First Responder to Genomic Information: A Guide for Primary Care Providers

Abstract

With rapid advances in genetics and genomics, the commercialization and access to new applications has become more widespread and omnipresent throughout biomedical research. Thus, increasingly more patients will have personal genomic information they may share with primary care providers (PCPs) to better understand the clinical significance of the data. To be able to respond to patient inquiries about genomic data, variant interpretation, disease risk and other issues, PCPs will need to be able to increase or refresh their awareness about genetics and genomics, and identify reliable resources to use or refer patients. While provider educational efforts have increased, with the rapid advances in the field, ongoing efforts will be needed to prepare PCPs to manage patient needs, integrate results into care, and refer as indicated.

1. Introduction

The scope and accessibility to genetic information is changing rapidly in response to advances in genome sciences and medicine. While not all clinical genomic applications have yet to demonstrate the desired evidence basis of clinical utility and cost-effectiveness [1], many of these tests are increasingly being used in various clinical settings. Furthermore, patients may obtain their genetic information through direct-to-consumer (DTC) testing companies or through participation in a research study. It has been recognized that the successful implementation of genetics and genomics in healthcare will require the participation of non-geneticist specialists [2]. Indeed, primary care providers (PCP) will play a central role in helping patients understand genomic information as PCPs will likely be the first point of contact for patients wanting to understand more about the clinical significance of genomic information [3–6]. Thus, even though they may not have ordered the test, PCPs will need to be prepared to respond to patient inquiries, review test results, direct them to accurate and reliable resources, or refer to specialists as warranted. For more than a few decades, papers have repeatedly reported the lack of provider knowledge of genetics and related clinical applications, even within their area of practice [7–9, 4]. Strategies to raise PCPs’ awareness will depend on continuing education, development of resources for providers and patients, and potentially more resources regarding clinical interpretation and evidence basis of genomic test results [10]. Incorporating PCPs’ views and extending from their knowledge base will be essential to successfully increasing awareness and competencies around genetics and genomics [11–13]. This paper will consider current and potential approaches to guiding PCPs to navigate this likely novel and unfamiliar terrain.

2. Rise of Genetics & Genomics

Since the completion of the first sequenced genomes in 2001 [14, 15], there has been a massive movement to understand the genetic etiology or role of genes in health and disease. The availability of a reference genome sequence and development of new technologies and analytical techniques has enabled more rapid and cheaper detection of genetic variants associated with various phenotypes. Known as genome-wide association studies (GWAS), genetic variants have been associated with hundreds of phenotypes [16, 17]. In addition, other types of technologies have enabled targeted analysis of genetic variants (e.g., microarrays), as well as assessment of gene expression, proteins, or metabolites, or the microbial composition of various tissues (known as the microbiome). Each layer of data can provide a more comprehensive understanding of the impact of DNA variation and environmental factors to inform development of screening and diagnostic tests and interventions [18, 19].

In the midst of this massive data generation period, the ability to identify genetic variants and associate them with various phenotypes has outpaced the understanding of the clinical significance and utility of the information. Furthermore, testing capabilities have also outpaced scientific understanding of the broader psychosocial implications of the information. As a result, while many clinical genetic and genomic tests are commercially available today, there is uncertainty for both patients and providers about how to evaluate some of the data and what actions, if any, should be taken based upon the data and how to minimize harms.

In the early 2000’s, the rise of DTC testing enabled consumers to purchase genetic tests through a website without health provider authorization as is typically required of clinical tests [20]. These online companies were the subject of much debate and scrutiny from scientists, clinicians, and federal agencies alike regarding the quality of their products and potentially misleading claims, and possible harms to consumers [21]. In 2010, the US Food and Drug Administration (FDA) halted the sale of DTC tests, requiring companies to first obtain clearance or approval from the agency [22]. Despite concerns, most consumers perceive value from testing and have not experienced any or minimal harms [23, 24]. In 2017, the company 23andMe gained FDA approval and re-initiated sale of a limited set of tests. In 2018, 23andMe gained additional approvals for the sale of limited breast and ovarian risk testing and pharmacogenetic testing. Some consumers who order DTC testing may opt to share the results with health providers to gain a better understanding of the implications for future disease risks and opportunities for screening or intervention [25]. While some encounters with health providers about DTC results have been reported as satisfying [25], providers have expressed concern about their knowledge to interpret genomic results, the actionability of results and potential harms to patients [26, 27]. Some companies will also make available the raw data in addition to a test report, or alternatively, sequence the DNA and provide only the raw data, leaving the consumer to identify another company to analyse and interpret the raw data [28, 29]. Again, in this instance, consumers may share the data or report with a general health provider [30, 31] or genetic specialist if accessible [32].

