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Jashvant D Unadkat - One of the best experts on this subject based on the ideXlab platform.
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Interindividual Variability of cyp2c19 catalyzed drug metabolism due to differences in gene diplotypes and cytochrome p450 oxidoreductase content
2016Co-Authors: Yoshiyuki Shirasaka, Bhagwat Prasad, Amarjit S Chaudhry, Matthew G Mcdonald, Timothy C Wong, Justina C Calamia, Alison E Fohner, Timothy A Thornton, Nina Isoherranen, Jashvant D UnadkatAbstract:Large Interindividual Variability has been observed in the metabolism of CYP2C19 substrates in vivo. The study aimed to evaluate sources of this Variability in CYP2C19 activity, focusing on CYP2C19 diplotypes and the cytochrome P450 oxidoreductase (POR). CYP2C19 gene analysis was carried out on 347 human liver samples. CYP2C19 activity assayed using human liver microsomes confirmed a significant a priori predicted rank order for (S)-mephenytoin hydroxylase activity of CYP2C19*17/*17 > *1B/*17 > *1B/*1B > *2A/*17 > *1B/*2A > *2A/*2A diplotypes. In a multivariate analysis, the CYP2C19*2A allele and POR protein content were associated with CYP2C19 activity. Further analysis indicated a strong effect of the CYP2C19*2A, but not the *17, allele on both metabolic steps in the conversion of clopidogrel to its active metabolite. The present study demonstrates that Interindividual Variability in CYP2C19 activity is due to differences in both CYP2C19 protein content associated with gene diplotypes and the POR concentration.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.58.
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Interindividual Variability in hepatic organic anion transporting polypeptides and p glycoprotein abcb1 protein expression quantification by liquid chromatography tandem mass spectroscopy and influence of genotype age and sex
2014Co-Authors: Bhagwat Prasad, Raymond Evers, Anshul Gupta, Laurent Salphati, Suneet Shukla, Suresh V Ambudkar, Jashvant D UnadkatAbstract:Interindividual Variability in protein expression of organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, OATP2B1, and multidrug resistance-linked P-glycoprotein (P-gp) or ABCB1 was quantified in frozen human livers (n = 64) and cryopreserved human hepatocytes (n = 12) by a validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. Membrane isolation, sample workup, and LC-MS/MS analyses were as described before by our laboratory. Briefly, total native membrane proteins, isolated from the liver tissue and cryopreserved hepatocytes, were trypsin digested and quantified by LC-MS/MS using signature peptide(s) unique to each transporter. The mean ± S.D. (maximum/minimum range in parentheses) protein expression (fmol/µg of membrane protein) in human liver tissue was OATP1B1- 2.0 ± 0.9 (7), OATP1B3- 1.1 ± 0.5 (8), OATP2B1- 1 1.7 ± 0.6 (5), and P-gp- 0.4 ± 0.2 (8). Transporter expression in the liver tissue was comparable to that in the cryopreserved hepatocytes. Most important is that livers with SLCO1B1 (encoding OATP1B1) haplotypes *14/*14 and *14/*1a [i.e., representing single nucleotide polymorphisms (SNPs), c.388A > G, and c.463C > A] had significantly higher (P < 0.0001) protein expression than the reference haplotype (*1a/*1a). Based on these genotype-dependent protein expression data, we predicted (using Simcyp) an up to ∼40% decrease in the mean area under the curve of rosuvastatin or repaglinide in subjects harboring these variant alleles compared with those harboring the reference alleles. SLCO1B3 (encoding OATP1B3) SNPs did not significantly affect protein expression. Age and sex were not associated with transporter protein expression. These data will facilitate the prediction of population-based human transporter-mediated drug disposition, drug-drug interactions, and Interindividual Variability through physiologically based pharmacokinetic modeling.
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Interindividual Variability in the hepatic expression of the human breast cancer resistance protein bcrp abcg2 effect of age sex and genotype
2013Co-Authors: Bhagwat Prasad, Yurong Lai, Yvonne S Lin, Jashvant D UnadkatAbstract:Breast cancer resistance protein (BCRP), an efflux transporter expressed at the bile canalicular membrane, is responsible for the biliary clearance of many drugs. Data on the Interindividual Variability of hepatic BCRP expression are needed for in vitro to in vivo extrapolation of the biliary clearance of a BCRP substrate drug. Therefore, we measured the expression of BCRP in human livers (n = 65) by liquid chromatography coupled with tandem mass spectrometry. A calibration curve was generated using a synthetic signature peptide (SSLLDVLAAR) as the calibrator and the corresponding synthetic stable isotope-labeled peptide as the internal standard. The analytical method was accurate and precise. BCRP expression in 50 livers, where it was measurable, was 137.9 ± 42.1 atmol/µg of membrane protein (range 69.7-246.4 atmol/µg of membrane protein). BCRP expression was not associated with age (7-70 years), sex, or mRNA expression. BCRP expression in livers with the variant C421A (rs2231142) allele (14 heterozygotes, two homozygotes; among these, eight livers were below lower limit of quantification) was significantly lower than that in the wild-type livers (p < 0.002). Integration of these data with data on the hepatic expression of other transporters will allow refinement of physiologically based pharmacokinetic models to predict the pharmacokinetics, hepatic exposure, and drug-drug interactions of drugs (and/or their metabolites).
