Editorial overview: Systems biology-the intersection of experiments and computation, underpinning biotechnology.

Curr Opin Biotechnol. 2016 May 9;

Authors: Styczynski MP, Theis FJ

PMID: 27173375 [PubMed - as supplied by publisher]

MicroRNAs in the Evaluation and Potential Treatment of Liver Diseases.

J Clin Med. 2016;5(5)

Authors: Mahgoub A, Steer CJ

Abstract
Acute and chronic liver disease continue to result in significant morbidity and mortality of patients, along with increasing burden on their families, society and the health care system. This in part is due to increased incidence of liver disease associated factors such as metabolic syndrome; improved survival of patients with chronic predisposing conditions such as HIV; as well as advances in the field of transplantation and associated care leading to improved survival. The fact that one disease can result in different manifestations and outcomes highlights the need for improved understanding of not just genetic phenomenon predisposing to a condition, but additionally the role of epigenetic and environmental factors leading to the phenotype of the disease. It is not surprising that providers continue to face daily challenges pertaining to diagnostic accuracy, prognostication of disease severity, progression, and response to therapies. A number of these challenges can be addressed by incorporating a personalized approach of management to the current paradigm of care. Recent advances in the fields of molecular biology and genetics have paved the way to more accurate, individualized and precise approach to caring for liver disease. The study of microRNAs and their role in both healthy and diseased livers is one example of such advances. As these small, non-coding RNAs work on fine-tuning of cellular activities and organ function in a dynamic and precise fashion, they provide us a golden opportunity to advance the field of hepatology. The study of microRNAs in liver disease promises tremendous improvement in hepatology and is likely to lay the foundation towards a personalized approach in liver disease.

PMID: 27171116 [PubMed]

Brain Radiation Information Data Exchange (BRIDE): integration of experimental data from low-dose ionising radiation research for pathway discovery.

BMC Bioinformatics. 2016;17(1):212

Authors: Karapiperis C, Kempf SJ, Quintens R, Azimzadeh O, Vidal VL, Pazzaglia S, Bazyka D, Mastroberardino PG, Scouras ZG, Tapio S, Benotmane MA, Ouzounis CA

Abstract
BACKGROUND: The underlying molecular processes representing stress responses to low-dose ionising radiation (LDIR) in mammals are just beginning to be understood. In particular, LDIR effects on the brain and their possible association with neurodegenerative disease are currently being explored using omics technologies.
RESULTS: We describe a light-weight approach for the storage, analysis and distribution of relevant LDIR omics datasets. The data integration platform, called BRIDE, contains information from the literature as well as experimental information from transcriptomics and proteomics studies. It deploys a hybrid, distributed solution using both local storage and cloud technology.
CONCLUSIONS: BRIDE can act as a knowledge broker for LDIR researchers, to facilitate molecular research on the systems biology of LDIR response in mammals. Its flexible design can capture a range of experimental information for genomics, epigenomics, transcriptomics, and proteomics. The data collection is available at: <bride.azurewebsites.net>.

PMID: 27170263 [PubMed - in process]

Molecular stripping in the NF-κB/IκB/DNA genetic regulatory network.

Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):110-5

Authors: Potoyan DA, Zheng W, Komives EA, Wolynes PG

Abstract
Genetic switches based on the [Formula: see text] system are master regulators of an array of cellular responses. Recent kinetic experiments have shown that [Formula: see text] can actively remove NF-κB bound to its genetic sites via a process called "molecular stripping." This allows the [Formula: see text] switch to function under kinetic control rather than the thermodynamic control contemplated in the traditional models of gene switches. Using molecular dynamics simulations of coarse-grained predictive energy landscape models for the constituent proteins by themselves and interacting with the DNA we explore the functional motions of the transcription factor [Formula: see text] and its various binary and ternary complexes with DNA and the inhibitor IκB. These studies show that the function of the [Formula: see text] genetic switch is realized via an allosteric mechanism. Molecular stripping occurs through the activation of a domain twist mode by the binding of [Formula: see text] that occurs through conformational selection. Free energy calculations for DNA binding show that the binding of [Formula: see text] not only results in a significant decrease of the affinity of the transcription factor for the DNA but also kinetically speeds DNA release. Projections of the free energy onto various reaction coordinates reveal the structural details of the stripping pathways.

