, no single professional group covers the entirety of this rapidly developing field. METHODS: To pursue a discussion of the minimal elements needed to develop evidence-based guidelines in genomics, the Centers for Disease Control and Prevention and the National Cancer Institute jointly held a workshop to engage representatives from 35 organizations with interest in genomics (13 of which make recommendations). The workshop explored methods used in evidence synthesis and guideline development and initiated a dialogue to compare these methods and to assess whether they are consistent with the Institute of Medicine report "Clinical Practice Guidelines We Can Trust." RESULTS: The participating organizations that develop guidelines or recommendations all had policies to manage guideline development and group membership, and processes to address conflicts of interests. However, there was wide variation in the reliance on external reviews, regular updating of recommendations, and use of systematic reviews to assess the strength of scientific evidence. CONCLUSION: Ongoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine.

Impact of family history assessment on communication with family members and health care providers: A report from the Family Healthware™ Impact Trial (FHITr).

OBJECTIVE: This study examines the impact of Family Healthware™ on communication behaviors; specifically, communication with family members and health care providers about family health history. METHODS: A total of 3786 participants were enrolled in the Family Healthware™ Impact Trial (FHITr) in the United States from 2005-7. The trial employed a two-arm cluster-randomized design, with primary care practices serving as the unit of randomization. Using generalized estimating equations (GEE), analyses focused on communication behaviors at 6month follow-up, adjusting for age, site and practice clustering. RESULTS: A significant interaction was observed between study arm and baseline communication status for the family communication outcomes (p's<.01), indicating that intervention had effects of different magnitude between those already communicating at baseline and those who were not. Among participants who were not communicating at baseline, intervention participants had higher odds of communicating with family members about family history risk (OR=1.24, p=0.042) and actively collecting family history information at follow-up (OR=2.67, p=0.026). Family Healthware™ did not have a significant effect on family communication among those already communicating at baseline, or on provider communication, regardless of baseline communication status. Greater communication was observed among those at increased familial risk for a greater number of diseases. CONCLUSION: Family Healthware™ prompted more communication about family history with family members, among those who were not previously communicating. Efforts are needed to identify approaches to encourage greater sharing of family history information, particularly with health care providers.

The NIH genetic testing registry: a new, centralized database of genetic tests to enable access to comprehensive information and improve transparency.

The National Institutes of Health Genetic Testing Registry (GTR; available online at http://www.ncbi.nlm.nih.gov/gtr/) maintains comprehensive information about testing offered worldwide for disorders with a genetic basis. Information is voluntarily submitted by test providers. The database provides details of each test (e.g. its purpose, target populations, methods, what it measures, analytical validity, clinical validity, clinical utility, ordering information) and laboratory (e.g. location, contact information, certifications and licenses). Each test is assigned a stable identifier of the format GTR000000000, which is versioned when the submitter updates information. Data submitted by test providers are integrated with basic information maintained in National Center for Biotechnology Information's databases and presented on the web and through FTP (ftp.ncbi.nih.gov/pub/GTR/_README.html).

Primary care physicians and laypersons' perceptions of multicancer detection clinical trial designs.

BACKGROUND: The National Cancer Institute Cancer Screening Research Network is launching a pilot study (Vanguard) to determine feasibility of successful completion of a clinical trial of multicancer detection tests. This focus group study reports perceptions of primary care physicians and laypersons of different clinical trial designs and willingness to participate in a multicancer detection clinical trial. METHODS: We undertook 14 focus groups with 88 laypersons and 6 focus groups with 45 primary care physicians. Participants were shown graphics of clinical trial designs and asked for their reactions. Focus group recordings were transcribed verbatim, and thematic analysis of the transcripts were conducted to identify emergent themes. RESULTS: Primary care physician and layperson participants recognized the importance of conducting clinical trials to determine the clinical utility of multicancer detection tests. Primary care physicians expressed reluctance to participate in trials because of workload burden, and laypersons expressed hesitancy about enrolling in the control group. Primary care physicians and laypersons expressed concern about a study design in which multicancer detection test results would not be returned to the control group (intended effect), but they respectively indicated a willingness to refer patients to, or participate in, a multicancer detection test clinical trial given transparent and clear communication on collection and use of biospecimens and data, particularly if a multicancer detection test would eventually be run and results eventually returned. CONCLUSION: This study yielded important insights to guide trial design in planning prospective evaluation of multicancer detection testing. Maintaining transparency and trust while possibly withholding multicancer detection test results to maximize trial feasibility and efficiency is of particular concern.