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Interindividual Variability in hepatic expression of the multidrug resistance associated protein 2 mrp2 abcc2 quantification by liquid chromatography tandem mass spectrometry
2012Co-Authors: Bhagwat Prasad, Larissa M Balogh, Jashvant D UnadkatAbstract:Multidrug-associated protein 2 (MRP2) is an efflux transporter that is expressed at the bile canalicular membrane. To allow in vitro to in vivo extrapolation of the contribution of MRP2 toward hepatic disposition of its substrates, data on the Interindividual Variability of hepatic MRP2 protein expression are required. Therefore, we quantified the expression of MRP2 in the University of Washington (UW) human liver bank (n = 51) using a modified version of a previously validated liquid chromatography/tandem mass spectrometry assay. An unlabeled (LTIIPQDPILFSGSLR) and stable isotope-labeled (LTIIPQDPILFSGSL[13C615N1]R) surrogate peptide for MRP2 were used as the calibrator and internal standard, respectively. After isolation of the membrane fraction from the liver tissue, in-solution tryptic digestion was conducted. Quality control samples created by spiking human serum albumin or pooled human liver (n = 51) matrix with three different MRP2 synthetic peptide concentrations generated error and precision values of less than 15%. As determined by the surrogate peptide, the average MRP2 expression in the UW liver bank samples was 1.54 ± 0.64 fmol/μg liver membrane protein and was found to be independent of age (7–63 years) or sex. A single nucleotide polymorphism in the promoter region (rs717620), previously thought to affect MRP2 expression, did not influence hepatic expression of MRP2. In contrast, the single nucleotide polymorphism 21214G>A (V417I; rs2273697) was associated with significantly higher hepatic MRP2 expression.
Bhagwat Prasad - One of the best experts on this subject based on the ideXlab platform.
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critical issues and optimized practices in quantification of protein abundance level to determine Interindividual Variability in dmet proteins by lc ms ms proteomics
2018Co-Authors: Deepak Kumar Bhatt, Bhagwat PrasadAbstract:Protein quantification data on drug metabolizing enzymes and transporters (collectively referred as DMET proteins) in human tissues are useful in predicting Interindividual Variability in drug disposition. While targeted proteomics is an emerging technique for quantification of DMET proteins, the methodology involves significant technical challenges especially when multiple samples are analyzed in a single study over a long period of time. Therefore, it is important to thoroughly address the critical variables that could affect DMET protein quantification.
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Interindividual Variability of cyp2c19 catalyzed drug metabolism due to differences in gene diplotypes and cytochrome p450 oxidoreductase content
2016Co-Authors: Yoshiyuki Shirasaka, Bhagwat Prasad, Amarjit S Chaudhry, Matthew G Mcdonald, Timothy C Wong, Justina C Calamia, Alison E Fohner, Timothy A Thornton, Nina Isoherranen, Jashvant D UnadkatAbstract:Large Interindividual Variability has been observed in the metabolism of CYP2C19 substrates in vivo. The study aimed to evaluate sources of this Variability in CYP2C19 activity, focusing on CYP2C19 diplotypes and the cytochrome P450 oxidoreductase (POR). CYP2C19 gene analysis was carried out on 347 human liver samples. CYP2C19 activity assayed using human liver microsomes confirmed a significant a priori predicted rank order for (S)-mephenytoin hydroxylase activity of CYP2C19*17/*17 > *1B/*17 > *1B/*1B > *2A/*17 > *1B/*2A > *2A/*2A diplotypes. In a multivariate analysis, the CYP2C19*2A allele and POR protein content were associated with CYP2C19 activity. Further analysis indicated a strong effect of the CYP2C19*2A, but not the *17, allele on both metabolic steps in the conversion of clopidogrel to its active metabolite. The present study demonstrates that Interindividual Variability in CYP2C19 activity is due to differences in both CYP2C19 protein content associated with gene diplotypes and the POR concentration.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.58.
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Interindividual Variability in cytochrome p450 mediated drug metabolism
2016Co-Authors: Timothy S Tracy, Kenneth E. Thummel, Bhagwat Prasad, Amarjit S Chaudhry, Hyunyoung Jeong, Erin G Schuetz, Xiaobo Zhong, Yun Chen Tien, Xian Pan, Laura M ShiremanAbstract:The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial Interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This Interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine Interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on Interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.
