Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Pharmacogenetic testing in the Veterans Health Administration (VHA): policy recommendations from the VHA Clinical Pharmacogenetics Subcommittee.

PURPOSE: The Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy. METHODS: After developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug-gene pairs with potential clinical application in VHA. Members met monthly to discuss each drug-gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation. RESULTS: Of 30 drug-gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens-Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing. CONCLUSION: Only half of drug-gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare.

Coordinating Care Across VA Providers and Settings: Policy and Research Recommendations from VA's State of the Art Conference.

Delivering well-coordinated care is essential for optimizing clinical outcomes, enhancing patient care experiences, minimizing costs, and increasing provider satisfaction. The Veterans Health Administration (VA) has built a strong foundation for internally coordinating care. However, VA faces mounting internal care coordination challenges due to growth in the number of Veterans using VA care, high complexity in Veterans' care needs, the breadth and depth of VA services, and increasing use of virtual care. VA's Health Services Research and Development service with the Office of Research and Development held a conference assessing the state-of-the-art (SOTA) on care coordination. One workgroup within the SOTA focused on coordination between VA providers for high-need Veterans, including (1) Veterans with multiple chronic conditions; (2) Veterans with high-intensity, focused, specialty care needs; (3) Veterans experiencing care transitions; (4) Veterans with severe mental illness; (5) and Veterans with homelessness and/or substance use disorders. We report on this workgroup's recommendations for policy and organizational initiatives and identify questions for further research. Recommendations from a separate workgroup on coordinating VA and non-VA care are contained in a companion paper. Leaders from research, clinical services, and VA policy will need to partner closely as they develop, implement, assess, and spread effective practices if VA is to fully realize its potential for delivering highly coordinated care to every Veteran.

Technical desiderata for the integration of genomic data with clinical decision support.

The ease with which whole genome sequence (WGS) information can be obtained is rapidly approaching the point where it can become useful for routine clinical care. However, significant barriers will inhibit widespread adoption unless clinicians are able to effectively integrate this information into patient care and decision-making. Electronic health records (EHR) and clinical decision support (CDS) systems may play a critical role in this integration. A previously published technical desiderata focused primarily on the integration of genomic data into the EHR. This manuscript extends the previous desiderata by specifically addressing needs related to the integration of genomic information with CDS. The objective of this study is to develop and validate a guiding set of technical desiderata for supporting the clinical use of WGS through CDS. A panel of domain experts in genomics and CDS developed a proposed set of seven additional requirements. These desiderata were reviewed by 63 experts in genomics and CDS through an online survey and refined based on the experts' comments. These additional desiderata provide important guiding principles for the technical development of CDS capabilities for the clinical use of WGS information.

Creation of a national resource with linked genealogy and phenotypic data: the Veterans Genealogy Project.

PURPOSE: Creation of a genealogy of the United States and its ancestral populations is under way. When complete, this US genealogy will be record linked to the National Veteran's Health Administration medical data representing more than 8 million US veterans. METHODS: Genealogical data are gathered from public sources, primarily the Internet. Record linking using data from relatives is accomplished to integrate multiple data sources and then to link genealogical data to the veteran's demographic data. RESULTS: This resource currently includes genealogy for more than 22 million individuals representing the Intermountain West and the East Coast. The demographic data for more than 40,000 veteran patients using Veterans Hospital Administration services in Utah and Massachusetts have already been record linked. CONCLUSION: The resource is only in its second year of creation and already represents the largest such combination of genealogy and medical data in the world. The data sources, the creation of the genealogy, record-linking methods and results, proposed genetic analyses, and future directions are discussed.

Dermatitis herpetiformis sera or goat anti-transglutaminase-3 transferred to human skin-grafted mice mimics dermatitis herpetiformis immunopathology.

Dermatitis herpetiformis (DH) is characterized by deposition of IgA in the papillary dermis. However, indirect immunofluorescence is routinely negative, raising the question of the mechanism of formation of these immune deposits. Sárdy et al. (2002. J. Exp. Med. 195: 747-757) reported that transglutaminase-3 (TG3) colocalizes with the IgA. We sought to create such deposits using passive transfer of Ab to SCID mice bearing human skin grafts. IgG fraction of goat anti-TG3 or control IgG were administered i.p. to 20 mice. Separately, sera from seven DH patients and seven controls were injected intradermally. Biopsies were removed and processed for routine histology as well as direct immunofluorescence. All mice that received goat anti-TG3 produced papillary dermal immune deposits, and these deposits reacted with both rabbit anti-TG3 and DH patient sera. Three DH sera high in IgA anti-TG3 also produced deposits of granular IgA and TG3. We hypothesize that the IgA class anti-TG3 Abs are directly responsible for the immune deposits and that the TG3 is from human epidermis, as this is its only source in our model. These deposits seem to form over weeks in a process similar to an Ouchterlony immunodiffusion precipitate. This process of deposition explains the negative indirect immunofluorescence results with DH serum.

Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting.

