Learn more about the genes covered by our tests, including examples of how they impact medication response.
The COMT gene, residing on chromosome 22, encodes the enzyme catechol-O-methyltransferase, which degrades catecholamines, such as the neurotransmitters dopamine, epinephrine, and norepinephrine. The activity of the COMT enzyme is modulated by genetic variants, one of the best characterized being rs4680 (also known as Val158Met variant or c.322G>A, 1947A>G). Patients homozygous for the COMT rs4680 variant (Met/Met genotype) have a greater likelihood of smoking cessation with nicotine replacement therapy and a lower morphine dose requirement for adequate pain relief when compared with patients with Val/Val or Val/Met genotypes. Tobacco remains the leading preventable cause of death worldwide, yet the efficacy of first-line therapies remains low. Testing COMT may be useful for early identification of patients who may show decreased likelihood of smoking cessation on nicotine replacement therapy, and who may benefit from additional support in the form of counseling or selection of alternative medication therapy.
Yates, A. et al. Ensembl 2016. 44, D710–6 (2015).
Nicotine chemistry, metabolism, kinetics and biomarkers. Handbook of Experimental Pharmacology. 2009. Benowitz N L, et al.
Association between catechol-O-methyltransferase (COMT) Val/Met genotype and smoking cessation treatment with nicotine: a meta-analysis. Pharmacogenomics. 2015. Choi H D, et al.
COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers. Pharmacogenomics Journal. 2013. Herman A I, et al.
Pharmacogenetics of smoking cessation in general practice: results from the patch II and patch in practice trials. Nicotine & Tobacco Research. 2011. David S P, et al.
Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain. 2007. Reyes-Gibby C C, et al.
Located on the plus strand of chromosome 15, CYP1A2 encodes the Cytochrome P450 family 1 subfamily A type A2 enzyme, which mediates liver metabolism of 9% of clinically important drugs (e.g., clozapine, olanzapine), procarcinogens (e.g., benzopyrene and aflatoxin b1), and endogenous substrates (e.g., steroids and arachidonic acid). For many drugs, CYP1A2 is not the sole metabolizing enzyme nor is it active at the rate-limiting step. The genetic component of variation in CYP1A2 activity is estimated at up to 75%, with environmental factors making up the remaining difference such as smoking (induction) and oral contraceptive use in women (inhibition). A recent pathway-based analysis in human liver samples estimated that genetic variants and non-genetic factors may account for 42%, 38%, and 33% of the variation of CYP1A2 at the catalytic activity, protein expression, and mRNA levels, respectively. CYP1A2 is important for dosing of several antipsychotics and for both drug efficacy and adverse drug reactions. CYP1A2 is the main CYP isoform involved in clozapine metabolism; case studies have shown that in ultrarapid metabolizers of clozapine who presented as resistant to treatment, improved patient outcomes were obtained by increased clozapine doses and co-administration with the CYP1A2 inhibitor fluvoxamine. For concomitant use of CYP1A2 inhibitors or inducers, the US Food and Drug Administration recommends clozapine dosage adjustments, monitoring for adverse reactions or lack of efficacy, or discontinuation of co-medication. Genotyping CYP1A2 may be useful in identifying patient phenotypes to assist drug therapy decision-making.
Clozapine FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenetics and Genomics. 2012. Thorn C F, et al.
Pathway-Targeted Pharmacogenomics of CYP1A2 in Human Liver. Frontiers in Pharmacogenomics. 2010. Klein K, et al.
Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. Journal of Clinical Psychopharmacology. 2004. Eap C B, et al.
Metabolism of clozapine by cDNA-expressed human cytochrome p450 enzymes. Drug Metabolism and Disposition. 1997. Linnet K and Olesen O V.
CYP1A2*1D and *1F polymorphisms have a significant impact on olanzapine serum concentrations. Therapeutic Drug Monitoring. 2015. Czerwensky F, Leucht S, Steimer W.
Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenomics Journal. 2009. Laika B, et al.
Cigarette smoking has a differential effect on the plasma level of clozapine in Taiwanese schizophrenic patients associated with the CYP1A2 gene −163A/C single nucleotide polymorphism. Psychiatric Genetics. 2016. Huang H C, et al.
Located on the plus strand of chromosome 19, CYP2B6 encodes the Cytochrome P450 family 2, subfamily B type 6 enzyme, which mediates liver and brain metabolism of 4% of the top 200 prescribed medications. CYP2B6 is highly inducible by several drugs and other xenobiotics. Variation in CYP2B6 expression varies over a 20-250-fold range, due to differences in transcriptional regulation and genetic variations. CYP2B6 is the primary enzyme involved in the metabolism of efavirenz and nevirapine, which have a narrow therapeutic window. Variants in CYP2B6 have been associated with efficacy and tolerability of adverse effects in efavirenz, ketamine, and bupropion, among others. Genotyping CYP2B6 can aid efavirenz dosing and may decrease the cost of HIV treatment.
Efavirenz FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Dose optimization of efavirenz based on individual CYP2B6 polymorphisms in Chinese patients positive for HIV. CPT Pharmacometrics Systems & Pharmacology. 2016. Hui K H, et al.
Cost-effectiveness of CYP2B6 genotyping to optimize efavirenz dosing in HIV clinical practice. Pharmacogenomics. 2015. Schackman B R, et al.
Located on the plus strand of chromosome 10, CYP2C9 encodes the Cytochrome P450 family 2 subfamily C type 9 enzyme, which is primarily expressed in the liver and mediates metabolic clearance of 15%-20% of all drugs undergoing Phase I metabolism. The gene coding for the CYP2C9 enzyme is highly polymorphic, including functional variants of major pharmacogenetic importance. Changes in metabolic activity caused by genetic variants in CYP2C9 play a major role in pathogenesis due to ADRs. Patients with low enzyme activity are at risk of adverse drug reactions (ADRs), especially for CYP2C9 substrates with a narrow therapeutic window, such as S-warfarin, phenytoin, glipizide, and tolbutamide. Professional guidelines exist for the use of CYP2C9 genotyping in guiding prescription of several medications, including warfarin, phenytoin, and celecoxib. For example, in patients who are known or suspected CYP2C9 poor metabolizers for celecoxib, the US Food and Drug Administration recommends caution when administering celecoxib with a dosage reduction by 50% or use of alternative therapy for juvenile rheumatoid arthritis. Genotyping CYP2C9 can aid with the selection and dosing of these medications and may prevent ADRs.
Celecoxib FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Clinical pharmacogenetics implementation consortium (CPIC) guideline for pharmacogenetics‐guided warfarin dosing: 2017 update. Clinical Pharmacology & Therapeutics. 2017. Johnson J, et al.
Major role of human liver microsomal cytochrome P450 2C9 (CYP2C9) in the oxidative metabolism of celecoxib, a novel cyclooxygenase-II inhibitor. Journal of Pharmacology and Experimental Therapeutics. 2000. Tang C, et al.
Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA‐B genotypes and phenytoin dosing. Clinical Pharmacology & Therapeutics. 2014. Caudle K E, et al.
CYP2C19, located on the plus strand of chromosome 10, encodes the Cytochrome P450 family 2 subfamily C type 19 enzyme, which mediates liver (and small intestinal) metabolic oxidation of 10-15% of clinically relevant drugs and drug classes, including antidepressants, benzodiazepines, mephenytoin, proton pump inhibitors, and the antiplatelet prodrug clopidogrel. Variants in the gene include loss-of-function alleles (e.g., *2, *3) and a promoter variant that causes increased gene expression (e.g., *17). CYP2C19 is the primary enzyme involved in the metabolism of clopidogrel, therefore genotyping for CYP2C19 may predict patient antiplatelet response to the drug. In addition, CYP2C19 genotyping is useful for dosing various antidepressants including tricyclic antidepressants (together with CYP2D6) and SSRIs, proton-pump inhibitors (PPIs) such as omeprazole, and the antifungal voriconazole. Professional guidelines exist for the use of CYP2C19 genotyping for guiding prescriptions of these medications. Specifically, the Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for clopidogrel treatment, indicating that poor or intermediate CYP2C19 metabolizers should use an alternative antiplatelet therapy (e.g., prasugrel, ticagrelor), and ultrarapid CYP2C19 metabolizers should follow label recommended dosage and administration even though at least one *17 allele may be associated with increased risk of bleeding. Genotyping CYP2C19 can aid clopidogrel dosing and lessen the risk of bleeding, decrease the risk of ADRs with antidepressants, and help achieve efficacy with PPIs and voriconazole.
Clopidogrel FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clinical Pharmacology and Therapeutics. 2013. Scott S A, et al.
Pharmacogenetics: from bench to byte—an update of guidelines. Clinical Pharmacology and Therapeutics. 2011. Swen J J, et al.
Omeprazole therapy and CYP2C19 genotype. Medical Genetics Summaries. Dean L. Available at: https://www.ncbi.nlm.nih.gov/books/NBK100895/.
Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2C19 and voriconazole therapy. Clinical Pharmacology and Therapeutics. 2016. Moriyama B, et al.
Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical Pharmacology and Therapeutics. 2017. Hicks J K, et al.
Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clinical Pharmacology and Therapeutics. 2015. Hicks J K et al.
rs12777823 is a single nucleotide polymorphism (SNP) in the CYP2C cluster near the CYP2C18 gene on chromosome 10. This SNP is associated with a clinically relevant effect on warfarin dose, as it significantly alters warfarin clearance independent of CYP2C9*2 and *3. A meta-analysis of a genome-wide association study in African Americans and the confirmatory replication cohort concluded that African Americans who are heterozygous or homozygous for the rs12777823 A allele require a dose reduction of ~7 or 9 mg/week. Regression analysis showed that addition of rs12777823 improves the dosing algorithm published by the International Warfarin Pharmacogenetics Consortium (IWPC) by 21% and further studies have demonstrated the importance of this SNP in African Americans. Based on the recent identification of the association between rs12777823 (g.96405502G>A) and warfarin dosing among African Americans, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published an update for pharmacogenetics-guided warfarin dosing. The guidelines are for adult and pediatric patients, are specific to continental ancestry, and are based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823.
Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet. 2013. Perera M A, et al.
Pharmacogenetic-guided warfarin dosing algorithm in African-Americans. Journal of Cardiovascular Pharmacology. 2016. Alzubiedi S & Saleh M I.
CYP2D6, located on the minus strand of chromosome 22, encodes the Cytochrome P450 family 2 subfamily D type 6 enzyme, which mediates hepatic first-pass metabolic oxidation of numerous drugs, including the anti-arrhythmics, antidepressants, antipsychotics, beta blockers-adrenergic blocking agents, antiemetics, analgesics, and antitussives. Variants in this gene may reduce or abolish enzyme function; variations in copy number also exist, which may lead to increased function or complete deletion of the gene, resulting in phenotypes ranging from no to increased function compared to normal. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for codeine, desipramine, fluvoxamine, nortriptyline, ondansetron, paroxetine, and tropisetron treatment based on CYP2D6 metabolizer status. For example in codeine guidelines, CPIC recommends use of alternative analgesics for CYP2D6 poor metabolizers based on lack of efficacy and for ultrarapid metabolizers based of potential for toxicity. CPIC recommends use of label age- or weight-specific dosing in normal and intermediate metabolizers with an additional recommendation for intermediate metabolizers to consider alternative analgesics such as morphine or a non-opioid if there is no response. CPIC also released therapeutic recommendations for tamoxifen based on CYP2D6 genotype in breast cancer treatment. Genotyping CYP2D6 can aid opioid treatment, antidepressant therapy, tamoxifen dosage and response, and it can prevent toxicity-related ADRs with all of these medications.
Codeine FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Clinical pharmacogenetics implementation consortium (CPIC) guidelines for cytochrome P450 2D6 (CYP2D6) genotype and codeine therapy: 2014 update. Clinical Pharmacology and Therapeutics. 2014. Crews K R, et al.
Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clinical Pharmacology and Therapeutics. 2015. Hicks J K, et al.
Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clinical Pharmacology and Therapeutics. 2018. Goetz M P, et al.
Cytochrome P450 family 3 subfamily A type 4 enzyme (CYP3A4) is encoded by the CYP3A4 gene located on the minus strand of chromosome 7. Along with CYP3A5, CYP3A4 is the predominant cytochrome P450 enzyme expressed in the adult human liver and is involved in the metabolism of about 50% of all drugs. CYP3A4 activity predominates in Caucasians, and CYP3A5 predominates in individuals of African descent; these enzymes have overlapping substrate specificities. Simvastatin is an HMG-CoA reductase inhibitor (statin) indicated in the treatment of elevated cholesterol and prevention of cardiovascular events. CYP3A4 is the primary enzyme involved in the metabolism of simvastatin; therefore it may help in predicting patient response to the medication. The US Food and Drug Administration warns of risk of myopathy and rhabdomyolysis which is increased by high plasma levels of simvastatin. The FDA recommends that using simvastatin concomitantly with CYP3A4 inhibitors (such as antifungal azoles like itraconazole and ketoconazole, the macrolide antibiotics erythromycin and clarithromycin, HIV protease inhibitors, or large quantities of grapefruit juice) should be avoided. Genotyping CYP3A4 can be useful in identifying patient phenotypes to aid in statin therapy decision-making.
Simvastatin FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Individual and combined associations of genetic variants in CYP3A4, CYP3A5, and SLCO1B1 with simvastatin and simvastatin acid plasma concentrations. Journal of Cardiovascular Pharmacology. 2015. Luzum J A, et al.
CYP3A4*22 and CYP3A5*3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort. Pharmacogenetics and Genomics. 2014. Kitzmiller J P, et al.
Cytochrome P450 family 3 subfamily A type 5 (CYP3A5) is encoded by the CYP3A5 gene, located on the minus strand of chromosome 7. Along with CYP3A4, CYP3A5 is the predominant cytochrome P450 enzyme expressed in the adult human liver. CYP3A4 activity predominates in Caucasians, and CYP3A5 predominates in individuals of African descent; these enzymes have overlapping substrate specificities. Most drugs metabolized by CYP3A4 are also metabolized by CYP3A5, with a few exceptions. For example, tacrolimus is a calceineurin inhibitor immunosuppressant used in transplant recipients and is predominantly affected by CYP3A5 genotype. Tacrolimus has a low therapeutic index with a wide range of side effects and large inter-individual variability in its pharmacokinetics. In particular, the dose required to reach target trough blood concentrations, thus necessitating routine therapeutic drug monitoring in clinical practice. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for tacrolimus, indicating that increasing the starting dose by 1.5 to 2 times the recommended starting dose in patients who are CYP3A5 intermediate or normal metabolizers, though total starting dose should not exceed 0.3 mg/kg/day. CPIC recommends poor CYP3A5 metabolizers initiate therapy with the standard recommended dose. Genotyping CYP3A5 may be useful in identifying patient phenotypes to assist drug therapy decision-making.