PMID: 26699500 [PubMed - indexed for MEDLINE]

Generating Systems Biology Markup Language Models from the Synthetic Biology Open Language.

ACS Synth Biol. 2015 Aug 21;4(8):873-9

Authors: Roehner N, Zhang Z, Nguyen T, Myers CJ

Abstract
In the context of synthetic biology, model generation is the automated process of constructing biochemical models based on genetic designs. This paper discusses the use cases for model generation in genetic design automation (GDA) software tools and introduces the foundational concepts of standards and model annotation that make this process useful. Finally, this paper presents an implementation of model generation in the GDA software tool iBioSim and provides an example of generating a Systems Biology Markup Language (SBML) model from a design of a 4-input AND sensor written in the Synthetic Biology Open Language (SBOL).

PMID: 25822671 [PubMed - indexed for MEDLINE]

Quo vadis? The challenges of recombinant protein folding and secretion in Pichia pastoris.

Appl Microbiol Biotechnol. 2015 Apr;99(7):2925-38

Authors: Puxbaum V, Mattanovich D, Gasser B

Abstract
The development of Pichia pastoris as a production platform for recombinant proteins has been a remarkable success story over the last three decades. Stable cheap production processes and the good protein secretion abilities were pacemakers of this development. However, limitations of protein folding, glycosylation or secretion have been identified quite early on. With the availability of genome sequences and the development of systems biology characterization in the last 5 years, remarkable success in strain improvement was achieved. Here, we focus on recent developments of characterization and improvement of P. pastoris production strains regarding protein folding, intracellular trafficking, glycosylation and proteolytic degradation.

PMID: 25722021 [PubMed - indexed for MEDLINE]

The proteomic response of cheliped myofibril tissue in the eurythermal porcelain crab Petrolisthes cinctipes to heat shock following acclimation to daily temperature fluctuations.

J Exp Biol. 2015 Feb 1;218(Pt 3):388-403

Authors: Garland MA, Stillman JH, Tomanek L

Abstract
The porcelain crab Petrolisthes cinctipes lives under rocks and in mussel beds in the mid-intertidal zone where it experiences immersion during high tide and saturating humid conditions in air during low tide, which can increase habitat temperature by up to 20°C. To identify the biochemical changes affected by increasing temperature fluctuations and subsequent heat shock, we acclimated P. cinctipes for 30 days to one of three temperature regimes: (1) constant 10°C, (2) daily temperature fluctuations between 10 and 20°C (5 h up-ramp to 20°C, 1 h down-ramp to 10°C) and (3) 10-30°C (up-ramp to 30°C). After acclimation, animals were exposed to either 10°C or a 30°C heat shock to analyze the proteomic changes in claw muscle tissue. Following acclimation to 10-30°C (measured at 10°C), enolase and ATP synthase increased in abundance. Following heat shock, isoforms of arginine kinase and glycolytic enzymes such as aldolase, triose phosphate isomerase and glyceraldehyde 3-phosphate dehydrogenase increased across all acclimation regimes. Full-length isoforms of hemocyanin increased abundance following acclimation to 10-30°C, but hemocyanin fragments increased after heat shock following constant 10°C and fluctuating 10-20°C, possibly playing a role as antimicrobial peptides. Following constant 10°C and fluctuating 10-20°C, paramyosin and myosin heavy chain type-B increased in abundance, respectively, whereas myosin light and heavy chain decreased with heat shock. Actin-binding proteins, which stabilize actin filaments (filamin and tropomyosin), increased during heat shock following 10-30°C; however, actin severing and depolymerization proteins (gelsolin and cofilin) increased during heat shock following 10-20°C, possibly promoting muscle fiber restructuring. RAF kinase inhibitor protein and prostaglandin reductase increased during heat shock following constant 10°C and fluctuating 10-20°C, possibly inhibiting an immune response during heat shock. The results suggest that ATP supply, muscle fiber restructuring and immune responses are all affected by temperature fluctuations and subsequent acute heat shock in muscle tissue. Furthermore, although heat shock after acclimation to constant 10°C and fluctuating 10-30°C showed the greatest effects on the proteome, moderately fluctuating temperatures (10-20°C) broadened the temperature range over which claw muscle was able to respond to an acute heat shock with limited changes in the muscle proteome.

