Higgins G.A.,University of Michigan |
Higgins G.A.,Assurex Health |
Allyn-Feuer A.,University of Michigan |
Athey B.D.,University of Michigan
Pharmacogenomics | Year: 2015
Aim: To provide insight into potential regulatory mechanisms of gene expression underlying addiction, analgesia, psychotropic drug response and adverse drug events, genome-wide association studies searching for variants associated with these phenotypes has been undertaken with limited success. We undertook analysis of these results with the aim of applying epigenetic knowledge to aid variant discovery and interpretation. Methods: We applied conditional imputation to results from 26 genome-wide association studies and three candidate gene-association studies. The analysis workflow included data from chromatin conformation capture, chromatin state annotation, DNase I hypersensitivity, hypomethylation, anatomical localization and biochronicity. We also made use of chromatin state data from the epigenome roadmap, transcription factor-binding data, spatial maps from published Hi-C datasets and 'guilt by association' methods. Results: We identified 31 pharmacoepigenomic SNPs from a total of 2024 variants in linkage disequilibrium with lead SNPs, of which only 6% were coding variants. Interrogation of chromatin state using our workflow and the epigenome roadmap showed agreement on 34 of 35 tissue assignments to regulatory elements including enhancers and promoters. Loop boundary domains were inferred by association with CTCF (CCCTC-binding factor) and cohesin, suggesting proximity to topologically associating domain boundaries and enhancer clusters. Spatial interactions between enhancer-promoter pairs detected both known and previously unknown mechanisms. Addiction and analgesia SNPs were common in relevant populations and exhibited large effect sizes, whereas a SNP located in the promoter of the SLC1A2 gene exhibited a moderate effect size for lithium response in bipolar disorder in patients of European ancestry. SNPs associated with drug-induced organ injury were rare but exhibited the largest effect sizes, consistent with the published literature. Conclusion: This work demonstrates that an in silico bioinformatics-based approach using integrative analysis of a diversity of molecular and morphological data types can discover pharmacoepigenomic variants that are suitable candidates for further validation in cell lines, animal models and human clinical trials. © 2015 Future Medicine Ltd.
Mrazek D.A.,Mayo Medical School |
Hornberger J.C.,Cedar Assoc. LLC |
Hornberger J.C.,Stanford University |
Altar C.A.,Assurex Health |
Degtiar I.,Cedar Assoc. LLC
Psychiatric Services | Year: 2014
Objective: This literature review assessed the burden of treatment-resistant depression in the United States by compiling published data about the clinical, societal, and economic outcomes associated with failure to respond to one ormore adequate trials of drug therapy. Methods: PubMed and the Tufts Cost-Effectiveness Analyses Registry were searched for English-language articles published between January 1996 and August 2013 that collected primary data about treatment-resistant depression. Two researchers independently assessed study quality and extracted data. Results: Sixty-two articles were included (N=59,462 patients). Patients with treatment-resistant depression had 3.8±2.1 prior depressive episodes and illness duration of 4.4±3.3 years and had completed 4.7±2.7 unsuccessful drug trials involving 2.1±.3 drug classes. Response rates for treatment-resistant depression were 36%±1%. A total of 17%±6% of patients had prior suicide attempts (1.1±.2 attempts per patient). Quality-of-life scores (scale of 0-1, with 0 indicating death and 1 indicating perfect health) for patients with treatment-resistant depression were .41±.8 and .26±.8 points lower, respectively, than for patients who experienced remission or response. Annual costs for health care and lost productivity were $5,481 and $4,048 higher, respectively, for patients with treatment-resistant versus treatment-responsive depression. Conclusions: Treatment-resistant depression exacts a substantial toll on patients' quality of life. At current rates of 12%-20% among all depressed patients, treatment-resistant depression may present an annual added societal cost of $29-$48 billion, pushing up the total societal costs of major depression by as much as $106-$118 billion. These findings underscore the need for research on the mechanisms of depression, new therapeutic targets, existing and new treatment combinations, and tests to improve the efficacy of and adherence to treatments for treatment-resistant depression.