Furthermore, sequencing technologies are increasingly used in biomedical research studies. With the need to enroll many participants to have sufficient power to ascertain a significantly associated variant with a given genotype, many individuals are being enrolled and sequenced. In some studies, researchers may provide either raw, summary (aggregate), or individual results [33].

3. Evaluating Genetic & Genomic Tests

When evaluating a test, determining whether a test is a ‘good’ test may be difficult, depending on what parameters of the test are assessed and whether information is available through the testing laboratory or publications to even enable assessment. Several different groups have developed matrices to evaluate genetic tests [34]. With increasing scrutiny about the quality of genetic tests, in the early 2000’s, the US Centers for Disease Control and Prevention (CDC) supported the development of a framework to evaluate genetic tests based on analytical validity, clinical validity, clinical utility and ethical, legal and social issues framework, otherwise known as ACCE [35]. These test features and definitions are described in detail by Teutsch et al [36]. This framework has been used for a variety of genetic tests and by various groups [37].

While many laboratories may offer similar or identical tests, providers should not consider the performance of these tests to be equivalent. It is important to understand the limitations of different testing platforms when comparing tests offered by different laboratories for similar indications. For example, labs may choose to use next-generation sequencing (targeted, whole exome, whole genome), microarrays (limited to analysis of known genetic variations), or another methodology (or more than one). Several reports have compared the outcomes of one or more genetic tests with similar indications, often comparing tests with different platforms [38, 39] or use of different types of specimens [40]. If a limited set of variants are analysed in a test, providers should also consider the prevalence of those variants in different populations to insure the test is appropriate for individuals of different racial/ethnic backgrounds given differences in allele prevalence between populations. The prevalence of the genetic variant impacts the predictive value of the test. As clinical studies tend to predominantly enroll individuals of European descent [41], the value of the test may be limited for individuals of other backgrounds.

Furthermore, given the rapid changes in knowledge about the clinical significance of genetic variants, laboratories may interpret the same finding differently. Genetic variants are classified into one of five categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign [42]. The category of ‘uncertain significance’ is often referred to as a ‘variant of uncertain significance’ or VUS or VOUS. Several papers have demonstrated discordance in the variant interpretation between labs [43–48]. The recommended evidence basis for determining variant pathogenicity still allows for some subjective conclusions and information about rare variants remains limited [49, 50]. Some laboratories may draw upon in-house data collected from years of testing that is not available to other labs, drawing calls for greater sharing and curation of genetic variant data [51]. Test reports are only likely to include pathogenic and likely pathogenic variants, and other variants detected may not be mentioned. As described in the subsequent section (Resources), there are several public genetic databases that provide information/evidence about the clinical significance of a given variant. Re-analysis of variant interpretation is offered by some laboratories due to the rapidly changing evidence basis, which may result in a re-classification of pathogenicity.

In addition to considering the test characteristics, the ethical, legal and social implications should be considered and discussed with the patient. Many issues have given pause regarding the appropriate use of testing (e.g., children vs. adults), the balance of benefits and harms, inaccurate results, psychological implications, familial implications, genetic discrimination and clinical actionability [52–57]. Given the range of issues, PCPs are unlikely to have the time and knowledge to help patients make an informed decision about testing and to comprehend the results and implications if testing is sought. Referral to a genetic specialist such as a genetic counselor can raise awareness of the myriad issues [58], but access to genetic counselors may be limited [59].

For patients that opt to obtain testing through a DTC company or other means and share the results with their PCP, PCPs should consider the above mentioned issues when reviewing the test report. If the test has already been ordered and there is uncertainty about the validity of the results, one initial fact that should be confirmed is whether the laboratory is accredited. All clinical laboratories are required to comply with the Clinical Laboratory Improvements Act (CLIA) and gain accreditation through the state or an approved accrediting organization. If they are CLIA-certified, an annual record of suspensions or other sanctions noted on biannual inspections is publicly available. In instances that patients share results obtained through research studies, the clinical validity of the testing may be lacking, and therefore, it may be appropriate for the PCP to recommend or refer for clinical confirmation in a CLIA-certified laboratory.