PMID: 25653421 [PubMed - indexed for MEDLINE]

Systems Medicine approaches to improving understanding, treatment, and clinical management of Neuroendocrine Prostate Cancer.

Curr Pharm Des. 2016 May 13;

Authors: Yadav KK, Khader S, Readhead B, Yadav SS, Li L, Kasarksis A, Tewari AK, Dudley JT

Abstract
BACKGROUND: Prostate cancer is the most commonly diagnosed cancer in men. More than 200,000 new cases are added each year in the US, translating to a lifetime risk of 1 in 7 men. Neuroendocrine prostate cancer (NEPC) is an aggressive and treatment-resistant form of prostate cancer. A subset of patients treated with aggressive androgen deprivation therapy (ADT) present with NEPC. Patients with NEPC have a reduced 5-year overall survival rate of 12.6%. Knowledge integration from genetic, epigenetic, biochemical and therapeutic studies suggests NEPC as an indicative mechanism of resistance development to various forms of therapy.
METHODS: In this perspective, we discuss various experimental, computational and risk prediction methodologies that can be utilized to identify novel therapies against NEPC. We reviewed literature from PubMed using key terms, and computationally analyzed publicly available genomics data to present different possibilities for developing systems medicine based therapeutic and curative models to understand and target prostate cancer and specifically NEPC.
RESULTS: Our study includes gene-set analyses, network analyses, genomics and phenomics aided drug development, microRNA and peptide-based therapeutics, pathway modeling, drug repositioning and cancer immunotherapies. We also discuss the application of cancer risk estimations and mining of electronic medical records to develop personalized risk predictions models for NEPC. Preemptive stratification of patients who are at risk of evolving NEPC phenotypes using predictive models could also help to design and deliver better therapies.
CONCLUSIONS: Collectively, understanding the mechanism of NEPC evolution from prostate cancer using systems biology approaches would help in devising better treatment strategies and is critical and unmet clinical need.

PMID: 27174811 [PubMed - as supplied by publisher]

Toward Repositioning Niclosamide for Antivirulence Therapy of Pseudomonas aeruginosa Lung Infections: Development of Inhalable Formulations through Nanosuspension Technology.

Mol Pharm. 2015 Aug 3;12(8):2604-17

Authors: Costabile G, d'Angelo I, Rampioni G, Bondì R, Pompili B, Ascenzioni F, Mitidieri E, d'Emmanuele di Villa Bianca R, Sorrentino R, Miro A, Quaglia F, Imperi F, Leoni L, Ungaro F

Abstract
Inhaled antivirulence drugs are currently considered a promising therapeutic option to treat Pseudomonas aeruginosa lung infections in cystic fibrosis (CF). We have recently shown that the anthelmintic drug niclosamide (NCL) has strong quorum sensing (QS) inhibiting activity against P. aeruginosa and could be repurposed as an antivirulence drug. In this work, we developed dry powders containing NCL nanoparticles that can be reconstituted in saline solution to produce inhalable nanosuspensions. NCL nanoparticles were produced by high-pressure homogenization (HPH) using polysorbate 20 or polysorbate 80 as stabilizers. After 20 cycles of HPH, all formulations showed similar properties in the form of needle-shape nanocrystals with a hydrodynamic diameter of approximately 450 nm and a zeta potential of -20 mV. Nanosuspensions stabilized with polysorbate 80 at 10% w/w to NCL (T80_10) showed an optimal solubility profile in simulated interstitial lung fluid. T80_10 was successfully dried into mannitol-based dry powder by spray drying. Dry powder (T80_10 DP) was reconstituted in saline solution and showed optimal in vitro aerosol performance. Both T80_10 and T80_10 DP were able to inhibit P. aeruginosa QS at NCL concentrations of 2.5-10 μM. NCL, and these formulations did not significantly affect the viability of CF bronchial epithelial cells in vitro at microbiologically active concentrations (i.e., ≤10 μM). In vivo acute toxicity studies in rats confirmed no observable toxicity of the NCL T80_10 DP formulation upon intratracheal administration at a concentration 100-fold higher than the anti-QS activity concentration. These preliminary results suggest that NCL repurposed in the form of inhalable nanosuspensions has great potential for the local treatment of P. aeruginosa lung infections as in the case of CF patients.