Tacrolimus FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clinical Pharmacology and Therapeutics. 2015. Birdwell K A, et al.
Cytochrome P450 family 4 subfamily F member 2 (CYP4F2) is encoded by the CYP4F2 gene, located on chromosome 19. CYP4F2 catalyzes the NADPH-dependent oxidation of the terminal carbon of long and very long-chain fatty acids, the side chains of vitamin K (K 1, K 2) and vitamin E (tocopherols and tocotrienols), arachidonic acid (AA), and leukotriene B 4 (LTB 4). Through its role as a vitamin K1 oxidase, the CYP4F2 variant rs2108622 was recently associated with warfarin dosage requirements in European and European-American populations, but not in African American populations. The Clinical Pharmacogenomics Implementation Consortium (CPIC) released updated warfarin dosing guidelines for adult and pediatric patients specific to European and European-American populations, and are based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823.
CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin dose in carriers of the V433M variant. Molecular Pharmacology. 2009. McDonald M G, et al.
Clinical pharmacogenetics implementation consortium (CPIC) guideline for pharmacogenetics-guided warfarin dosing: 2017 update. Clinical Pharmacology and Therapeutics. 2017. Johnson J A, et al.
The DPYD gene, located on the minus strand of chromosome 1, encodes the dihydropyrimidine dehydrogenase (DPD) enzyme which is involved in the degradation pathway of fluoropyrimidines, such as 5-fluorouracil and capecitabine. Decreased activity of DPD can lead to severe or fatal toxicity when fluoropyrimidines are given at normal doses. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidelines for 5-fluorouracil and capecitabine based on the activity score of DPYD variants . Patients homozygous for non-functional variants or with an activity score of 0 should use an alternative drug. Poor metabolizers with an activity score of 0.5 should use an alternative drug; if no suitable alternative is available, the drug should be started at a highly reduced dose with early therapeutic drug monitoring. In intermediate metabolizers with an activity score of 1 or 1.5, the starting dose should be reduced by 50%. Based on recent case reports, patients homozygous for 2846A>T (DPYD activity score of 1) should reduce the starting dose by greater than 50%. Current data on the impact of DPYD variants on tegafur toxicity risk is limited. Genotyping DPYD may be useful in identifying patients at increased risk for toxicity when considering fluoropyrimidine treatment.
Fluorouracil FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clinical Pharmacology and Therapeutics. 2018. Amstutz U, et al.
The DRD2 gene, residing on the minus strand of chromosome 11, encodes dopamine receptor D2. Dopamine receptor D2 is a G protein-coupled receptor highly expressed in the pituitary gland and central nervous system. This receptor is targeted by many antiparkinsonian agents (acting as agonists) as well as typical and atypical antipsychotics (acting as antagonists). Variants in this gene have been associated with efficacy and toxicity of antipsychotics. In particular, rs1799978 A>G is a promoter variation that influences the transcript expression. Evidence shows that this variant is related to likelihood of response to risperidone in patients with schizophrenia. However, the response to risperidone is influenced by many other clinical and genetic factors. Genotyping DRD2 may be useful in determining possible causes for poor response to risperidone.
Risperidone FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. Pharmacogenomics. 2008. Ikeda M, et al.
The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients. International Journal of Neuropsychopharmacology. 2007. Xing Q, et al.
The F2 gene, residing on chromosome 11, encodes prothrombin (coagulation factor II), which is cleaved to form the serine protease thrombin during blood clotting. Variations in the 3' untranslated region of this gene (AA or GA genotype) are associated with increased risk of deep vein thrombosis for women taking hormonal contraceptives (ethinyl estradiol/norelgestromin) as compared to women with the GG genotype who are not taking oral contraceptives. Genotyping F2 may be useful in identifying patients at increased risk of thrombosis due to prothrombin thrombophilia.
Ethinyl estradiol FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors. Journal of Thrombosis and Haemostatsis. 2015. Bruzelius M, et al.
The F5 gene, residing on the minus strand of chromosome 1, encodes the coagulation cofactor Factor 5. Genetic variations of F5 are associated with an increased risk of thrombosis in women taking estrogen-containing products (e.g. contraceptives), in addition to the baseline risk with estrogen-containing products alone. These variants can lead to the formation of the Factor V Leiden protein, which cannot be inactivated normally by activated protein C (APC). The prolonged time for APC to inactivate Factor V Leiden leads to a prolonged clotting process, increasing the chance of developing abnormal blood clots. The FDA label for estrogen-containing products state the use of these medications is contraindicated in patients with thrombophilia - either acquired or hereditary, as the risk for thrombosis is further increased. Additionally, the WHO's 5th edition of the Medical Eligibility Criteria for Contraceptive Use (2015) states the risk of thrombosis with oral contraceptives increases 2-20 times among women with thrombogenic variants. It is important to note other factors also contribute to thrombotic risk in addition to oral contraceptives or estrogen replacement therapy, including age, obesity, injury, surgery, smoking, and pregnancy. Genotyping F5 may be useful in identifying patients at increased risk of thrombosis due to Factor V Leiden thrombophilia.
Medical eligibility criteria for contraceptive use. Fifth edition, 2015. World Health Organization. Available at: https://www.who.int/reproductivehealth/publications/family_planning/MEC-5/en/.
The GRIK4 gene, residing on chromosome 11, encodes the glutamate receptor, ionotropic, kainate 4. It is involved in glutamate neurotransmission, with glutamate being the main neurotransmitter in the human brain. A variant in this gene may help predict response to the SSRI citalopram. Response to citalopram depends on multiple genetic and clinical factors (including HTR2A), therefore a treatment decision should not be made based on GRIK4 alone. Genotyping GRIK4 may be useful in determining possible causes for poor response to citalopram.
GRIK4 polymorphism and its association with antidepressant response in depressed patients: a meta-analysis. Pharmacogenomics. 2014. Kawaguchi D M, et al.
Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology 2010. Horstmann S, et al.
Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Molecular Psychiatry. 2010. Kato M, et al.
Pharmacogenetics studies in STAR*D: strengths, limitations, and results. Psychiatric Services (Washington D.C.). 2009. Laje G, et al.
Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort. The American Journal of Psychiatry. 2007. Paddock S, et al.
The HLA-A gene, located at chromosome 6p22.1, codes for the major histocompatibility complex (MHC), class I, A molecules. This group of proteins, also called human leukocyte antigens (HLAs), are major players in normal immune response, specifically in adaptive immunity as their role is to present antigen peptides to T lymphocytes. Certain alleles are associated with allergic drug reactions. The HLA-A*31:01 allele has been associated with hypersensitivity reactions including Stevens-Johnson syndrome (SJS), maculopapular exanthema (MEP) and toxic epidermal necrolysis (TEN) following carbamazepine administration, particularly in Japanese, Korean and Caucasian populations. The US Food and Drug Administration recommends weighing the risks and benefits of carbamazepine therapy before initiating treatment in patients known to be positive for HLA-A*31:01. Recent studies indicate that HLA-A*31:01 may not be associated with hypersensitivity reactions due to anti-epileptic medications exhibiting a chemical structure close to carbamazepine, namely with phenytoin and lamotrigine. However, the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) recommends caution with eslicarbazepine, oxcarbazepine, fosphenytoin, phenytoin, and lamotrigine since data is still scarce and cross-reactivity cannot be ruled out.
Clinical role of human leukocyte antigen in health and disease. Scandinavian Journal of Immunology. 2015. Mosaad Y M.
Immunobiology: the immune system in health and disease. Garland Science. 2001. Janeway C A, et al.
The HLA-A*31:01 allele: influence on carbamazepine treatment. Pharmacogenomics and Personalized Medicine. 2017. Yip V, et al.
HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. New England Journal of Medicine. 2011. McCormack M, et al.
Genotype–phenotype association between HLA and carbamazepine-induced hypersensitivity reactions: strength and clinical correlations. Journal of Dermatological Science. 2014. Hsiao Y H, et al.
Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Research. 2011. Kim S H, et al.
Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population. Human Molecular Genetics. 2011. Ozeki T, et al.
Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions. Pharmacogenomics. 2012. McCormack M, et al.
Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia. 2014. Amstutz U, et al.
The HLA-B gene, located at chromosome 6p21.33, codes for the major histocompatibility complex (MHC) class I, B molecules. This group of proteins, also called human leukocyte antigens (HLAs) are major players in normal immune response, specifically in adaptive immunity as their role is to present antigen peptides to T lymphocytes. Certain alleles are associated with allergic drug reactions. In particular, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01 have been reported to be strongly associated with adverse reactions induced by medications. The HLA-B*15:02 allele has been strongly associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) induced by carbamazepine, phenytoin and fosphenytoin, lamotrigine, oxcarbazepine and likely eslicarbazepine. The Canadian Pharmacogenomics Network for Drug Safety (CPNDS), the Clinical Pharmacogenetics Implementation Consortium (CPIC), and the US Food and Drug Administration (FDA) recommend avoiding these medications in patients positive for HLA-B*15:02. Both CPIC and FDA recommend testing for HLA-B*57:01 prior to abacavir prescription. The HLA-B*58:01 allele has been strongly associated with severe cutaneous adverse reactions induced by allopurinol. CPIC and the American College of Rheumatology recommend that allopurinol should not be used in patients positive for HLA-B*58:01.
Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clinical Pharmacology and Therapeutics. 2014. Caudle K E, et al.
Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing: 2014 update. Clinical Pharmacology and Therapeutics. 2014. Martin M A, et al.
Clinical pharmacogenetics implementation consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clinical Pharmacology and Therapeutics. 2013. Hershfield M S, et al.
Clinical pharmacogenetics implementation consortium (CPIC) guidelines for human leukocyte antigen-B (HLA-B) genotype and allopurinol dosing: 2015 update. Clinical Pharmacology and Therapeutics. 2016. Saito Y, et al.
2012 American college of rheumatology guidelines for management of gout. part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Research. 2012. Khanna D, et al.
The HTR2A gene, residing on chromosome 13, encodes the 5-hydroxytryptamine (serotonin) receptor 2A. This metabotropic receptor mediates the response of many antidepressant and antipsychotic drugs (especially second generation) and is found to be downregulated as a pharmacodynamics effect of chronic administration of selective serotonin reuptake inhibitors (SSRIs) and first generation antipsychotics. Patient response to many of these drugs may be predicted by variants in this gene, in particular rs7997012 A>G. Response to citalopram depends on multiple genetic and clinical factors, therefore a treatment decision should not be made based on HTR2A alone. However, genotyping HTR2A may be useful in determining possible causes for poor response to citalopram.
Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology. 2010. Horstmann S, et al.
The HTR2C gene, residing on the X chromosome, encodes the 5-hydroxytryptamine (serotonin) receptor 2C. Many antipsychotics and antidepressants target this metabotropic receptor as either agonists or antagonists, leading to downregulation in both cases. Variants in HTR2C have been associated with a protective effect from weight gain in patients with schizophrenia treated with olanzapine or clozapine. Genotyping HTR2C may be useful in identifying patients on olanzapine or clozapine with reduced risk of weight gain.
Olanzapine FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
HTR2C polymorphisms, olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: a meta-analysis. International Journal of Psychiatry in Clinical Practice. 2014. Ma X, et al.
Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. Pharmacogenomics Journal. 2010. Laika B, et al.
Genetic variants impacting metabolic outcomes among people on clozapine: a systematic review and meta-analysis. Psychopharmacology (Berl). 2017. Suetani RJ, et. al.
The IFNL4 gene, residing on the minus strand of chromosome 19, encodes interferon, lambda 4, and was recently identified as important to the immune response to hepatitis C. The IFNL4 gene encodes for the functional protein interferon, lambda 4 in most people from African origin; in about half of people from European origin and most of people from Asian origin, IFNL4 exhibits a variant that renders the gene non functional. Another variant in this gene, rs12979860 C>T, is associated with deviation of sustained virologic response (SVR) rates. The hypothesis is the rs12979860 C>T variant improves innate immune response and increased viral kinetics. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for pegylated-interferon alpha containing regimens, indicating that this variant is the strongest baseline predictor of response to peginterferon alpha containing regimens in HCV genotype 1 patients. CPIC guidelines state patients with the favorable response genotype (rs12979860 CC) have increased likelihood of response (higher SVR rate) to peginterferon alpha containing regimens as compared to patients with unfavorable response genotype (rs12979860 CT or TT). These guidelines are also reflected in the FDA label for peginterferon alpha-based regimens. Genotyping the rs12979860 C>T variant may be useful in predicting responsiveness to peginterferon alpha containing regimens in patients with hepatitis C viral infections. Until recently, rs12979860 C>T was thought to be located in a regulatory region upstream of IFNL3 (also referred to as IL28B). Therefore, current CPIC guidelines and the FDA label refer to these genes as IL28B and IFNL3.