4. Education

In the past few decades, many different approaches to educate non-geneticist providers have been developed and evaluated [60–63]. While medical school curricula include basic science lectures on cell and molecular biology, genetics, and some applications such as prenatal screening, diagnosis of inherited disorders, cancer susceptibility and precision medicine, the material is not likely consistent and the depth may vary [64, 65]. Various approaches to incorporating genetics and genomics into curricula and residency programs [66–69] have been developed including genomic autopsies or genomic analysis to determine a cause of death [70, 71], continuing education [72], and personal sequencing [73]. To inform development of curricula and training, several groups have develop genetics and genomics competencies [74–76].

But providers will need to update their knowledge continuously given the rapid developments in the field [60]. Similar to formal training, various approaches have been developed for continuing education including web-based interactive modules [77, 78, 72, 79, 80], and personal sequencing [81, 82, 73, 83]. While some interactive educational intervention efforts have been shown to increase PCP knowledge, translation into behaviour changes may be more difficult to achieve [77, 84, 85]. In addition, several massive open online courses (MOOCs) are available on personalized or precision medicine, genetics and genomics, which can provide a good refresher on new tests. To guide content of educational programs, several core competencies in genetics for non-geneticist providers and milestone templates have been developed [86–88]. At the point of care, efforts have focused on developing clinical decision support (CDS) to raise provider awareness about availability of testing, clinical guidelines, or recommended action items based on a patient’s test result [89, 90]. Accessibility of such supports may be limited in community practice settings depending on their electronic medical record vendor.

While there are several resources to gain a better understanding of a disease and evidence basis for a particular genetic variant, education about the ethical, legal, and social issues (ELSI) is also critical [91]. More comprehensive resources for ELSI and skills-based learning opportunities such as patient communication about genetics are needed. For example, use of the term ‘variation’ and descriptors of ‘pathogenic’ or ‘benign’ is recommended in place of ‘mutation’, but general practitioners may not be aware about the change [42]. The absence of a detection of a pathogenic variant on a test report does not necessarily absolve a patient’s risk for a given disease, and providers should be able to explain some of the principles of genetics, multi-factorial diseases, and risk.

5. Resources

While there are some resources available about genetics, genomics, and variant interpretation and guidelines, sometimes they are not easy to find or identify [92]. For example, there are numerous genetic variation databases available to help decipher the clinical significance of a genetic variant or obtain information about a genetic condition [93, 94], but there is no single primary or comprehensive resource (Table 1). ClinVar is a public database of genetic variations and evidence of clinical pathogenicity operated by the US National Institutes of Health (NIH) [95, 96]. New variants and evidence of clinical pathogenicity are submitted by registered laboratories and researchers. Users can look up a specific phenotype, gene, or variant. A related NIH database, Clinical Genome Resource (ClinGen), provides comprehensive gene-disease information along with multiple curation interfaces, for example, on clinical pathogenicity and actionability [97]. Several disease-specific working groups review data and evidence in their respective areas for both ClinGen and ClinVar [98–101]. Some limitations should be noted about genetic and genomic databases -- not all of them may be very user-friendly for the general practitioner in search of gathering more information about a particular genetic variant. Some of these databases are broad (non-disease specific) or limited to a group of diseases (cancer) or genome (e.g., mitochondrial) [102, 103]; the source of the data deposited may vary as well as the quality of data [104]. Analysis of genetic variants in databases for the same disease have shown some disparities [105], and thus, it may be necessary to review multiple databases to gain a comprehensive assessment of the mutational spectrum.

Table 1.

Provider and patient resources for genetic diseases and genetic variant interpretation.