PMID: 25974285 [PubMed - indexed for MEDLINE]

BelSmile: a biomedical semantic role labeling approach for extracting biological expression language from text.

Database (Oxford). 2016;2016

Authors: Lai PT, Lo YY, Huang MS, Hsiao YC, Tsai RT

Abstract
Biological expression language (BEL) is one of the most popular languages to represent the causal and correlative relationships among biological events. Automatically extracting and representing biomedical events using BEL can help biologists quickly survey and understand relevant literature. Recently, many researchers have shown interest in biomedical event extraction. However, the task is still a challenge for current systems because of the complexity of integrating different information extraction tasks such as named entity recognition (NER), named entity normalization (NEN) and relation extraction into a single system. In this study, we introduce our BelSmile system, which uses a semantic-role-labeling (SRL)-based approach to extract the NEs and events for BEL statements. BelSmile combines our previous NER, NEN and SRL systems. We evaluate BelSmile using the BioCreative V BEL task dataset. Our system achieved an F-score of 27.8%, ∼7% higher than the top BioCreative V system. The three main contributions of this study are (i) an effective pipeline approach to extract BEL statements, and (ii) a syntactic-based labeler to extract subject-verb-object tuples. We also implement a web-based version of BelSmile (iii) that is publicly available at iisrserv.csie.ncu.edu.tw/belsmile.

PMID: 27173520 [PubMed - as supplied by publisher]

29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/05/14

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids.

Physiol Behav. 2015 Oct 15;150:38-42

Authors: Gutierrez-Aguilar R, Thompson A, Marchand N, Dumont P, Woods SC, de Launoit Y, Seeley RJ, Ulrich-Lai YM

Abstract
The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis.

PMID: 25813907 [PubMed - indexed for MEDLINE]

Filtering large-scale event collections using a combination of supervised and unsupervised learning for event trigger classification.

J Biomed Semantics. 2016;7:27

Authors: Mehryary F, Kaewphan S, Hakala K, Ginter F

Abstract
BACKGROUND: Biomedical event extraction is one of the key tasks in biomedical text mining, supporting various applications such as database curation and hypothesis generation. Several systems, some of which have been applied at a large scale, have been introduced to solve this task. Past studies have shown that the identification of the phrases describing biological processes, also known as trigger detection, is a crucial part of event extraction, and notable overall performance gains can be obtained by solely focusing on this sub-task. In this paper we propose a novel approach for filtering falsely identified triggers from large-scale event databases, thus improving the quality of knowledge extraction.
METHODS: Our method relies on state-of-the-art word embeddings, event statistics gathered from the whole biomedical literature, and both supervised and unsupervised machine learning techniques. We focus on EVEX, an event database covering the whole PubMed and PubMed Central Open Access literature containing more than 40 million extracted events. The top most frequent EVEX trigger words are hierarchically clustered, and the resulting cluster tree is pruned to identify words that can never act as triggers regardless of their context. For rarely occurring trigger words we introduce a supervised approach trained on the combination of trigger word classification produced by the unsupervised clustering method and manual annotation.
RESULTS: The method is evaluated on the official test set of BioNLP Shared Task on Event Extraction. The evaluation shows that the method can be used to improve the performance of the state-of-the-art event extraction systems. This successful effort also translates into removing 1,338,075 of potentially incorrect events from EVEX, thus greatly improving the quality of the data. The method is not solely bound to the EVEX resource and can be thus used to improve the quality of any event extraction system or database.
AVAILABILITY: The data and source code for this work are available at: http://bionlp-www.utu.fi/trigger-clustering/.