Peginterferon alfa-2a FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Clinical pharmacogenetics implementation consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and peginterferon alpha based regimens. Clinical Pharmacology and Therapeutics. 2013. Muir A J, et al.
A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nature Genetics. 2013. Prokunina-Olsson L, et al.
Loss of function of the new interferon IFN-λ4 may confer protection from hepatitis C. Nature Genetics. 2013. Booth D & George J.
IFN-λ4: The paradoxical new member of the interferon lambda family. Journal of Interferon & Cytokine Research. 2014. O'Brien T R, et al.
The MTHFR gene, residing on the minus strand of chromosome 1, encodes the enzyme methylenetetrahydrofolate reductase. This enzyme is integrally involved in the DNA synthesis pathway, specifically the conversion of homocysteine to methionine through the methylation cycle of folic acid. Common variants in this gene, namely 677C>T (rs1801133) and 1298A>C (rs1801131), can disrupt this pathway, altering folic acid metabolism and/or leading to hyperhomocysteinemia, putting individuals carrying the variant at an increased risk for thrombosis. However, the American College of Medical Genetics and Genomics (ACMG) determined that MTHFR polymorphism testing has minimal clinical utility as part of the routine evaluation for thrombophilia, and that MTHFR status does not change the recommendation that women of childbearing age should take the standard dose of folic acid supplementation.
PharmGKB summary: very important pharmacogene information for MTHFR. 2017. Thorn C F. Available at: https://www.pharmgkb.org/vip/769171882.
ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine. 2013. Hickey S E, et al.
The NUDT15 gene, residing on the plus strand of chromosome 13, encodes nucleotide diphosphate linked moiety X (nudix)-type hydrolase motif 15. This type of protein catalyzes the hydrolysis of nucleoside diphosphates that are oxidized bases that can result in base mispairing during nucleic acid synthesis, and thereby cause translational errors. NUDT15 also inactivates thiopurine (e.g., azathioprine, mercaptopurine, and thioguanine) metabolites. Patients carrying variants in this gene may be at higher risk of developing leukopenia or alopecia as a result of thiopurine treatment for inflammatory bowel diseases or acute lymphoblastic leukemia compared to patients without these variants. Functionally, rs116855232 C>T has been associated with impaired NUDT15 activity. Genotyping NUDT15 is useful in predicting potential for toxicity to thiopurine drugs.
NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nature Genetics. 2016. Moriyama T, et al.
Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. Journal of Clinical Oncology. 2015. Yang J, et al.
NUDT15 polymorphisms are better than thiopurine S‐methyltransferase as predictor of risk for thiopurine‐induced leukopenia in Chinese patients with Crohn's disease. Alimentary Pharmacology & Therapeutics. 2016. Zhu, et al.
NUDT15 and TPMT genetic polymorphisms are related to 6‐mercaptopurine intolerance in children treated for acute lymphoblastic leukemia at the Children's Cancer Center of Lebanon. Pediatric Blood Cancer. 2017. Zgheib N, et al.
TPMT and NUDT15 genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay. British Journal of Haematology. 2017. Soler A, et al.
The OPRM1 gene, residing on chromosome 6, encodes the mu-1 opioid receptor, a G protein-coupled receptor highly expressed in the spinal cord and other areas of the central nervous system, which is the primary site of action of opioids like morphine, alfentanil, tramadol, fentanyl, and methadone. Variants in this gene have been linked to differential efficacy of opioids for pain. The rs1799971 A>G variant has been linked to response to certain medications, in particular alfentanil, codeine, fentanyl, morphine, and tramadol. This variant codes for different isoforms of the protein, and the impact on the function of the OPRM1 receptor is unclear, potentially modulating affinities to endogenous endorphins. Although OPRM1 likely plays a role in the clinical response of opioids, evidence is contradictory for many of these medications, as effects of pain medication involve multiple genes that contribute to the global response. For OPRM1 specifically, clinical data is mostly consistent on alfentanil, codeine, and tramadol, while fentanyl and morphine have stronger data. Evidence shows the pharmacokinetics of various opioids is the main modulator of response to treatment. Genotyping OPRM1 may be useful in predicting response to various opioids.
Mu-opioid receptor (A118G) single-nucleotide polymorphism affects alfentanil requirements for extracorporeal shock wave lithotripsy: a pharmacokinetic-pharmacodynamic study. British Journal of Anaesthesia. 2009. Ginosar Y, et al.
The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenetics and Genomics. 2006. Oertel B G, et al.
Study of the OPRM1 A118G genetic polymorphism associated with postoperative nausea and vomiting induced by fentanyl intravenous analgesia. Minerva Anestesiologica. 2011. Zhang W, et al.
The pharmacogenetics of codeine pain relief in the postpartum period. Pharmacogenomics Journal. 2015. Baber M, et al.
Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers. Clinical Pharmacology & Therapeutics. 2012. Sistonen J, et al.
The SLC6A4 gene, residing on chromosome 17, encodes the serotonin transporter (SERT), or 5HTT, which is the site of action for selective serotonin reuptake inhibitors (SSRIs). A 44 base pair insertion in the promoter region of SLC6A4 gives rise to two variants: the "L" or long variant and the "S" or short variant. The L variant is associated with increased transcriptional efficacy of the serotonin transporter and is also linked to the rs25531 T>C variant, which further modulates transcription. The minor allele substitution A>G is almost always in phase with the L allele and reduces the transcriptional efficacy comparable to that of S allele. The S/S genotype has been associated with reduced likelihood and potentially slower response to the SSRIs fluoxetine and fluvoxamine and possibly citalopram and escitalopram. The opposite trend in response has been observed in East Asian populations, showing increased likelihood and potentially quicker response in carriers of the S allele. The S/S genotype is more frequent in the East Asian population, compared to the Caucasian and African American population. In combination with other genetic findings and clinical factors, SLC6A4 genotype may be useful in understanding patient response to SSRIs.
Population frequencies of the triallelic 5HTTLPR in six ethnically diverse samples from North America, Southeast Asia, and Africa. Behavior Genetics. 2015. Haberstick B, et al.
Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. European Neuropsychopharmacology. 2012. Porcelli S, et al.
Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Molecular Psychiatry. 2006. Serretti A, et al.
The influence of 5-HTTLPR and STin2 polymorphisms in the serotonin transporter gene on treatment effect of selective serotonin reuptake inhibitors in depressive patients. Psychiatric Genetics. 2008. Smits K, et al.
Located on the plus strand of chromosome 19, SLCO1B1 encodes the OATP1B1 transporter, which mediates the transport of statins from the blood into the liver. SLCO1B1 variants affect the transporter function, which can affect the efficacy and tolerability of statin medications. Clinically, rs4149056 T>C (characterizing *5, *15 and *17) has been associated with reduced SLCO1B1 function and increased risk for simvastatin-induced myopathy. In other words, the presence of at least one *5, *15 or *17 allele yield the same phenotype and clinical recommendation with respect to the risk of myopathy. Recent research indicates that rs4149056 T>C may also be associated, and potentially higher rosuvastatin, atorvastatin, and fluvastatin levels with unknown effect on their efficacy. In addition, the rs4149015 G>A SNP (characterizing 17 and 21) has also been associated with higher area under the curve (AUC) and reduced efficacy of pravastatin, which demonstrate an effect of rs4149015 G>A on SLCO1B1 function in vivo. The effect of rs4149015 G>A on simvastatin remains unclear. To the best of our knowledge, no study reports data on this location independently from the rs4149056 T>C variant (i.e., effects of rs4149015 G>A have likely been studied in a *17 background). A recent publication suggests that rs4149015 G>A may affect the pharmacokinetics of simvastatin in a Chinese cohort. Therefore, an impact of rs4149015 G>A on simvastatin cannot be excluded, but the increased risk of myopathy remains to be demonstrated. Recently, studies also demonstrated an impact of rs4149056 T>C on methotrexate toxicity in patients with acute lymphoblastic leukemia (ALL), where methotrexate is typically used at high dose. For simvastatin, the US Food and Drug Administration recommends against 80mg daily dosage in patients with the C allele at SLCO1B1 rs4149056, as there are modest increases in myopathy risk even at lower simvastatin doses (40mg daily); if optimal efficacy is not achieved with a lower dose, the FDA recommends alternate agents should be considered. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for simvastatin, indicating recommended dosing based on SLCO1B1 phenotype. Genotyping SLCO1B1 may be useful for predicting statin-associated myopathy for various statins.
Clinical pharmacogenetics implementation consortium (CPIC) guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clinical Pharmacology and Therapeutics. 2014. Ramsey L B, et al.
Clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clinical Pharmacology and Therapeutics. 2012. Wilke R A, et al.
Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenetics and Genomics. 2005. Niemi M, et al.
Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood. 2013. Radtke S, et al.
Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. Pharmacogenomics Journal. 2012. Brunham L R, et al.
Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort. Pharmacogenetics and Genomics. 2015. Meyer zu Schwabedissen H E, et al.
Impact of CYP2D6, CYP3A5, CYP2C19, CYP2A6, SLCO1B1, ABCB1, and ABCG2 gene polymorphisms on the pharmacokinetics of simvastatin and simvastatin acid. Pharmacogenetics and Genomics. 2015. Choi H Y, et al.
The ROCK/GGTase Pathway Are Essential to the Proliferation and Differentiation of Neural Stem Cells Mediated by Simvastatin. Journal of Molecular Neuroscience. 2016. Zhang C, et al.
Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. Journal of Clinical Oncology. 2009 Treviño L R, et al.
The TPMT gene, residing on the minus strand of chromosome 6, encodes the thiopurine S-methyltransferase enzyme that catalyzes S-methylation of heterocyclic sulfhydryl compounds such as azathioprine, mercaptopurine, and thioguanine. The methylation of these drugs is the inactivation pathway, so decreased activity of this enzyme leads to toxicity due to overexposure to active drug. The 3A allele is comprised of the two SNPs rs1800460 and rs1142345, which are in high linkage disequilibrium, though may occur as individual variations, denoted as 3B and 3C respectively. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for thioguanine based on TPMT genotype, which recommend initiating therapy with reduced doses and continual adjustment of doses based on the degree of myelosuppression and disease-specific guidelines. Reduced doses of thioguanine are recommended for patients with one nonfunctional TPMT allele, or drastically reduced doses for patients with malignancy and two nonfunctional alleles. CPIC also recommends considering alternative nonthiopurine immunosuppressant therapy for patients with nonmalignant conditions and two nonfunctional alleles. Genotyping TPMT may be useful in predicting potential for toxicity to thiopurine drugs.
Thioguanine FDA Drug Label; mercaptopurine FDA label; azathioprine FDA label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation. Pharmacogenetics and Genomics. 2013. Liang J J, et al.
Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clinical Pharmacology and Therapeutics. 2013. Relling M V, et al.
The UGT1A1 gene, located on chromosome 2, belongs to the family of UDP-glucuronosyltransferases, which mediate glucuronidation of target substrates. Glucuronidation renders the substrates water soluble, thus making them available for biliary or renal elimination. UGT1A1 is expressed in the liver, colon, intestine, and stomach. In the liver, it is the sole enzyme responsible for the metabolism of bilirubin, the hydrophobic breakdown product of heme catabolism. UGT1A1 also is involved in the metabolism of irinotecan, nilotinib, pazopanib, atazanavir, and belinostat, and genetic variation in UGT1A1 may increase the risk for adverse effects (neutropenia, hyperbilirubinemia and other toxicities) related to the exposure to these drugs. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir that recommend considering advising individuals who carry two decreased function UGT1A1 alleles about a substantial likelihood of developing jaundice, which may cause non-adherence. The CPIC dosing guideline recommends that alternative agents be considered if the risk of non-adherence due to jaundice is high. The risk of jaundice-related discontinuation is low and very low for individuals carrying one or no decreased function UGT1A1 alleles. For irinotecan, nilotinib, pazopanib, and belinostat, increased risk of toxicities are reported and warnings exist in the FDA labels of these medications. Genotyping UGT1A1 may be useful for identifying patients at increased risk of adverse drug reactions with these medications used in oncology and infectious disease.
Atazanavir, belinostat, irinotecan, nilotinib and pazopanib FDA Drug Labels. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.
Clinical pharmacogenetics implementation consortium (CPIC) guideline for UGT1A1 and atazanavir prescribing. Clinical Pharmacology and Therapeutics. 2015. Gammal R S, et al.
The VKORC1 gene, residing on the minus strand of chromosome 16, encodes Vitamin K epoxide reductase, which is a key enzyme in the Vitamin K cycle. VKORC1 mediates conversion of Vitamin K-epoxide to Vitamin K, which is the rate-limiting step in physiological Vitamin K recycling. The availability of reduced Vitamin K is of particular importance for several coagulation factor proteins that require it as a cofactor. It is of therapeutic interest for its contribution to inter-individual variation in warfarin anticoagulant dose requirements. A single variant in VKORC1 promoter, rs992323 G>A is largely responsible for the variation in individual warfarin daily dose requirements. Individuals with GG genotypes require higher (or normal) warfarin daily maintenance doses, while individuals with variants in VKORC1, including heterozygote GA and homozygote AA genotypes, require lower warfarin daily maintenance doses. However, the overall warfarin daily maintenance dose depends on age, gender, height, weight, diet, genotypes of CYP2C9 and VKORC1, and other known/unknown genetic and environmental factors. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for warfarin, indicating recommendations for dosing for adult and pediatric patients specific to continental ancestry, and is based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823. Genotyping VKORC1 may be useful for identifying patients who may require warfarin dosing adjustments.
Warfarin FDA Drug Label. US Food Drug Adm. 2018. Available at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm289739.htm.