News Article | August 17, 2015
CINCINNATI--(BUSINESS WIRE)--Meridian Bioscience, Inc. announces that on August 11, 2015, the Board of Directors of Meridian Bioscience, Inc. elected two new independent directors, Catherine A. Sazdanoff and John C. McIlwraith, effective August 14, 2015. Ms. Sazdanoff is the CEO and President of Sazdanoff Consulting LLC, specializing in business development, management and strategy consulting. In addition, she is Strategic Advisor to mProve Health LLC, a mobile health technology company located in Arlington, Virginia. From 2006 to 2015, Ms. Sazdanoff held a number of executive positions with Takeda Pharmaceutical International, Inc. including Vice President, Head of Corporate Projects, VP, Global Business Development and VP, Corporate Development. Prior to her time at Takeda, Ms. Sazdanoff spent 22 years with Abbott Laboratories, where she held numerous executive positions. Ms. Sazdanoff received a B.A. from the University of Notre Dame and a J.D. from Northwestern University School of Law. Mr. McIlwraith co-founded Allos Ventures, a venture capital firm, in March 2010 and has served as a Managing Director there since that time. Prior to founding Allos Ventures, Mr. McIlwraith was a Managing Director of Blue Chip Venture Company, a Cincinnati-based venture capital and private equity firm, which he joined in 1997. He has served on the board of directors of more than 20 healthcare or information technology companies, and is currently the lead director of Assurex Health, Inc., an informatics-based precision medicine company providing treatment decision support to health care providers for behavioral health conditions. Prior to 1997, Mr. McIlwraith served as Senior Vice President of Strategic Planning and General Counsel of publicly-traded Quantum Health Resources, Inc., and was a partner in the Jones Day law firm. Mr. McIlwraith received a B.A. from Hillsdale College and a J.D. from Case Western Reserve University. John A. Kraeutler, Chairman and Chief Executive Officer, commented, “With the election of Catherine and John to the Board of Directors of Meridian Bioscience we have added key strategic and operating strengths to help guide our future growth. Our Nominating Committee has been working diligently for more than a year to add specific skills to the Board. During that period, we have met and interviewed many talented individuals and we are very pleased that Catherine and John have agreed to join our team. I look forward to working closely with both Catherine and John, along with our existing directors, as we build a strong future for Meridian Bioscience.” Meridian is a fully integrated life science company that develops, manufactures, markets and distributes a broad range of innovative diagnostic test kits, purified reagents and related products and offers biopharmaceutical enabling technologies. Utilizing a variety of methods, these products and diagnostic tests provide accuracy, simplicity and speed in the early diagnosis and treatment of common medical conditions, such as gastrointestinal, viral and respiratory infections. Meridian’s diagnostic products are used outside of the human body and require little or no special equipment. The Company's products are designed to enhance patient well-being while reducing the total outcome costs of health care. Meridian has strong market positions in the areas of gastrointestinal and upper respiratory infections, serology, parasitology and fungal disease diagnosis. In addition, Meridian is a supplier of rare reagents, specialty biologicals and related technologies used by biopharmaceutical companies engaged in research for new drugs and vaccines. The Company markets its products and technologies to hospitals, reference laboratories, research centers, diagnostics manufacturers and biotech companies in more than 60 countries around the world. The Company’s shares are traded on the NASDAQ Global Select Market, symbol VIVO. Meridian's website address is www.meridianbioscience.com.
News Article | April 2, 2015
Assurex Health, a precision medicine company providing industry-leading treatment decision support to healthcare providers for behavioral health and chronic pain conditions, today announced that its new, 60,000 square-foot headquarters and laboratory will anchor a mixed-use development in Mason’s Oak Park District. Adding to the district’s growing bioscience and high tech investment, the new facility is anticipated to be built on 30 acres on Innovation Way just off the Western Row exit of I-71. Part of New “Business Gateway” to Mason Assurex Health has retained the Tenant Advisory Group at DTZ to manage the design and development of the facility, which will incorporate a plan for an additional 30,000 square-foot expansion space. DTZ also will lead the development of a master plan for the entire 30 acre site with Assurex Health and the City of Mason, according to Donald R. Wright, Chief Operating Officer at Assurex Health, to ensure it can effectively accommodate a larger bioscience mixed-use campus. The site will be near a new, planned 1-71 interchange which will create a new business “gateway” to the city. DTZ is a global leader in commercial real estate services providing occupiers, tenants and investors around the world with a full spectrum of property solutions. “Assurex Health is the perfect partner to anchor what will be a key asset within our bioscience cluster and pivotal development for the Oak Park District,” said City of Mason Mayor David F. Nichols. “We look forward to working closely with Assurex Health leadership and DTZ to make this a marque site that will showcase what a strong public private partnership can achieve. “ The Assurex Health headquarters will be designed to encourage employee wellness and to nurture a collaborative, entrepreneurial