PMID: 27175227 [PubMed - as supplied by publisher]

Mining chemical patents with an ensemble of open systems.

Database (Oxford). 2016;2016

Authors: Leaman R, Wei CH, Zou C, Lu Z

Abstract
The significant amount of medicinal chemistry information contained in patents makes them an attractive target for text mining. In this manuscript, we describe systems for named entity recognition (NER) of chemicals and genes/proteins in patents, using the CEMP (for chemicals) and GPRO (for genes/proteins) corpora provided by the CHEMDNER task at BioCreative V. Our chemical NER system is an ensemble of five open systems, including both versions of tmChem, our previous work on chemical NER. Their output is combined using a machine learning classification approach. Our chemical NER system obtained 0.8752 precision and 0.9129 recall, for 0.8937 f-score on the CEMP task. Our gene/protein NER system is an extension of our previous work for gene and protein NER, GNormPlus. This system obtained a performance of 0.8143 precision and 0.8141 recall, for 0.8137 f-score on the GPRO task. Both systems achieved the highest performance in their respective tasks at BioCreative V. We conclude that an ensemble of independently-created open systems is sufficiently diverse to significantly improve performance over any individual system, even when they use a similar approach.Database URL: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/tmTools/.

PMID: 27173521 [PubMed - as supplied by publisher]

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("orphan disease" OR "rare disease" OR "orphan diseases" OR "rare diseases")

These pubmed results were generated on 2016/05/12

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Flipping Content to Improve Student Examination Performance in a Pharmacogenomics Course.

Am J Pharm Educ. 2015 Sep 25;79(7):103

Authors: Munson A, Pierce R

Abstract
Objective. To develop, implement, and evaluate active learning in a flipped class to improve student examination performance in the genetic foundations of pharmacogenomics. Design. The flipped classroom model was adopted in which a guided-inquiry learning activity was developed and conducted to complement recorded, previously viewed didactic lectures. The activity was constructed to focus on critical thinking and application of core principles of genetic crosses and pedigree analysis. A combination of independent work and active discussion with volunteer and guided student response provided student-facilitator interaction. Assessment. Student learning was evaluated by comparing pretest and posttest formative assessment results and by the comparison of prior years' examination performance on a subset of content for which no flipped classroom learning activities occurred. There was no significant difference between examination scores between the flipped classroom and previous approaches. An item-by-item analysis of the content reflected a significant change in performance on questions addressed in the flipped classroom exercise. Conclusion. The flipped class instructional model in this project included active-learning activities and formative assessments that provided students spaced and repetitive curricular engagement. The intervention transformed the classroom interactions of faculty members and students and contributed to improved student examination performance.

PMID: 27168616 [PubMed - as supplied by publisher]

Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population.

Pharmacogenomics J. 2016 May 10;

Authors: van der Weide K, Loovers H, Pondman K, Bogers J, van der Straaten T, Langemeijer E, Cohen D, Commandeur J, van der Weide J

Abstract
Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P=0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P=0.05). In patients developing neutropenia, ABCB1 3435TT and homozygosity for GSTT1(null) (glutathione-S-transferase; conjugates reactive clozapine metabolites into glutathione) were more frequent compared with control (34% versus 20%, P=0.05 and 31% versus 14%, P=0.03), whereas GSTM1(null) was less frequent in these patients (31% versus 52%, P=0.03). To investigate whether combinations of the identified genetic risk factors have a higher predictive value, should be confirmed in a larger case-control study.The Pharmacogenomics Journal advance online publication, 10 May 2016; doi:10.1038/tpj.2016.32.

PMID: 27168101 [PubMed - as supplied by publisher]

Gene-gene interactions in the NAMPT pathway, plasma visfatin/NAMPT levels, and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy.