Resource requirements to accelerate clinical applications of next-generation sequencing and radiomics: workshop commentary and review.

The National Institutes of Health-US Food and Drug Administration Joint Leadership Council Next-Generation Sequencing and Radiomics Working Group was formed by the National Institutes of Health-Food and Drug Administration Joint Leadership Council to promote the development and validation of innovative next-generation sequencing tests, radiomic tools, and associated data analysis and interpretation enhanced by artificial intelligence and machine learning technologies. A 2-day workshop was held on September 29-30, 2021, to convene members of the scientific community to discuss how to overcome the "ground truth" gap that has frequently been acknowledged as 1 of the limiting factors impeding high-quality research, development, validation, and regulatory science in these fields. This report provides a summary of the resource gaps identified by the working group and attendees, highlights existing resources and the ways they can potentially be employed to accelerate growth in these fields, and presents opportunities to support next-generation sequencing and radiomic tool development and validation using technologies such as artificial intelligence and machine learning.

Perceptions of Multicancer Detection Tests Among Primary Care Physicians and Laypersons: A Qualitative Study.

INTRODUCTION: Multicancer detection tests (MCDs) are blood-based tests designed to detect multiple cancer types. It is currently unclear whether these cancer screening tests improve mortality. To understand awareness of MCDs among providers and patients, as well as explore how they perceive the benefits, harms, and acceptability of MCDs, we have undertaken a focus group study in primary care physicians (PCPs) and laypersons to explore knowledge, attitudes, and expectations of cancer screening using MCDs. METHODS: We conducted six focus groups with 45 PCP participants and 12 focus groups with 80 layperson participants. Participants were identified via a consumer research firm and found eligible following the completion of a screener survey. Moderators used a semi-structured guide containing open-ended questions and prompts to facilitate the discussion. Recordings were transcribed and coded line by line using a codebook developed based on questions and emerging discussion concepts, and emergent themes were identified. RESULTS: Both PCP and layperson participants felt the that benefits of MCDs included ease of use and potential ability to detect cancers early. However, they felt that additional data is needed to overcome some of the concerns related to MCDs. PCP participants expressed concerns related to lack of practice guidelines, cost of diagnostic follow-ups, privacy and insurance issues, fear/anxiety related to confirmation of MCD results, and malpractice liability related to perceived false negative test results. Layperson participants expressed concerns related to costs, insurance coverage, and privacy, as well as anxiety over the confirmation of a positive test result. CONCLUSIONS: There is a major need for more rigorous data regarding MCDs to inform the development of guidelines for use as cancer screening tools.

Lexicon for blood-based early detection and screening: BLOODPAC consensus document.

In the United States, 2.0 million new cancer cases and around 600,000 cancer deaths are estimated to occur in 2024. Early detection gives cancer patients the best chance for treatment success. Currently, cancer screening in the general population is recommended for a limited set of cancers; as a result, most cancer types are not regularly screened. Thus, in recent years, we have seen a wave of novel, non-invasive, single- and multi-cancer detection tests (SCD and MCD), promising detection of cancer signals prior to the onset of symptoms and/or clinical diagnosis. To accelerate the development, access, and adoption of these tests, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative infrastructure for developing standards and best practices, established the Early Detection & Screening (ED&S) Working Group. The early detection space is in need of consensus around definitions for SCD and MCD tests that harmonize terminology across diverse stakeholders, thereby reducing communication barriers and ultimately advancing the discipline. To this end, the ED&S Working Group compiled a lexicon of terms, chosen based on perceived importance, frequency of use, lack of clarity, and unique challenges in the context of SCD and MCD tests. This lexicon was submitted to the FDA for their feedback, which was incorporated. In this work, we present the first installment of the lexicon, consisting of 14 primary terms, that will be part of an online dictionary and provide a foundation for future projects of BLOODPAC's ED&S Working Group.

