Indiana Biobank (IB)

poster abstractThe Indiana Biobank (IB) was established in July 2010 as a conduit in the new era of personalized medicine to serve the needs of the Indiana research communities and to make an impact on Hoosier health. The overall objective of the Indiana Biobank is to create a collection of high quality biospecimens that are well annotated and linked to the electronic health record, genomic and proteomic data, to provide to the research community to carry out translational research. The ability to successfully do research and translate to the clinical setting is greatly facilitated by the availability of an extensive biorepository of biological samples, with accompanying clinical and genomic data, procured from patients at IU Health, Wishard and other clinical venues throughout Indiana

Dynamics of the northern flicker hybrid zone : a test of the bounded-hybrid superiority hypothesis

The bounded-hybrid superiority hypothesis (BHSH) predicts stable hybrid zones are characterized by hybrids having the highest fitness within the zone. The dynamic-equilibrium hypothesis (DEH) predicts hybrids to have the lowest fitness and mating should be strongly assortative in the hybrid zone. I used phenotypic-based hybrid indices (HI) to assess mating patterns, reproductive success, and survival of hybridizing northern flickers (Colaptes auratus) within the hybrid zone at Riske Creek, British Columbia. Contrary to the BHSH, flickers showed significant assortative pairing (P = 0.038) which may result via passive mate choice if yellow and red flickers migrate from allopatric winter ranges. North American band recoveries show red-shafted and yellow-shafted flickers winter on different sides of the Rocky Mountains while red-orange hybrids from Riske Creek winter in the range of red-shafted flickers. Arrival dates of phenotypes did not support the idea that mating patterns are caused passively via different arrival schedules. However, assortative mating patterns did correlate with regional weather patterns along flicker migration routes as well as the North Atlantic Oscillation (NAO) a continental weather pattern that has been shown to influence various aspects of the annual cycle in other birds. If variable weather patterns result in different mating patterns by affecting migration, the geographic location of the northern portion of the zone may be variable due to the migratory behaviour of individuals.There were no differences among yellow, orange and red flickers to win more agonistic contests or have earlier nest initiation dates, larger clutch sizes, greater hatching success, or produce more fledglings. No colour group had a higher likelihood of having a successful compared to a depredated nesting attempt. Aggression was similar between red (N = 21) and yellow flickers (N = 20) during taxidermy model presentations of pure red-shafted and yellow-shafted flickers. Using Akaike’s information criterion (AIC) in Program MARK, I determined survival was best modeled as either constant between males and females or varying annually according to weather. Models incorporating HI had less support but suggested that survival is best modeled as a linear relationship where red-shafted flickers have the highest survival. Survival modeled in quadratic relationships found hybrid flickers to have the highest apparent survival estimates in support of the BHSH. Overall there was no support for reduced hybrid fitness, but survival appears to be influenced more by annual variation rather than strictly by an individual’s HI. Overall, I failed to find reduced hybrid fitness in support of the DEH but also failed to find increased hybrid fitness as predicted by the BHSH. Annual changes in selection pressure could prevent introgression of hybrid genes throughout the zone if selection favours red-shafted genes in some years and yellow-shafted genes in other years

The Unfinished Business of US Drug Safety Regulation

Posted with permission from FDLI ; Food and Drug Law Journal Various proposals have been advanced in response to recent problems with the safety of Food and Drug Administration (FDA)-approved drugs. Many call for incremental change, such as new safety oversight bodies or minor expansions of FDA's existing powers. "Fixing" FDA may not fix the problem, without related reform of the broader legal framework in which FDA operates. Key reform challenges include promoting clinical compliance with important safety warnings while preserving needed flexibility for physicians to adapt drug use to the individual patient; developing a clearer distinction between pre- and postapproval safety regulation; and devising mechanisms for funding investments in safety improvements. Until these fundamental problems are addressed, the United States will face ongoing problems with drug safety and patients will be denied the full measure of safety and therapeutic benefit that today's technologies could support. This article proposes a new direction to address these problems in the context of an insurance-based framework for promoting drug safety

Is personalized medicine achievable in obstetrics?