text:
A lesson from a palm wine tapper | Juwon Ogungbe
A public intellectual of blessed memory once offered a story about a palm wine tapper who lived in the homestead of his forebears. The moral of the tale made a lot of sense when the piece was published on several online platforms, but it is probably even more relevant today.
The writer had a good rapport with this particular tapper, who kept him refreshed on a daily basis when he spent time on vacation with his mother. The teachable moment in their relationship came on a day when the tapper couldn't deliver a keg of fresh palm wine to the writer, as he usually did.
What did the tapper do? He called the scholar on his mobile phone. When asked of his whereabouts, he revealed that he was at the top of a palm tree, doing his job.
The writer reflected on the fact that Africans of all walks of life, literate or illiterate, posh or from humble origins, no longer need any spokespersons or intermediaries to tell their stories. A phone call, photograph or video clip can provide the scope for expression from anyone.
Perhaps we're living in times when everyone should speak for one's self.
Originally published at https://juwonogungbe.com on February 10, 2021.
the history of cannabis use: the victorian era
cbd handbook
Wild Card: History Makers or Takers?
Shelby Rumer in The Threads of My Family Tapestry
Why I assigned myself to an assault mission in Vietnam
Dalton Narine
The 10 Historical Weapons That Would Absolutely Shock You Today
Peter Preskar in History of Yesterday
From Neighbors to Foreigners
Mitul Iyengar
Romans Go…Where?
Elena Giusti in EIDOLON
ROBESPIERRE AND THE FRENCH REVOLUTION — LITERATURE SURVEY ON RUTH SCURR'S FATAL-PURITY
VYSYAKH AJITH
The Birth And Death Of Privacy: 3,000 Years of History Told Through 46 Images
Greg Ferenstein in The Ferenstein Wire