Lynch syndrome is the most common cause of inherited colorectal cancer, accounting for approximately 3% of all colorectal cancer cases in the United States. In 2009, an evidence-based review process conducted by the independent Evaluation of Genomic Applications in Practice and Prevention Working Group resulted in a recommendation to offer genetic testing for Lynch syndrome to all individuals with newly diagnosed colorectal cancer, with the intent of reducing morbidity and mortality in family members. To explore issues surrounding implementation of this recommendation, the Centers for Disease Control and Prevention convened a multidisciplinary working group meeting in September 2010. This article reviews background information regarding screening for Lynch syndrome and summarizes existing clinical paradigms, potential implementation strategies, and conclusions which emerged from the meeting. It was recognized that widespread implementation will present substantial challenges, and additional data from pilot studies will be needed. However, evidence of feasibility and population health benefits and the advantages of considering a public health approach were acknowledged. Lynch syndrome can potentially serve as a model to facilitate the development and implementation of population-level programs for evidence-based genomic medicine applications involving follow-up testing of at-risk relatives. Such endeavors will require multilevel and multidisciplinary approaches building on collaborative public health and clinical partnerships.

Veterans Affairs Pharmacogenomic Testing for Veterans (PHASER) clinical program.

In 2019, the Veterans Affairs (VA), the largest integrated US healthcare system, started the Pharmacogenomic Testing for Veterans (PHASER) clinical program that provides multi-gene pharmacogenomic (PGx) testing for up to 250,000 veterans at approximately 50 sites. PHASER is staggering program initiation at sites over a 5-year period from 2019 to 2023, as opposed to simultaneous initiation at all sites, to facilitate iterative program quality improvements through Plan-Do-Study-Act cycles. Current resources in the PGx field have not focused on multisite, remote implementation of panel-based PGx testing. In addition to bringing large scale PGx testing to veterans, the PHASER program is developing a roadmap to maximize uptake and optimize the use of PGx to improve drug response outcomes.

Legal terms of use and public genealogy websites.

Public genealogy websites, to which individuals upload family history, genealogy, and sometimes individual genetic data, have been used in an increasing number of public health, epidemiological, and genetic studies. Yet there is little awareness among researchers of the legal rules that govern the use of these online resources. We analyzed the online Terms of Use (TOU) applicable to 17 popular genealogy websites and found that none of them expressly permit scientific research, while at least 13 contain restrictions that may limit or prohibit scientific research using data obtained from those sites. In order to ensure that researchers who use genealogy and other data from these sites for public health and other scientific research purposes do not inadvertently breach applicable TOUs, we recommend that genealogy website operators consider revising their TOUs to permit this activity.

Population genealogy resource shows evidence of familial clustering for Alzheimer disease.

OBJECTIVE: To show the potential of a resource consisting of a genealogy of the US record linked to National Veterans Health Administration (VHA) patient data for investigation of the genetic contribution to health-related phenotypes, we present an analysis of familial clustering of VHA patients diagnosed with Alzheimer disease (AD). METHODS: Patients with AD were identified by the International Classification of Diseases code. The Genealogical Index of Familiality method was used to compare the average relatedness of VHA patients with AD with expected relatedness. Relative risks for AD were estimated in first- to fifth- degree relatives of patients with AD using population rates for AD. RESULTS: Evidence for significant excess relatedness and significantly elevated risks for AD in relatives was observed; multiple pedigrees with a significant excess of VHA patients with AD were identified. CONCLUSIONS: This analysis of AD shows the nascent power of the US Veterans Genealogy Resource, in early stages, to provide evidence for familial clustering of multiple phenotypes, and shows the utility of this VHA genealogic resource for future genetic studies.

BRCA testing within the Department of Veterans Affairs: concordance with clinical practice guidelines.

Guideline-concordant cancer care is a priority within the Department of Veterans Affairs (VA). In 2009, the VA expanded its capacity to treat breast cancer patients within VA medical centers (VAMCs). We sought to determine whether male and female Veterans diagnosed with breast cancer received BRCA testing as recommended by the National Comprehensive Cancer Network (NCCN) guidelines on Genetic/Familial High-Risk Assessment in Breast and Ovarian Cancer (v. 1.2010-1.2012). Using the 2011-2012 VA Central Cancer Registry and BRCA test orders from Myriad Genetics, we conducted a retrospective study. The outcome variable was a recommendation for genetic counseling or BRCA testing, determined by chart review. Independent variables expected to predict testing included region, site of care, and patient characteristics. We performed descriptive analysis of all patients and conducted multivariable logistic regression on patients who sought care at VAMCs that offered BRCA testing. Of the 462 Veterans who met NCCN testing criteria, 126 (27 %) received guideline-concordant care, either a referral for counseling or actual testing. No BRCA testing was recommended in 49 (50 %) VAMCs that provide cancer treatment. Surprisingly, patients with second primary breast cancer were less likely to be referred/tested (OR 0.39; CI 0.17, 0.89; p = 0.025). For patients under age 51, a yearly increase in age decreased likelihood of referral or testing (OR 0.85; CI 0.76, 0.94; p < 0.001). There were no differences in testing by race. In conclusion, there was significant underutilization and lack of access to BRCA testing for Veterans diagnosed with breast cancer. Our research suggests the need for clinical decision support tools to facilitate delivery of guideline-concordant cancer care and improve Veteran access to BRCA testing.