Pharmacogenomics J. 2016 May 10;

Authors: Luizon MR, Palei AC, Belo VA, Amaral LM, Lacchini R, Duarte G, Cavalli RC, Sandrim VC, Tanus-Santos JE

Abstract
Nicotinamide phosphorybosil transferase (NAMPT) polymorphisms affect visfatin/NAMPT levels and may affect the responsiveness to therapy in hypertensive disorders of pregnancy. We examined whether NAMPT polymorphisms (rs1319501 T>C and rs3801266 A>G), or haplotypes, and gene-gene interactions in the NAMPT pathway affect plasma visfatin/NAMPT levels and the response to antihypertensive therapy in 205 patients with preeclampsia (PE) and 174 patients with gestational hypertension. We also studied 207 healthy pregnant controls. Plasma visfatin/NAMPT levels were measured by ELISA. Non-responsive PE patients with the TC+CC genotypes for the rs1319501 T>C, and with the AG+GG genotypes for the rs3801266 A>G polymorphism had lower and higher visfatin/NAMPT levels, respectively. The 'C, A' haplotype was associated with response to antihypertensive therapy, and with lower visfatin/NAMPT levels in PE. Interactions among NAMPT, TIMP-1 and MMP-2 genotypes were associated with PE and with lack of response to antihypertensive therapy in PE. Our results suggest that NAMPT polymorphisms affect plasma visfatin/NAMPT levels in nonresponsive PE patients, and that gene-gene interactions in the NAMPT pathway not only promote PE but also decrease the response to antihypertensive therapy in PE.The Pharmacogenomics Journal advance online publication, 10 May 2016; doi:10.1038/tpj.2016.35.

PMID: 27168100 [PubMed - as supplied by publisher]

Prevalence and implications of cytochrome P450 substrates in Massachusetts hospital discharges.

Pharmacogenomics J. 2016 May 10;

Authors: McCoy TH, Castro VM, Cagan A, Roberson AM, Perlis RH

Abstract
The cytochrome P450 (CYP450) system of drug-metabolizing enzymes may contribute to individual variation in drug response. We examined prevalence of CYP450 substrates at hospital discharge for patients in two cohorts: insurance claims of Massachusetts residents and the medical records of two academic medical centers. The claims cohort included 47 473 individuals (38.2%) treated with at least one CYP450 2D6, 2C19, 3A4 or 1A2 substrate. The electronic medical records cohort included 45 905 individuals (57.4%) treated with at least one substrate. In adjusted models, substrates of CYP450 2D6 and 2C19 were associated with greater risk for 90-day readmission in both cohorts (odds ratios of 1.104 and 1.128 (P<0.001), respectively). Presence of any CYP450 substrate was associated with increased monthly medical costs (+$397, P<0.003). These analyses of more than 300 000 admissions using two different cohorts and data types indicate that CYP450 substrates are associated with greater readmission rates and greater health-care cost.The Pharmacogenomics Journal advance online publication, 10 May 2016; doi:10.1038/tpj.2016.24.

PMID: 27168099 [PubMed - as supplied by publisher]

Assessment of pharmacogenetic tests: presenting measures of clinical validity and potential population impact in association studies.

Pharmacogenomics J. 2016 May 10;

Authors: Tonk EC, Gurwitz D, Maitland-van der Zee AH, Janssens AC

Abstract
The progressing discovery of genetic variants associated with drug-related adverse events has raised expectations for pharmacogenetic tests to improve drug efficacy and safety. To further the use of pharmacogenetics in health care, tests with sufficient potential to improve efficacy and safety, as reflected by good clinical validity and population impact, need to be identified. The potential benefit of pharmacogenetic tests is often concluded from the strength of the association between the variant and the adverse event; measures of clinical validity are generally not reported. This paper describes measures of clinical validity and potential population health impact that can be calculated from association studies. We explain how these measures are influenced by the strength of the association and by the frequencies of the variant and the adverse event. The measures are illustrated using examples of testing for HLA-B*5701 associated with abacavir-induced hypersensitivity and SLCO1B1 c.521T>C (*5) associated with simvastatin-induced adverse events.The Pharmacogenomics Journal advance online publication, 10 May 2016; doi:10.1038/tpj.2016.34.

PMID: 27168098 [PubMed - as supplied by publisher]