redpajama_set_name: RedPajamaCommonCrawl


A highly attractive Sterling Silver Pendant, featuring the Jacobean Butterfly and enhanced with Amethyst colour stones. The chrysalis symbolises hope for the Stuarts' grand return from exile and it was used as a secret symbol by Jacobites.
For over 300 years the story of the Jacobites has fascinated people. and has been the subject of books by many famous authors, including Sir Walter Scott and more recently Diana Gabaldon and her Outlander series of historical novels.
The aim of the Jacobites was to restore the Roman Catholic Stuart King James VII of Scotland (II of England and Ireland) and his heirs to the thrones of England, Scotland and Ireland.
They get their name from 'Jacobus', the Latin form of James. Jacobites rebelled against the British government on five occasions between 1688 and 1746, the last ending in the crushing defeat at Culloden and Bonnie Prince Charlie's flight to France.
The House of Stuart was a dynasty that was riven by in-fighting and plots, with the most damaging split being religious – Catholic against Protestant. By the late 1600s the populations of both England & Scotland were overwhelmingly Protestant, with only about 2% being practicing Catholics. The situation in the sparsely populated Highlands of Scotland was however different, with some Clans sticking to the old form of Catholic worship, whilst others were as passionately Protestant.
When the Catholic James VII & II succeeded the throne in 1685 from his late Protestant brother Charles II, he attempted to make changes to the religious order, causing social turmoil. He was eventually deposed in 1688 and replaced by his Protestant daughter Mary II, ruling jointly with her husband and first cousin (James's nephew) William III.
The Jacobite movement was, therefore, closely linked with Catholicism from the outset, and subsequently never supported by the majority of the population. Historians today generally accept that the Jacobite kings and princes were largely pawns, used by France to create diversions in a much wider European war they were fighting with the British.
Following the defeat at Culloden many Jacobites went into exile abroad, with those who stayed at home using secret symbols and emblems, such as a White Rose, Butterfly, Acorn & Oak Leaves and the Scottish Thistle as a clandestine way of showing their allegiance.


Did you know that USF offers one of the lowest tuition rates in the United States? It's true! Kiplinger's Personal Finance rated us a "Top 100 Best Value in Public Colleges" for 2016.
Tuition and fees are based on a number of factors, including undergraduate or graduate status, residency and the type of housing chosen. However, our costs are often competitive with the rates at your local university. Take a look and dare to compare!
* International students are required to have health insurance which is an additional cost of $2,403.
Additional costs may be assessed depending on your course of study.
All international students are required to have health insurance for themselves and their families. Learn more about the health insurance and immunization requirements at USF.
Tuition and fees are assessed according to the student's Florida residency classification. Most international students are classified as non-Florida residents and pay out-of-state tuition.
Actual costs of housing are dependent on the type of on-campus or off-campus housing selected. Visit Housing & Residence Education for more information on living on campus at USF.
This website is maintained by International Admissions.