Personalized medicine seeks to identify the right dose of the right drug for the right patient at the right time. Typically, individualization of therapy is based on the pharmacogenomic makeup of the individual and environmental factors that alter drug disposition and response. In addition to these factors, during pregnancy, a woman's body undergoes many changes that can impact the therapeutic efficacy of medications. Yet, there is minimal research regarding personalized medicine in obstetrics. Adoption of pharmacogenetic testing into the obstetrical care is dependent on evidence of analytical validity, clinical validity, and clinical utility. Here, we briefly present information regarding the potential utility of personalized medicine for treating the obstetric patient for pain with narcotics, hypertension, and preterm labor, and discuss the impediments of bringing personalized medicine to the obstetrical clinic

Stereoselective pharmacokinetics of stable isotope (+/-)-[13C]-pantoprazole: Implications for a rapid screening phenotype test of CYP2C19 activity

AIMS: We have previously shown that the (±)-[(13) C]-pantoprazole breath test is a promising noninvasive probe of CYP2C19 activity. As part of that trial, plasma, breath test indices and CYP2C19 (*2, *3, and *17) genotype were collected. Here, we examined whether [(13) C]-pantoprazole exhibits enantioselective pharmacokinetics and whether this enantioselectivity is correlated with indices of breath test. METHODS: Plasma (-)- and (+)-[(13) C]-pantoprazole that were measured using a chiral HPLC were compared between CYP2C19 genotypes and correlated with breath test indices. RESULTS: The AUC( 0-∞) of (+)-[(13) C]-pantoprazole in PM (*2/*2, n = 4) was 10.1- and 5.6-fold higher that EM (*1/*1or *17, n = 10) and IM (*1/*2or *3, n = 10) of CYP2C19, respectively (P < 0.001). The AUC( 0-∞) of (-)-[(13) C]-pantoprazole only significantly differed between PMs and EMs (1.98-fold; P = 0.05). The AUC( 0-∞) ratio of (+)-/(-)-[(13) C]-pantoprazole was 3.45, 0.77, and 0.67 in PM, IM, and EM genotypes, respectively. Breath test index, delta over baseline show significant correlation with AUC( 0-∞) of (+)-[(13) C]-pantoprazole (Pearson's r = 0.62; P < 0.001). CONCLUSIONS: [(13) C]-pantoprazole exhibits enantioselective elimination. (+)-[(13) C]-pantoprazole is more dependent on CYP2C19 metabolic status and may serve as a more attractive probe of CYP2C19 activity than (-)-[(13) C]-pantoprazole or the racemic mixture

A Penalized Mixture Model Approach in Genotype/Phenotype Association Analysis for Quantitative Phenotypes

A mixture normal model has been developed to partition genotypes in predicting quantitative phenotypes. Its estimation and inference are performed through an EM algorithm. This approach can conduct simultaneous genotype clustering and hypothesis testing. It is a valuable method for predicting the distribution of quantitative phenotypes among multi-locus genotypes across genes or within a gene. This mixture model’s performance is evaluated in data analyses for two pharmacogenetics studies. In one example, thirty five CYP2D6 genotypes were partitioned into three groups to predict pharmacokinetics of a breast cancer drug, Tamoxifen, a CYP2D6 substrate (p-value = 0.04). In a second example, seventeen CYP2B6 genotypes were categorized into three clusters to predict CYP2B6 protein expression (p-value = 0.002). The biological validities of both partitions are examined using established function of CYP2D6 and CYP2B6 alleles. In both examples, we observed genotypes clustered in the same group to have high functional similarities. The power and recovery rate of the true partition for the mixture model approach are investigated in statistical simulation studies, where it outperforms another published method

Steroid Pathway Genes and Neonatal Respiratory Distress After Betamethasone Use in Anticipated Preterm Birth