Resource (URL)	Description
ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/)	Maintained by the NIH/National Center for Biotechnology Information, this site has information about genomic variation and disease; can search by disease name, gene name or specific genetic variants; many clinical domain expert working groups responsible for data curation
ClinGen (https://www.clinicalgenome.org/)	A National Institutes of Health (NIH)-funded resource about the clinical relevance of genes and variants
Genetic Home Reference (https://ghr.nlm.nih.gov/)	A very patient-friendly National Institutes of Health/National Library of Medicine website with lots of general descriptions of genetic terms and principles as well as disease-specific descriptions; many links to other NIH websites provided.
NIH Genetic Testing Registry (https://www.ncbi.nlm.nih.gov/gtr/)	Another National Institutes of Health/National Library of Medicine searchable database of genetic testing laboratories; listings are based on submissions (no verification)
Online Mendelian Inheritance in Man (https://www.omim.org/)	An online, curated catalog of inherited diseases; a rich resource that is well-linked to other resources
Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/)	A comprehensive e-book of >700 chapters of clinically relevant and medically actionable information for inherited conditions authored by experts; chapters are regularly updated every 2-4 years
DiseaseInfoSearch (https://www.diseaseinfosearch.org/)	Provides quality information for 10,000 diseases, including support groups, resources, clinical trials, articles, and more; initially was a feature of the Genetic Alliance website (2005) to enable broader sharing of disease support group information; in 2013, it became a standalone websites with more extensive information
Gene-Equip (Genetics Education for Primary Care) (www.primarycaregenetics.org)	Co-funded by the EU and Erasmus+ the content of this site is Developed/contributed by a team of clinical geneticists, genetic counselors, and educators from six EU countries. The multi-lingual site provides continuing medical or professional education in genetics in online learning modules and webinars, practical tools, and patient stories.
Genetics Education Canada-Knowledge Organization (https://geneticseducation.ca/)	A not-for-profit organization supported with funding from two Canadian hospitals, this site includes several provider, patient resources and specific materials for hereditary breast/ovarian cancer, epilepsy, and prenatal and carrier testing.
Genetics/Genomic Competency Center (g-2-c-2.org)	Funded and maintained by the US National Human Genome Research Institute, this site provides educational resources for group instruction or self-directed learning in genetics/genomics by health care educators and practitioners. It also includes curriculum competencies for various types of health providers.
The Jackson Laboratory - Clinical and Continuing Education (https://www.jax.org/education-and-learning/clinical-and-continuing-education)	This site includes a range of online courses in personalized medicine and clinical genomics as well as resources for various conditions and factsheets.

While PCPs can always search the biomedical literature through PubMed or Google Scholar, there are some databases with curated publications focused specifically on genetics and genomics, saving learners valuable time in identifying relevant publications. For example, the Public Health Genomics Knowledge Base [106], maintained by the CDC, is an extensive database of publications that are easily searchable [107]. More recently, publications related to disorders of the heart, lung, blood, and sleep (HLBS) and population genomics can be found in the HLBS-PopOmics database [108, 109]. Several reviews have been published on various types of technologies like next-generation sequencing [38, 110], interpretation of genetic variants [111], or current clinical applications in specific disciplines [112].

The laboratory report can also be a good resource. Depending on the laboratory and the type of test, some of these reports are quite lengthy, including more descriptive information about variants and clinical recommendations than typical of a standard clinical report and references [113, 114]. Given some of the complexity of the test results and clinical pathogenicity, some groups are re-evaluated the test format of molecular reports [115]. Standardized formatting of test reports can facilitate integration into EHRs and enable inclusion of additional informational resources (e.g., Infobuttons) [116]

6. Conclusion

Precision medicine will be integrated into many clinical practice settings, including primary care. In addition to ordering tests for their own patients, PCPs are likely to be consulted about results obtained from tests ordered by other providers or patients themselves, or even raw data obtained from an online testing laboratory or research study. Thus, PCPs will need to become adequately knowledgeable to either respond to patient inquires, consult resources to gain further understanding about a particular phenotype or genotype, and/or if needed, recognize when and to whom to refer patients for follow-up care. Several educational efforts and resources have been developed to raise provider awareness and knowledge about genetic and genomics and specific applications. However, with the complexity of variant interpretation, more widespread genomic testing, the rapidly changing evidence basis, and commercialization of new tests, provider learning will be ongoing for the foreseeable future in this field.

Key Points.

• Primary care providers will increasingly face clinical situations warranting consideration of genetic testing or integration of test results into care.

• One of the major barriers to the appropriate integration of genetics and genomics into general practice is the limited training of on-geneticist providers and the rapidly changing genetics and genomics applications that require ongoing training.

• Many genetics and genomics competencies have been developed to inform course curricula and training programs, as well as development of novel learning opportunities such as personal sequencing or inclusion of genetics/genomics in non-traditional disciplines such as anatomy.