The new Automobiles site introduces aggregated feeds, a new listings section, and vertical navigation. The new features mirror recent moves made by sports site SI.com and Time.com, among others that aggregate content from other sources with the goal to create the best one-stop destination for visitors who are passionate about a subject.
One of the key enhancements of the redesign is that NYTimes.com's own auto content is now buttressed by information on car makes and models from other sources such as New Car Test Drive, a popular source of auto information.
"We wanted to surround our own auto content with supporting information for any new make or model [data, pricing, rebates, photos], as well as third-party content," said Ira Silberstein, vice president of product development, NYTimes.com. "We want to be a resource for consumers so that they can get a wealth of information…reviews from us, from other parties, ratings, pricing and specs all in one place.
The Times, like all other media brands, is fighting tooth and nail against disintermediation, principally by search, but also by other aggregators like TechMeme (where I find all NYT articles on media and technology) and Digg.
B2B publishers now get more revenue from events than print advertising, and custom publishing and digital media advertising are the fastest growing sources of revenue. Print ad pages declined 3% year-over-year in January 2007.
According to a compilation of 2006 revenue data released Monday by American Business Media, "face-to-face revenue" has surpassed print advertising sales for the first time in the history of the industry. By face-to-face revenues, the ABM means conferences, trade shows and events, which garnered $11.3 billion among ABM members participating in the association's Business Information Network tracking reports. That brings events to a 36% share of B-to-B revenues, nudging out B-to-B print advertising's 35% share for the first time ever.
It's a trend that is not likely to reverse itself. The ABM estimates that events is the third fastest growing source of revenues for B-to-B publishers, surpassed only by the rapid rise of digital (online) advertising sale and custom publishing. Print advertising, by comparison, has been steadily declining.
The magazine industry has stopped reporting monthly ad page totals, moving to quarterly reporting. Why deliver bad news more frequently when you can deliver it less frequently?
In the latest move in an ongoing trend reducing the flow of information about the advertising performance of major traditional media, the magazine industry Tuesday announced it would discontinue its monthly reports on advertising pages and revenues booked by major consumer magazine publishers. The reports, which have been distributed publicly to advertisers, agencies and the industry's trade press by the Publishers Information Bureau for more than a quarter century, will now be released quarterly effective with the first-quarter 2007 report.
Do MySpace Users Care That It's Not Really THEIR Space?


text:
Benoît Hogue (* 28. Oktober 1966 in Repentigny, Québec) ist ein ehemaliger kanadischer Eishockeyspieler, der im Verlauf seiner aktiven Karriere zwischen 1983 und 2002 unter anderem für die Buffalo Sabres, New York Islanders, Toronto Maple Leafs, Dallas Stars, Tampa Bay Lightning, Phoenix Coyotes, Boston Bruins und Washington Capitals in der National Hockey League auf der Position des linken Flügelstürmers bestritten hat. Seinen größten Karriereerfolg feierte Hogue in Diensten der Dallas Stars mit dem Gewinn des Stanley Cups im Jahr 1999.

Karriere
Benoît Hogue begann seine Karriere als Eishockeyspieler bei den Castors de Saint-Jean, für die er von 1983 bis 1986 in der kanadischen Juniorenliga Ligue de hockey junior majeur du Québec aktiv war. In diesem Zeitraum wurde er im NHL Entry Draft 1985 in der zweiten Runde als insgesamt 35. Spieler von den Buffalo Sabres ausgewählt. Mit deren Farmteam, den Rochester Americans aus der American Hockey League, für die er in seinen ersten beiden Spielzeiten im Franchise der Buffalo Sabres fast ausschließlich spielte, gewann er in der Saison 1986/87 den Calder Cup. In der folgenden Spielzeit gab der Angreifer sein Debüt in der National Hockey League für die Sabres, wobei er in drei Spielen ein Tor erzielte und eine Vorlage gab. Es folgten drei Jahre als Stammspieler in der NHL für Buffalo, ehe er am 25. Oktober 1991 zusammen mit Pierre Turgeon, Uwe Krupp und Dave McLlwain im Tausch für Pat LaFontaine, Randy Hillier, Randy Wood und einem Viertrunden-Wahlrecht im NHL Entry Draft 1992 an die New York Islanders abgegeben wurde.

Bei den New York Islanders lief Hogue drei Jahre lang regelmäßig in der NHL auf, bevor er kurz vor dem Ende der Trade Deadline in der Saison 1994/95 zu den Toronto Maple Leafs transferiert wurde. Diese verließ er nach nicht einmal einem Jahr bereits wieder, um sich den Dallas Stars anzuschließen. Nach drei Jahren verließ der Linksschütze die Texaner 1998 zunächst wieder, ehe er kurz vor Ende der Saison 1998/99 von den Verantwortlichen zurückgeholt wurde. Mit Dallas gewann er in den folgenden Playoffs zum ersten und einzigen Mal den prestigeträchtigen Stanley Cup. Zu diesem Erfolg trug er mit zwei Vorlagen in 14 Playoff-Spielen bei. Die nächste Spielzeit verbrachte der Kanadier bei den Phoenix Coyotes, ehe er für weitere eineinhalb Jahre bei den Dallas Stars unterschrieb. Nachdem er die Saison 2001/02 bei den Boston Bruins und Washington Capitals abgeschlossen hatte, beendete Hogue im Alter von 35 Jahren seine aktive Laufbahn.

Erfolge und Auszeichnungen
 1987 Calder-Cup-Gewinn mit den Rochester Americans
 1999 Stanley-Cup-Gewinn mit den Dallas Stars

Karrierestatistik

Weblinks

Eishockeyspieler (Castors de Saint-Jean)
Eishockeyspieler (Rochester Americans)
Eishockeyspieler (Buffalo Sabres)
Eishockeyspieler (New York Islanders)
Eishockeyspieler (Toronto Maple Leafs)
Eishockeyspieler (Dallas Stars)
Eishockeyspieler (Tampa Bay Lightning)
Eishockeyspieler (Phoenix Coyotes)
Eishockeyspieler (Boston Bruins)
Eishockeyspieler (Washington Capitals)
Stanley-Cup-Sieger
Kanadier
Geboren 1966
Mann

redpajama_set_name: RedPajamaWikipedia


text:
The Delegation of FHC Assessoria Sul Brasil Ltda Visited Dejian International
On 4thSeptember , Mr. Sobral, Chairman of FHC Assessoria Sul Brasil Ltda, and his delegation visited Dejian International for business communication.
At 9 o'clock AM, the two sides held a discussion and exchange at the Conference Room of DejianInternational. Mr. Li Ruiguo, General Manager of Dejian International, Mr. Xu Hongfeng, Deputy GM, Mr. Huang Meng Deputy GM and relevant department managers attended the meeting. During the meeting, Mr. Li Ruiguo gave a brief introduction on the distribution of Dejian's businesssegments and the development of overseas markets. Later, he fully demonstrated the overall capacity and performance of Dejian Groupby watching the promotional videos.
Mr. Sobral highly appreciated the development of Dejian and was full of confidence in the future cooperation between the two sides in the field of housing construction. He emphasized that FHC Assessoria Sul Brasil Ltda's vision for cooperation between the two sides is based on the urban expansion model to build high-end integrated buildings in Brazil. Furthermore, Brazil is rich in rare earths and beef, etc. In the future, the two sides can further expand trade channels and strengthen trade business.
Subsequently, Mr. Jin Haiyang,Chairman of the Board of Dejian Holdings met with the guests in the conference room on 21st floor. Mr. Jin Haiyang firstly expressed his warm welcome to the Brazilian guests and made a sincere gratitude to the delegation for their warm reception during last visit to Brazil. Mr. Sobral said that hewasmissing Mr. Jin since last meeting in Brazil and he was very happy to meet in the beautiful city-Dezhou. Besides, the two sides conducted in-depth exchanges on projects that are expected to cooperate in the future.
In the afternoon, the Brazilian guests visited the Steel Structure Prefabricated Industrial Park of Dejian Construction of Science and Technology Co., the Second Construction Branch'sYou Yan Site, the Group's Prefabricated Concrete Industrial Park, the Tian Heyuan Marketing Center and the Qian WeiResettlement Area project, accompanied by Mr. Ma Zhixin, General Manager of Dejian Group, and Mr.Li Ruiguo, General Manager of Dejian International. Mr. Ma Zhixin gave a detailed introduction to the above-mentioned projects, and emphasized that the development of prefabricated buildings is a development direction consistent with the national strategy. It is characterized by energy conservation, environmental protection, safety and green, and it is a revolution of great significance. Under the tide of the prefabricated revolution, Dejian Group has invested a lot in research and development, and bravely rides the tide. The comprehensive strength of Dejian is second to none in Dezhou. Mr. Sobral expressed his high praise for the great achievements made by the Dejian Group in the field of construction, and highly praised the professional and innovative capabilities of the company."We are full of expectations for mutually beneficial cooperation in the future."He said.
The arrival of the delegation of FHC Assessoria Sul Brasil Ltdahas played an important role in promoting Dejian International's expansion of the South American market.
Dejian International/Wang Qian
President of Standard Chartered Bank's East Africa Region Visited Dejian International
Love warm Angola /Angola Engineering Company donates relief supplies to the local people


text:
Q: mariadb: table not viewable from user root With adminer, user root, in debian busters, a table in a mariadb database isn't read:

Why cannot I see the table UserHistory like the others?
I suppose that the mariadb root user has all the privileges like the linux root user... or am I wrong?