Challenges to Using Big Data in Cancer.

Big data in healthcare can enable unprecedented understanding of diseases and their treatment, particularly in oncology. These data may include electronic health records, medical imaging, genomic sequencing, payor records, and data from pharmaceutical research, wearables, and medical devices. The ability to combine datasets and use data across many analyses is critical to the successful use of big data and is a concern for those who generate and use the data. Interoperability and data quality continue to be major challenges when working with different healthcare datasets. Mapping terminology across datasets, missing and incorrect data, and varying data structures make combining data an onerous and largely manual undertaking. Data privacy is another concern addressed by the Health Insurance Portability and Accountability Act, the Common Rule, and the General Data Protection Regulation. The use of big data is now included in the planning and activities of the FDA and the European Medicines Agency. The willingness of organizations to share data in a precompetitive fashion, agreements on data quality standards, and institution of universal and practical tenets on data privacy will be crucial to fully realizing the potential for big data in medicine.

Case Studies for Overcoming Challenges in Using Big Data in Cancer.

The analysis of big healthcare data has enormous potential as a tool for advancing oncology drug development and patient treatment, particularly in the context of precision medicine. However, there are challenges in organizing, sharing, integrating, and making these data readily accessible to the research community. This review presents five case studies illustrating various successful approaches to addressing such challenges. These efforts are CancerLinQ, the American Association for Cancer Research Project GENIE, Project Data Sphere, the National Cancer Institute Genomic Data Commons, and the Veterans Health Administration Clinical Data Initiative. Critical factors in the development of these systems include attention to the use of robust pipelines for data aggregation, common data models, data deidentification to enable multiple uses, integration of data collection into physician workflows, terminology standardization and attention to interoperability, extensive quality assurance and quality control activity, incorporation of multiple data types, and understanding how data resources can be best applied. By describing some of the emerging resources, we hope to inspire consideration of the secondary use of such data at the earliest possible step to ensure the proper sharing of data in order to generate insights that advance the understanding and the treatment of cancer.

Alcohol and tobacco lower the age of presentation in sporadic pancreatic cancer in a dose-dependent manner: a multicenter study.

OBJECTIVES: The objective of this study was to examine the association between tobacco and alcohol dose and type and the age of onset of pancreatic adenocarcinoma (PancCa). METHODS: Prospective data from the Pancreatic Cancer Collaborative Registry were used to examine the association between age of onset and variables of interest including: gender, race, birth country, educational status, family history of PancCa, diabetes status, and tobacco and alcohol use. Statistical analysis included logistic and linear regression, Cox proportional hazard regression, and time-to-event analysis. RESULTS: The median age to diagnosis for PancCa was 66.3 years (95% confidence intervals (CIs), 64.5-68.0). Males were more likely than females to be smokers (77% vs. 69%, P=0.0002) and heavy alcohol and beer consumers (19% vs. 6%, 34% vs. 19%, P<0.0001). In univariate analysis for effects on PancCa presentation age, the following were significant: gender, alcohol and tobacco use (amount, status and type), family history of PancCa, and body mass index. Both alcohol and tobacco had dose-dependent effects. In multivariate analysis, alcohol status and dose were independently associated with increased risk for earlier PancCa onset with greatest risk occurring in heavy drinkers (HR 1.62, 95% CI 1.04-2.54). Smoking status had the highest risk for earlier onset pancreatic cancer with a HR of 2.69 (95% CI, 1.97-3.68) for active smokers and independent effects for dose (P=0.019). The deleterious effects for alcohol and tobacco appear to resolve after 10 years of abstinence. CONCLUSIONS: Alcohol and tobacco use are associated with a dose-related increased risk for earlier age of onset of PancCa. Although beer drinkers develop pancreatic cancer at an earlier age than nondrinkers, alcohol type did not have a significant effect after controlling for alcohol dose.

Family physicians' awareness and knowledge of the Genetic Information Non-Discrimination Act (GINA).