Genetic predisposition to melanoma.

Malignant melanoma is a rare, often fatal form of skin cancer with a complex multigenic etiology. The incidence of melanoma is increasing at an alarming rate. A number of heritable factors contribute to a patient's overall melanoma risk, including response to ultraviolet light, nevus number, and pigmentation characteristics, such as eye and hair color. Approximately 5%-10% of melanoma cases are familial, yet the majority of familial cases lack identifiable germ-line mutations in known susceptibility genes. Additionally, most familial melanomas lack germ-line mutations in genes that are commonly mutated in sporadic melanoma. Candidate and systematic genome-wide association studies have led to an improved understanding of the risk factors for melanoma and the identification of susceptibility genes. In this review, we provide an overview of the major risk factors and known genes implicated in familial melanoma susceptibility.

The Scourge of the Spurge Family-An Imitator of Rhus Dermatitis.

The Euphorbiaceae family (commonly known as "spurge") is a large, diverse, and widely distributed family of plants that encompass around 300 genera and more than 8000 species. Their attractiveness and hearty nature have made them popular for both indoor ornamentation and outdoor landscaping. Despite their ubiquity, the potential to cause irritant contact dermatitis (ICD) is often overlooked in favor of more notorious causes of phytodermatitis, namely, Toxicodendron species and nettles. We examined case reports spanning 40 years and discovered that spurge-induced ICD tends to befall children and middle-aged adults who unwittingly encounter the plant through play or horticulture, respectively. Clinical presentation is pleomorphic. Erythema, edema, burning, vesicles, and pruritus of acute onset and rapid resolution are frequently observed. We present a classic case of ICD in a 12-year-old girl after exposure to Euphorbia myrsinites and review the literature on phytodermatitis caused by members of the Euphorbiaceae family.

Longitudinal assessment of the nevus phenotype in a melanoma kindred.

Phenotypic characteristics of members of a melanoma prone kindred with a V126D CDKN2A gene mutation were monitored over approximately 15 y. Thirty-eight previously studied subjects were recruited. Participants underwent a complete skin examination by the same dermatologist who examined them initially. The size and location of all nevi were recorded on a body map diagram. Total nevus number (TNN) and total nevus density (TND) were determined. CDKN2A sequencing verified 13 mutation carriers and 16 non-carriers. Nine participants were spouse controls without a history of melanoma and did not carry a CDKN2A mutation. Mutation carriers demonstrated a greater mean TNN and TND at initial and follow-up examinations compared with non-carriers and continued to develop nevi rather than show nevus regression seen in non-carriers and spouse controls. Non-carriers showed an intermediate nevus phenotype between mutation carriers and spouse controls. Four of the 13 mutation carriers and one non-carrier have developed invasive melanoma. Over a 15-y interval, TNN and TND were increased in mutation carriers compared with non-carriers and spouse controls. Continued accumulation of nevi in mutation carriers supports a nevogenic role for this CDKN2A mutation. An intermediate nevus phenotype in non-carrier family members suggests the presence of additional modifier genes.

Influx and efflux of amphetamine and N-acetylamphetamine in keratinocytes, pigmented melanocytes, and nonpigmented melanocytes.

To establish an in vitro model of drug incorporation into hair and to elucidate the potential roles of hair cell selectivity and hair color in the incorporation of certain drugs into hair, the basic drug amphetamine and its nonbasic analog N-acetylamphetamine (N-AcAp) were analyzed for influx and efflux into and out of keratinocytes, pigmented melanocytes (PM), and nonpigmented melanocytes (NPM) as a model for incorporation and efflux of these drugs from hair cells. NPM were of the same melan-a cell line as PM, but cultured in the presence of the tyrosinase inhibitor phenylthiocarbamide. Results show that PM take up large amounts of the basic drug amphetamine (levels of uptake dependent on melanin content), whereas keratinocytes and NPM take up only small amounts of amphetamine. None of the cells take up N-AcAp above background levels. Interestingly, whereas keratinocytes and NPM quickly efflux most of the influxed drug, PM are slow to efflux and only efflux approximately 65% of influxed drug, if efflux media is not refreshed. (If efflux media is periodically refreshed, PM will eventually redistribute essentially all influxed drug back into the media.) These results demonstrate that pigmented cells take up greater amounts of the basic drug amphetamine, and efflux it more slowly than nonpigmented cells. Also, these results are consistent with previous data for in vivo incorporation of amphetamine in animal hair. In combination with previous data, an overall comparison of the amphetamine and N-AcAp incorporation data support a non-diffusion mediated model for drug incorporation into hair cells.