culture as the company grows. In the past three years, Assurex Health has more than tripled its employment to nearly 300 and quadrupled the number of patients that have received its GeneSight® tests to more than 140,000. “We are appreciative of the support we continue to receive from Mason and the State of Ohio,” said President and CEO Virginia C. Drosos. “Mason has a strong commitment to health care and community wellness. This is a great environment for our company and employees.” DTZ’s first task is to identify architects for the project. Assurex Health expects to choose a firm by June 1 and have initial drawings by July 1. “This site offers great access to our regional science partners and to top talent,” said Wright. “We also want to ensure it is integrated into the community. Our discussions about the vision of the site and how it can bring to life the culture of wellness and creativity and innovation in our company and in Mason are exciting.” It is anticipated that the project will be completed in 2016. Assurex Health is a commercial-stage, informatics-based precision medicine company providing treatment decision support to clinicians for behavioral health conditions. Assurex Health’s proprietary GeneSight technology is based on combinatorial pharmacogenomics (CPGx™) – the application of multiple genetic factors that influence an individual’s response to medications – as well as evidence-based medicine and clinical pharmacology. Assurex Health has licensed patented technology from Mayo Clinic and Cincinnati Children’s Hospital Medical Center, both of whom continue to be research collaborators. Learn more at http://www.assurexhealth.com
News Article | March 3, 2015
The combinatorial, multi-gene GeneSight test has been found to better predict antidepressant treatment outcomes for patients with depression, and their use of health care resources, than any of the individual genes that comprise the test, according to a peer-reviewed analysis by investigators from the Mayo Clinic and Assurex Health, and published online by The Pharmacogenomics Journal i. The proprietary technology of the GeneSight Psychotropic test is based on combinatorial pharmacogenomics (CPGx™), the study of how variations in multiple genes collaborate to influence an individual’s response to medications, and evidence-based medicine and the known clinical pharmacology of various drugs. “This new publication shows that the combinatorial GeneSight test predicts which patients are likely to experience poorer antidepressant outcomes and use more health care services, whereas single gene diagnostics mostly did not,” said lead author and Assurex Health Senior Vice President, C. Anthony Altar, Ph.D. “The robust evidence from these analyses reinforce the advantage of the combinatorial GeneSight test in helping clinicians guide antidepressant and anti-anxiety treatment decisions. This and other features of GeneSight distinguish our pharmacogenomic products from all others.” The GeneSight Psychotropic test helps inform clinicians’ treatment selection for commonly prescribed medications including those for depression, post-traumatic stress disorder (PTSD), anxiety, bipolar disorder and schizophrenia. The test is covered by Medicare, the U.S. Department of Veterans Affairs, and a growing number of commercial payers. The CPGx approach that generates the GeneSight report examines DNA variations of multiple genes since these variations can change the efficacy, metabolism, and adverse effects of many psychiatric drugs. Using a patient’s unique genetics, the GeneSight Psychotropic test creates a personalized report that places 38 U.S. Food and Drug Administration (FDA)-approved medications for depression and other mental health conditions into three color-coded categories for clinicians to review: “Use as Directed” in green, “Use with Caution” in yellow, or “Use with Increased Caution and with More Frequent Monitoring” in red. The GeneSight report also alerts healthcare providers to the implications of the patient’s genetic information to a drug’s dosage, and FDA-approved package insert information. Most single gene tests have high variability and are less accurate in predicting patient responses to psychotropic medications. The GeneSight approach compensates for these limitations by aggregating predictions by the drug metabolism and response genes to better predict patient’s responses. “Nearly 90 percent of antidepressant and antipsychotic medications are metabolized by at least two of the liver cytochrome P450 (CYP) enzymes, and many interact with the brain serotonin transporter (SLC6A4) or the serotonin 2A receptor (HTR2A),” explained the authors. “The GeneSight Psychotropic test accounts for this complexity by measuring and combining the DNA sequence variations within drug response and drug metabolism genes. This analysis looked at the GeneSight test that included the liver metabolism genes CYP2D6, CYP2C19, CYP2C9, and CYP1A2, and the two drug response genes, SLC6A4 and HTR2A.” Since these studies were conducted, Assurex Health has enhanced the GeneSight test to include two more genes, CYP3A4 and CYP2B6, making it the first and only psychiatric pharmacogenomic test to offer CYP3A4 analysis distinct and separate from CYP3A5. The CYP2B6 gene affects medications including bupropion (Wellbutrin®), the third most commonly prescribed antidepressant. In The Pharmacogenomics Journal article, the authors examined pooled data from three clinical trials, including two open-label studies and one randomized, double-blind controlled trial. Depression outcomes were recorded over 8 to 10 weeks for 119 fully blinded, treatment-resistant patients who were tested but neither they nor their clinicians received the GeneSight report. They were treated with standard of care and antidepressants were