redpajama_set_name: RedPajamaStackExchange


But local expertise requires effort, particularly in persuading employees to declare their own areas of knowledge. Many years ago I was responsible for the employee directory at a UK professional services firm. Random memories include being sworn at by members of marketing, the most senior person in the firm flatly refusing to complete his profile, and (literally) chasing a manager around the office trying to get his photo. Driving adoption was a nightmare.
While enterprise social networks have made finding experts much easier than the static knowledge management systems of the past, the winners and commended entries of this year's Intranet Innovation Awards are still developing new ways to categorize, find and report on experts. These approaches are influenced by external social media and the sharing economy.
The Intranet Innovation Awards, organized by Step Two Designs, are global awards that celebrate innovation and new thinking in the intranet and digital workplace space. Running for the past nine years, this year's global judging panel includes recognized intranet experts consisting of both consultants and practitioners including James Robertson, Susan Hanley, Sam Marshall, Emily Staresina and Jonathan Phillips. Output each year includes a report, with many of the winners also being invited to speak at different conferences.
The practice of endorsing colleagues for their areas of knowledge is commonplace on LinkedIn but has seldom been applied as the primary approach to recording expertise within the enterprise. Now SPIE-ICS has tried this approach, with some success.
SPIE-ICS is an IT services companies based in Switzerland, which designs, builds, implements and manages IT infrastructures. Recording expertise accurately is critical to ensure that the right project teams are assigned to clients. Using a highly inefficient process (emailing CVs) meant that rival companies were sourcing project teams more quickly and winning more work.
A social business program within the firm sought to remedy this issue, producing a new intranet, which allowed individuals to anonymously endorse each other for areas of knowledge. The expertise of employees in different subjects is ranked from "inexperienced" to "expert," all through anonymous endorsements.
A wizard is accessible through different entry points on the intranet such as a knowledge area page or a user profile. The wizard allows people to refer a colleague, declare their own levels of expertise and make further suggestions.
The results have been significant, with 70 percent of staff endorsing others for areas of knowledge. It has also made assigning staff to client projects far more efficient, reducing the time by an average of four days and helping to support growth in the number of successful assignments by 7 percent. It will be interesting to see if this approach is taken up elsewhere.
At SPIE-ICS a wizard helps employees endorse co-workers for areas of knowledge. Screenshot appears courtesy of SPIE-ICS and Step Two.
In the sharing economy, service marketplaces like Freelancer and Upwork help match freelancers looking for work with those seeking help, often with relatively small projects or even single tasks.
Canadian engineering firm BCG Engineering took inspiration from that approach to deliver a lightweight solution to short-term resourcing needs on projects. Often either a specialist skill or an extra pair of hands might be needed at the last moment on a particular client assignment. The firm also had a priority to improve staff utilization rates and ensure all employees had work assigned to them.
Similar to sites like Upwork, BCG Engineering's "Hands Up" app matches staff who have availability with those who are seeking help. Each party declares their need or availability, which is then displayed on the system. To encourage adoption, the app is displayed prominently on the intranet, and the process for logging requests and availability is quick and straightforward.
The Hands Up app displaying "Help Wanted." Screenshot appears courtesy of BCG Engineering and Step Two.
Another challenge for organizations is how to display the collective expertise of teams, departments and even the entire organization. The reasons for doing this are numerous but can include aiding resource planning, identifying skill gaps and internal marketing for divisions.
In this year's Intranet Innovation Awards, organizations with joined-up systems were able to present dynamic rolled-up dashboards of expertise and skills on their intranets. At Robin Partington & Partners, a small, innovative architectural practice with a custom-built digital workplace, a skills map shows which employees have particular expertise in different software used around the firm. This is used to help design learning interventions within the company.
At Mitre Corp., a not-for-profit organization that operates research and development centers sponsored by the US government, there is a long tradition of knowledge management. The organizational structure is also highly complex, with many internal divisions and departments.
To help staff navigate through the complexity, Mitre developed new intranet pages for each internal structure, saying what each department or division does, linking to individual profiles and latest projects and also representing collective expertise and knowledge.
A section of Mitre's organizational pages with a rolled-up view of expertise. Screenshot appears courtesy of Mitre and Step Two.
While the approaches described above have had some tangible benefits such as better client service or use rates, perhaps it is the act of connecting employees together that creates the most benefits. Connecting individuals creates stronger networks and helps build a knowledge-sharing culture. It also has the potential to create opportunities, enhance individual job satisfaction and build a broader sense of community.
It is quite possible these less tangible benefits will be the most important in the long run. The act of finding is key — but the actual act of connecting delivers the real value.


text:
\section{Introduction}
\label{sec:intro}
\input{files/intro}
\input{files/algorithm}

\section{Preliminaries and Related Work}\label{sect:related}
\input{files/related}

\section{Theoretical Justification}\label{sect::theory}
\input{files/theory}

\section{Empirical Evaluation}\label{sect::exp_in_d}
\input{files/in_distribution}

\input{files/mc_dropout_tables}
\input{files/ood}

\input{files/stat}

\input{files/mcdropout}

\input{files/conclusion}

{\small
\bibliographystyle{ieee_fullname}

\subsection{Experiment Setup}
\paragraph{Datasets and Architectures.}
In our experiments, we follow the Uncertainty Baselines Benchmark~\cite{nado2021uncertainty} and focus our analysis on CIFAR10/100 \cite{Krizhevsky09learningmultiple} and ImageNet-ILSVRC2012 \cite{deng2009imagenet}  with several corruption types added during inference of various severity levels. We use five architectures: VGG16 and VGG19 \cite{simonyan2014very}, ResNet18 and ResNet50 \cite{He2016}, and Wide-ResNet-28-10 \cite{zagoruyko2016wide} to examine the impact of both architecture size and residual links in convolutional neural networks. Examples of corruption types include Gaussian noise, JPEG compression, spattering, and blurring, among others. See \cite{nado2021uncertainty} for details.

\paragraph{Training Setup.}To calibrate neural networks using either temperature scaling or LATES, we split the data into three parts: (1) \emph{training}, 90\% of standard training split, (2) \emph{hold-out}, 10\% of standard training split, and (3) \emph{test}. The original architecture and probes are trained on the training split while the calibration rule is trained on the hold-out data.

We train the baseline model with $\ell_{2}$ regularization of $10^{-4}$ for 200 epochs on CIFAR10/100, with a batch size of 128 using SGD with learning rate 0.1 and momentum 0.9. We decay the learning rate using cosine scheduling \cite{loshchilov2016sgdr}. In ImageNet-ILSVRC2012, we train for 90 epochs in addition to a 5-epoch warm-up phase using a batch size of 256 with initial learning rate of 0.1 with $10\times$ decay at 30\%, 60\%, and 90\% of the training steps. On the input pipeline, we standardize the input to have values in the unit interval $[0,\,1]$ and use only right-left random flipping as data augmentation. We train on NVIDIA Tesla V100 GPUs for CIFAR10/100 and on TPUs for ImageNet-ILSVRC2012.

In LATES, we flatten the intermediate activations and reduce dimensionality using average pooling. We place a probe after every convolutional block in ResNet and Wide-ResNet architectures, and after every convolutional layer in VGG16/19. This results in 8 probes in ResNet18, 16 probes in ResNet50, 12 probes in Wide-ResNet-28-10, 14 probes in VGG16, and 17 probes in VGG19. We train each probe with a learning rate of 0.01 and momentum 0.9 with $2\times$ decay after every 10 epochs. All probes are trained together (in parallel) for 50 epochs,  although we observe that they converge much faster. Finally, we train the aggregator model for 50 epochs with a fixed learning rate of 0.005, using the hold-out part of the dataset. We repeat all experiments five times and report averages.

\subsection{In-Distribution Data}
For in-distribution CIFAR10/100, experimental results are summarized in Figure \ref{fig:cifarind}. We observe a consistent improvement in LATES over temperature scaling across all metrics. In CIFAR10, while the accuracy does not improve, LATES improves calibration. In addition, the advantage of LATES compared to temperature scaling becomes bigger  in the low-data regime, as demonstrated in Figure \ref{fig:lowdata}.

In ImageNet-ILSVRC2012, we compare LATES against temperature scaling using RESNET50 to evaluate whether the improvement of LATES extends to much bigger datasets. As shown in Table \ref{table:ind-imagenet}, we observe a significant improvement in calibration in LATES (e.g. ECE is reduced from 0.06 to 0.023 and NLL is reduced from 1.16 to 1.04). In addition, LATES boosts accuracy as well.

\input{files/imagenetid}

\begin{figure}
    \centering
    \includegraphics[width=\columnwidth]{figures/lowdata.pdf}
    \caption{A summary of the relative gain of LATES compared to temperature scaling when the model is trained on 25\%, 50\%, and 90\% of the standard training splits while the temperatures (in both temperature scaling and LATES) are trained on the same 10\% hold-out dataset. Here, ``relative gain'' is the percentage-wise improvement in the metric. Negative values indicate a drop in performance compared to temperature scaling. In general, the advantage of LATES tends to increase for small data sizes.}
    \label{fig:lowdata}
\end{figure}

Nevertheless, only a single temperature parameter is trained in temperature scaling. By contrast, LATES trains multiple temperatures  (one for each probe). We use this observation to evaluate if temperature scaling can yield better results when more data is used when training the original model. We vary the hold-out data split to make up $(2\%, 4\%, 6\%, 8\%, 10\%)$ of the standard training split in both CIFAR10 and CIFAR100 and compare performance across all metrics.  We do not observe any improvement in temperature scaling in the latter case. In fact, calibration tends to get \emph{worse} as expected, since the temperature parameter is now trained on less data. For example, a reduction in the size of the hold-out dataset increases the ECE in temperature scaling in about 65\% of the cases. On the other hand, LATES improves \emph{both} accuracy and calibration.
\subsection{Out-of-Distribution Data}
Next, we evaluate LATES in the OOD setting, where various types of corruptions are added to the test data. For that, we follow the corruption types and five severity levels available in the Uncertainty Baselines Benchmark~\cite{nado2021uncertainty}. Figure \ref{fig:ood_curves} summarizes the results. We observe, again, an improvement in LATES compared to temperature scaling, particularly for large distribution shifts (i.e. when the corruption severity level is large). In particular, the improvement in LATES with respect to AUC is quite significant in all three datasets.