Objective: To test several key glucocorticoid genes that are enhanced in lung development for associations with respiratory distress syndrome (RDS) after antenatal corticosteroid use. Methods: A prospective cohort of women received betamethasone to accelerate fetal lung maturity for threatened preterm delivery. DNA was obtained from mothers and newborns. Neonatal RDS was the primary outcome. Genotyping for single-nucleotide polymorphisms (SNPs) in 68 glucocorticoid genes found to be differentially expressed during lung development was performed. Multivariable analysis tested for associations of SNPs in the candidate genes with RDS. Results: Genotypic results for 867 SNPs in 96 mothers and 73 babies were included. Thirty-nine (53.4%) babies developed RDS. Maternal SNPs in the centromeric protein E (CENPE), GLRX, CD9, and AURKA genes provided evidence of association with RDS (P < .01). In newborns, SNPs in COL4A3, BHLHE40, and SRGN provided evidence of association with RDS (P < .01). Conclusion: Single-nucleotide polymorphisms in several glucocorticoid responsive genes suggest association with neonatal RDS after antenatal corticosteroid use

Differential quantification of CYP2D6 gene copy number by four different quantitative real-time PCR assays

Copy number variations (CNVs) in the CYP2D6 gene contribute to interindividual variation in drug metabolism. As the most common duplicated allele in Asian populations is the nonfunctional CYP2D6*36 allele, the goal of this study was to identify CNV assays that can differentiate between multiple copies of the CYP2D6*36 allele and multiple copies of other CYP2D6 alleles. We determined CYP2D6 gene copy numbers in 32 individuals with known CYP2D6 CNVs from the Coriell Japanese-Chinese panel using four quantitative real-time PCR assays. These assays target different regions of the CYP2D6 gene: 5'-flanking region, intron 2, intron 6, and exon 9 (Ex9). The specific target site of the Ex9 assay was verified by sequencing the PCR amplicon. Three of the CYP2D6 CNV assays (5'-flanking region, intron 2, and intron 6) estimated CYP2D6 copy numbers that were concordant for all 32 individuals. However, the Ex9 assay was concordant in only 10 of 32 samples. The 10 concordant samples did not contain any CYP2D6*36 alleles and the 22 discordant samples contained at least one CYP2D6*36 allele. In addition, the Ex9 assay accurately quantified all of the non-CYP2D6*36 alleles in all samples. Ex9 amplicon sequencing indicated that it targets a region of CYP2D6 exon 9 that undergoes partial gene-conversion in the CYP2D6*36 allele. In conclusion, CYP2D6 Ex9 CNV assay can be used to determine the copy number of non-CYP2D6*36 alleles. Selective amplification of non-CYP2D6*36 sequence by the Ex9 assay should be useful in determining the number of functional copies of CYP2D6 in Asian populations

Miniaturized photoacoustic trace gas sensing using a raman fiber amplifier

This paper presents the development of a Raman fiber amplifier optical source with a maximum output power of 1.1 W centered around 1651 nm, and its application in miniaturized 3D printed photoacoustic spectroscopy (PAS) trace gas sensing of methane. The Raman amplifier has been constructed using 4.5 km of dispersion shifted fiber, a 1651 nm DFB seed laser and a commercial 4W EDFA pump. The suppression of stimulated Brillouin scattering (SBS) using a high frequency modulation of the seed laser is investigated for a range of frequencies, leading to an increase in optical output power of the amplifier and reduction of its noise content. The amplifier output was used as the source for a miniature PAS sensor by applying a second modulation to the seed laser at the resonant frequency of 15.2 kHz of the miniature 3D printed gas cell. For the targeted methane absorption line at 6057 cm-1 the sensor system performance and influence of the SBS suppression is characterized, leading to a detection limit (1σ) of 17 ppb methane for a signal acquisition time of 130 s, with a normalized noise equivalent absorption coefficient of 4.1•10-9 cm-1 W Hz-1/2 for the system