prescribed without pharmacogenomic guidance. After the studies were completed, the investigators used the GeneSight test results for each patient to determine the GeneSight color classification of their medications. The antidepressant outcomes of the 119 patients were predicted by the GeneSight classification (p=0.008), based on improvements of depressive symptoms measured by the Hamilton Depression scale (HAM-D17). Patients who entered the studies on one or more GeneSight red category medications showed significantly less improvement in depressive symptoms than those prescribed medications classified as yellow or green. The investigators then created five subgroups comprised of those patients who were prescribed one or more drugs that are metabolized by either of the CYP enzymes or either of the serotonin effector proteins. The GeneSight test again predicted the improvement in depressive symptoms for patients prescribed medications metabolized via the CYP2D6 (117 patients, p=0.003), CYP2C19 (80, p=0.04) or CYP1A2 (35, p=0.03) enzymes. In the exact same patient groups, clinical improvements were not predicted by either of the single gene tests based on their traditional classification of patients as poor, intermediate, extensive, or ultrarapid CYP metabolizers. This publication also reports similar findings from a retrospective chart review of medical information collected for one year of treatment for a different group of 96 depressed patients. Investigators found that the GeneSight test predicted more total healthcare visits, medical visits and disability claims among patients who had been prescribed one or more medications classified in the red category. Similar to results with depression outcomes, GeneSight predicted significantly more total healthcare visits and disability claims among patients prescribed red category medications metabolized by CYP2D6 (p=0.04, p=0.002, respectively) or CYP2C19 (p=0.04, p=0.001, respectively), and predicted total healthcare visits (p=0.01) and medical visits (p=0.02) for patients prescribed CYP1A2-metabolized drugs. In comparison, only one of the five single gene tests, that for CYP2C19, predicted differences, and only for total healthcare visits or medical visits. Multiple peer-reviewed clinical studies have demonstrated the efficacy and utility of GeneSight. Compared with the current standard of care, pooled data from these peer-reviewed studies ii ,iii, iv show that patients whose treatment was guided by GeneSight experienced a 53 percent greater improvement in depressive symptoms and double the likelihood of response compared with those not guided by the test. Studies have also shown that clinicians who incorporate GeneSight when evaluating medication decisions for their depressed patients can help reduce annual health care costs per patient by more than $2,500, potentially saving millions of dollars in healthcare expenditures.v Altar's co-authors on the paper, “Clinical Validity: Combinatorial Pharmacogenomics Predicts Antidepressant Responses and Healthcare Utilizations Better than Single Gene Phenotypes,” include Daniel Hall-Flavin, M.D., Associate Professor of Psychiatry at the Mayo Clinic, and Joseph Carhart, M.A., Josiah D. Allen, Bryan M. Dechairo, Ph.D. and Joel G. Winner, M.D., of Assurex Health. The full article can be viewed at http://genesight.com/reprint-combinatorial-pharmacogenomics. Assurex Health funded the paper. About GeneSight GeneSight helps health care providers make more precise treatment decisions based on how a patient’s unique genetic makeup affects their individual response to 38 FDA-approved medications for depression, anxiety, posttraumatic stress disorder (PTSD), bipolar disorder, schizophrenia and/or other mental health conditions. GeneSight is the only neuropsychiatric combinatorial pharmacogenomic test validated in multiple, peer-reviewed, published clinical studies. GeneSight analyzes over 785,000 permutations of an individual’s genes and available medications, and presents the results in an easy to read, color-coded report available typically within 36 hours after Assurex Health receives a patient’s cheek swab. Many commercial and government insurance plans, including Medicare and the U.S. Department of Veterans Affairs, reimburse all or part of the cost of GeneSight. Assurex Health also offers financial assistance programs for patients who qualify. Learn more at http://www.genesight.com. About Assurex Health Assurex Health is a commercial-stage, informatics-based precision medicine company providing treatment decision support to clinicians for behavioral health conditions. Assurex Health’s proprietary GeneSight technology is based on combinatorial pharmacogenomics (CPGx™) – the application of multiple genetic factors that influence an individual’s response to medications – as well as evidence-based medicine and clinical pharmacology. Assurex Health has licensed patented technology from Mayo Clinic and Cincinnati Children’s Hospital Medical Center, both of whom continue to be research collaborators. Learn more at http://www.assurexhealth.com. i Altar, CA, et al. (2015) Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes. Pharmacogenomics J advance online publication, February 17, 2015; doi:10.1038/tpj.2014.85. ii Hall-Flavin DK, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics. 2013 Oct;23(10):535-48. [PMID: 24018772]. iii Hall-Flavin DK, et al. Using a pharmacogenomic algorithm to guide the treatment of depression. Transl Psychiatry. 2012 Oct 16;2:e172. [PMID: 23047243]. iv Winner JG, et al. A prospective, randomized double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med. 2013 Nov;16(89):219-27. [PMID: 24229738]. v Winner JG, et al. Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Transl Psychiatry. 2013 Mar 19;3:e242. [PMID: 23511609].