\subsection{Complementing Monte Carlo Dropout}
LATES can also be combined with other existing techniques to improve their performance further. We illustrate this using the popular Monte Carlo Dropout \cite{gal2016dropout}, in which the method matches with state-of-the-art results as reported by the Uncertainty Baselines Benchmark~\cite{nado2021uncertainty}.

In Monte Carlo dropout, multiple predictions are generated for the same instance $\xb\in\mathcal{X}$ by adding dropout layers to the model and using them at \emph{both} training and test time. Then, the model's uncertainty can be estimated by averaging the predictions.
In our experiments, we use the implementation of the Monte Carlo dropout available at the Uncertainty Baselines Benchmark~\cite{nado2021uncertainty}. We use the same implementation details and hyper-parameters suggested by the benchmark, which uses the Wide-ResNet-28-10 architecture, and combine it with LATES. We also test on different values of the dropout rate. Final results are in Table~\ref{table:mc-cifar}.

The state-of-the-art results on CIFAR10 reported in the Uncertainty Baseline Benchmark uses the Spectral Normalized Neural Gaussian Processes (SNGP)~\cite{liu2020simple} when combined with Augmentation Mixup (AugMix)~\cite{hendrycks2019augmix} and achieves ECE of 0.0045 at 96\% accuracy. We achieve the same ECE at 95.7\% accuracy with very limited data augmentation (only left/right flipping). On CIFAR100 we achieve near SOTA ECE with much less parameters compared to the best methods that use an ensemble of SNGP models combined with Monte Carlo Dropout. However when comparing with the same number of parameters, we achieve less ECE for the same accuracy. Specifically, our ECE in CIFAR100 of 0.016 with a 35M-parameter model is below the best ECE of 0.017 reported in the benchmark that uses a comparable model size of 35M parameters \cite{nado2021uncertainty}. The accuracy is 79\% in both cases.

\subsection{Statistical Analysis}\label{sect:stat}
To verify statistical significance, we use  the non-parametric Wilcoxon signed rank test for comparing  LATES with temperature scaling \cite{demvsar2006statistical}. We use all corruption types at all severity levels across all architectures and random seeds.
Table \ref{table:stat} summarizes the main results. We observe that the improvement in LATES compared to temperature scaling is statistically significant at the 99.9\% confidence level in all metrics and datasets; nearly all $p$ values are below $10^{-9}$. The only exception is accuracy in ImageNet, in which there is no statistically significant difference. However, as shown in Figure \ref{fig:ood_scatter}, LATES improves AUC in ImageNet significantly under distribution shift. In Table \ref{table:anova}, we provide a different analysis of statistical significance using the Analysis of Variance (ANOVA).

\begin{table}
\scriptsize

\caption{A summary of $p$-values using the non-parametric Wilcoxon signed rank test for comparing  LATES with temperature scaling. All improvements in LATES are statistically significant with $p$-values less than $10^{-9}$, with the exception of improving accuracy in ImageNet in which there is no statistically significant difference. Since the $p$ values are quite small, statistical significance remains valid even after correcting for multiple hypothesis testing using Holm's step down procedure \cite{demvsar2006statistical}.}\vspace{1mm}\label{table:stat}
\begin{tabularx}{\columnwidth}{@{}lXXXXX@{\hspace{0.1em}}}
\toprule
Dataset
& ECE & NLL & Brier & ACC & AUC
    \\ \midrule
 CIFAR100 &  $<10^{-9}$
    & $<10^{-9}$ & $<10^{-9}$ &$<10^{-9}$ & $<10^{-9}$  \\
 CIFAR10 &  $<10^{-9}$
    & $<10^{-9}$ & $<10^{-9}$ &$<10^{-9}$ & $<10^{-9}$  \\
 ImageNet &  $<10^{-9}$
    & $<10^{-9}$ & $<10^{-9}$ &$0.18$ & $<10^{-9}$  \\ \bottomrule
\end{tabularx}
\end{table}
\section{Conclusion}
In this paper, we introduce layer-stack temperature scaling (LATES); a simple, effective technique to improve both the calibration and accuracy of deep neural networks. It is inspired by several lines of work, which relate example difficulty to the activations at the intermediate layers of the neural network. We motivate LATES theoretically and demonstrate that it leads to a significant improvement over temperature scaling both in- and out-of-distribution, especially in the low-data regime. In particular, LATES provides a significant improvement in AUC under large distribution shifts. We support these conclusions by a comprehensive statistical analysis. Finally, we demonstrate that LATES can match state-of-the-art results on CIFAR10 and CIFAR100 when combined with Monte Carlo Dropout.

redpajama_set_name: RedPajamaArXiv


Safari lodges in Tanzania located at the areas in the heart of the Serengeti, where all game safaris drive, balloon safaris, and catching planes take place every day of the year. We have a selection of safari lodges in Tanzania which allow you to see animals from the windows of your rooms. The Safari lodges we offer correspond with those of the western deluxe hotels. There are Lodge chains such as Serena hotels and Sopa lodges and a few other privately owned safari lodges and tented camps keeping a very high standard of services. Reasonable safari lodges that we use, such as the Eileen's Tree and Umali Lodges are of a good standard for those who do not wish to spend the nights in luxury lodges and hotels.
Safari Lodges and camps of this standard are situated inside the parks and reserves or at the outskirts and facilitate most safari itineraries. The safari vehicles we use on tour are safari land cruisers with popup open roof hatched for easy animal sightings.
How Safari lodges in Tanzania and hotels are?
Each lodge has a dining lounge where you can join with other visitors before dinner and have a glass of wine or beers to refresh yourself while evaluating the ending day, this time is when you can ask your safari driver any question you may have after a long day. Exchange with other guests before you stay down to for the prepared dinner. All lodges offer many kinds of drinks including alcoholic drinks such as beers, wines and champagne, sprits, and brands, Liqueur, Rum, Gin, Vodka and Whiskey etc and non-alcoholic mixers such as water, juice, sparkling beverages, coffee, chocolate etc.
Dinner is offered either on delicious 3-course menu basis or buffet with a great selection of variety foot to choose from. The lodges cater for any types of customized menu and can accommodate any kind of diet requirement including vegetarian and religious menu. Safari lodges in Tanzania. Safari lodges in Tanzania.


The power of the National Rifle Association's 501(c)(4) political apparatus was well in evidence this week as voters in Colorado recalled two state senators, including the Colorado senate president, because of their support for stricter gun control laws. The gun advocates' campaign theme was "ready, aim, fired." While the NRA wasn't the only player behind the recalls, its donation of $360,000 was significant.
Senate Democrats didn't do themselves any favors when they introduced seven gun control bills in this legislative session and scheduled seven hearings on them in one day, leaving scores of people unable to testify. Given the Democrats' control of the senate, that ploy looked heavy-handed. With the recalls of Giron and Senate President John Morse, the Democrats' margin in the state senate has been reduced to only one.
Colorado has been an epicenter of gun violence, with massacres at a movie theater in Aurora and at Columbine High School. Despite a significant financial commitment from New York City's billionaire mayor Michael Bloomberg, Eisenberg is suggesting that nonprofits of all stripes can and should be engaged in grassroots mobilization for gun control, in his view, a more important sector focus than its effort against potential reductions in the deductibility of charitable gifts by wealthy taxpayers.
The other issue is about democracy. At one time, recalls were largely for politicians who engaged in corrupt activities while in office. This political device, once rarely used, is now increasingly the norm. Once someone is elected, the recall planning starts. For nonprofits concerned about democracy, recalls are an issue. Typically, a recall is organized by a narrow special interest group, empowering groups like the National Rifle Association and Americans for Prosperity that can target a flood of money and efforts into isolated local or state elections. Increasingly, U.S. elections are becoming the province of special interest groups, aiming for a narrower electoral scope. Both parties do it; witness the attempted recall of Wisconsin's Governor Scott Walker and the successful recall of California ex-governor Gray Davis.


Product categories of High Speed Door, we are specialized manufacturers from China, High Speed Door, PVC High Speed Door suppliers/factory, wholesale high-quality products of Aluminum High Speed Door R & D and manufacturing, we have the perfect after-sales service and technical support. Look forward to your cooperation!
High speed shutter door is a rapid operating, anti-crash shutter door for indoor application . The most advantage of this door is that the opening/closing speed can reach to 0.6-1.8m/s, really fast action a lot than tranditional rollling shutter door. short opening and closing times reduce cooling loss, avoid airflow and enable a smooth operating procedure. They can also be designed in larger dimensions for the mining and aircraft industries.
High Speed Door can be easily installed, economical,quiet and efficient with electromechanical drive.
This door quickly though in/out open gate, ideal for warehouses,factories, hangars use, widths can be from 2m to 20 meters.
The material of this door are variety: PVC curtain to keep the insdie clean, heavy duty aluminum door with wind-resisitant function can wrok in heavy windy weather, and also the freezer door can be used in cold warehouse or somewhere like that.
Including models are:PVC High Speed Door, Aluminum Spiral High Speed Door, Self-Recovery repair door, Cold Storage Room Fast Door.