Historically, physicians have expressed concern about their patients' risk of genetic discrimination, which has acted as a barrier to uptake of genetic services. The Genetic Information Nondiscrimination Act of 2008 (GINA) is intended to protect patients against employer and health insurance discrimination. Physicians' awareness and knowledge of GINA has yet to be evaluated. In 2009, we mailed surveys to 1500 randomly selected members of the American Academy of Family Physicians. Questions measured physicians' current knowledge of GINA and their level of concern for genetic discrimination. In total, 401 physicians completed the survey (response rate 26.9%). Approximately half (54.5%) of physicians had no awareness of GINA. Of physicians who reported basic knowledge of GINA, the majority were aware of the protections offered for group health insurance (92.7%), private health insurance (82.9%), and employment (70.7%). Fewer physicians were aware of GINA's limitations regarding life insurance (53.7%) and long-term care insurance (58.8%). Physicians demonstrated highest levels of concern for health insurance, life insurance, and long-term care insurance discrimination, with less concern for employer and family/social discrimination. Level of concern for the risk of genetic discrimination did not correlate significantly with awareness of GINA. Approximately 17 months after GINA was signed into federal law, physicians' knowledge remained limited regarding the existence of this legislation and relevant details. Physicians who are aware of GINA continue to have significant concerns regarding the risk of genetic discrimination. This study reveals the need to further educate physicians about the existence of GINA and the protections offered.

Quantitating and assessing interoperability between electronic health records.

OBJECTIVES: Electronic health records (EHRs) contain a large quantity of machine-readable data. However, institutions choose different EHR vendors, and the same product may be implemented differently at different sites. Our goal was to quantify the interoperability of real-world EHR implementations with respect to clinically relevant structured data. MATERIALS AND METHODS: We analyzed de-identified and aggregated data from 68 oncology sites that implemented 1 of 5 EHR vendor products. Using 6 medications and 6 laboratory tests for which well-accepted standards exist, we calculated inter- and intra-EHR vendor interoperability scores. RESULTS: The mean intra-EHR vendor interoperability score was 0.68 as compared to a mean of 0.22 for inter-system interoperability, when weighted by number of systems of each type, and 0.57 and 0.20 when not weighting by number of systems of each type. DISCUSSION: In contrast to data elements required for successful billing, clinically relevant data elements are rarely standardized, even though applicable standards exist. We chose a representative sample of laboratory tests and medications for oncology practices, but our set of data elements should be seen as an example, rather than a definitive list. CONCLUSIONS: We defined and demonstrated a quantitative measure of interoperability between site EHR systems and within/between implemented vendor systems. Two sites that share the same vendor are, on average, more interoperable. However, even for implementation of the same EHR product, interoperability is not guaranteed. Our results can inform institutional EHR selection, analysis, and optimization for interoperability.

Encoding laboratory testing data: case studies of the national implementation of HHS requirements and related standards in five laboratories.

OBJECTIVE: Assess the effectiveness of providing Logical Observation Identifiers Names and Codes (LOINC®)-to-In Vitro Diagnostic (LIVD) coding specification, required by the United States Department of Health and Human Services for SARS-CoV-2 reporting, in medical center laboratories and utilize findings to inform future United States Food and Drug Administration policy on the use of real-world evidence in regulatory decisions. MATERIALS AND METHODS: We compared gaps and similarities between diagnostic test manufacturers' recommended LOINC® codes and the LOINC® codes used in medical center laboratories for the same tests. RESULTS: Five medical centers and three test manufacturers extracted data from laboratory information systems (LIS) for prioritized tests of interest. The data submission ranged from 74 to 532 LOINC® codes per site. Three test manufacturers submitted 15 LIVD catalogs representing 26 distinct devices, 6956 tests, and 686 LOINC® codes. We identified mismatches in how medical centers use LOINC® to encode laboratory tests compared to how test manufacturers encode the same laboratory tests. Of 331 tests available in the LIVD files, 136 (41%) were represented by a mismatched LOINC® code by the medical centers (chi-square 45.0, 4 df, P < .0001). DISCUSSION: The five medical centers and three test manufacturers vary in how they organize, categorize, and store LIS catalog information. This variation impacts data quality and interoperability. CONCLUSION: The results of the study indicate that providing the LIVD mappings was not sufficient to support laboratory data interoperability. National implementation of LIVD and further efforts to promote laboratory interoperability will require a more comprehensive effort and continuing evaluation and quality control.