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Interindividual Variability in hepatic organic anion transporting polypeptides and p glycoprotein abcb1 protein expression quantification by liquid chromatography tandem mass spectroscopy and influence of genotype age and sex
2014Co-Authors: Bhagwat Prasad, Raymond Evers, Anshul Gupta, Laurent Salphati, Suneet Shukla, Suresh V Ambudkar, Jashvant D UnadkatAbstract:Interindividual Variability in protein expression of organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, OATP2B1, and multidrug resistance-linked P-glycoprotein (P-gp) or ABCB1 was quantified in frozen human livers (n = 64) and cryopreserved human hepatocytes (n = 12) by a validated liquid chromatography tandem mass spectroscopy (LC-MS/MS) method. Membrane isolation, sample workup, and LC-MS/MS analyses were as described before by our laboratory. Briefly, total native membrane proteins, isolated from the liver tissue and cryopreserved hepatocytes, were trypsin digested and quantified by LC-MS/MS using signature peptide(s) unique to each transporter. The mean ± S.D. (maximum/minimum range in parentheses) protein expression (fmol/µg of membrane protein) in human liver tissue was OATP1B1- 2.0 ± 0.9 (7), OATP1B3- 1.1 ± 0.5 (8), OATP2B1- 1 1.7 ± 0.6 (5), and P-gp- 0.4 ± 0.2 (8). Transporter expression in the liver tissue was comparable to that in the cryopreserved hepatocytes. Most important is that livers with SLCO1B1 (encoding OATP1B1) haplotypes *14/*14 and *14/*1a [i.e., representing single nucleotide polymorphisms (SNPs), c.388A > G, and c.463C > A] had significantly higher (P < 0.0001) protein expression than the reference haplotype (*1a/*1a). Based on these genotype-dependent protein expression data, we predicted (using Simcyp) an up to ∼40% decrease in the mean area under the curve of rosuvastatin or repaglinide in subjects harboring these variant alleles compared with those harboring the reference alleles. SLCO1B3 (encoding OATP1B3) SNPs did not significantly affect protein expression. Age and sex were not associated with transporter protein expression. These data will facilitate the prediction of population-based human transporter-mediated drug disposition, drug-drug interactions, and Interindividual Variability through physiologically based pharmacokinetic modeling.
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Interindividual Variability in the hepatic expression of the human breast cancer resistance protein bcrp abcg2 effect of age sex and genotype
2013Co-Authors: Bhagwat Prasad, Yurong Lai, Yvonne S Lin, Jashvant D UnadkatAbstract:Breast cancer resistance protein (BCRP), an efflux transporter expressed at the bile canalicular membrane, is responsible for the biliary clearance of many drugs. Data on the Interindividual Variability of hepatic BCRP expression are needed for in vitro to in vivo extrapolation of the biliary clearance of a BCRP substrate drug. Therefore, we measured the expression of BCRP in human livers (n = 65) by liquid chromatography coupled with tandem mass spectrometry. A calibration curve was generated using a synthetic signature peptide (SSLLDVLAAR) as the calibrator and the corresponding synthetic stable isotope-labeled peptide as the internal standard. The analytical method was accurate and precise. BCRP expression in 50 livers, where it was measurable, was 137.9 ± 42.1 atmol/µg of membrane protein (range 69.7-246.4 atmol/µg of membrane protein). BCRP expression was not associated with age (7-70 years), sex, or mRNA expression. BCRP expression in livers with the variant C421A (rs2231142) allele (14 heterozygotes, two homozygotes; among these, eight livers were below lower limit of quantification) was significantly lower than that in the wild-type livers (p < 0.002). Integration of these data with data on the hepatic expression of other transporters will allow refinement of physiologically based pharmacokinetic models to predict the pharmacokinetics, hepatic exposure, and drug-drug interactions of drugs (and/or their metabolites).
Michael H Court - One of the best experts on this subject based on the ideXlab platform.
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Interindividual Variability in hepatic drug glucuronidation studies into the role of age sex enzyme inducers and genetic polymorphism using the human liver bank as a model system
2010Co-Authors: Michael H CourtAbstract:The human liver bank has provided an invaluable model system for the study of Interindividual Variability in expression and activity of the major hepatic UGTs, including UGT1A1, 1A4, 1A6, 1A9, 2B7, and 2B15. Based on studies using UGT-isoform–selective probes, the rank order of activity Variability is UGT 1A1>1A6>2B15>1A4 = 1A9>2B7, with coefficient of variation values ranging from 92 to 45%. Liver donor age, sex, enzyme inducers, and genetic polymorphism are factors that have been implicated as sources of this Variability in UGT activity. The expression of UGTs prior to, and immediately following, birth is quite limited, explaining the susceptibility of neonates to certain drug toxicities. Old age appears to have minimal effect on UGT function. Sex differences in UGT activity are relatively small and are confined to several UGTs, including UGT2B15, which shows higher activity in males, compared with females. Enzyme inducers, including coadministered drugs, smoking, and alcohol, may increase hepatic UGT l...
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Interindividual Variability in hepatic drug glucuronidation studies into the role of age sex enzyme inducers and genetic polymorphism using the human liver bank as a model system
2010Co-Authors: Michael H CourtAbstract:The human liver bank has provided an invaluable model system for the study of Interindividual Variability in expression and activity of the major hepatic UGTs, including UGT1A1, 1A4, 1A6, 1A9, 2B7, and 2B15. Based on studies using UGT-isoform-selective probes, the rank order of activity Variability is UGT 1A1>1A6>2B15>1A4 = 1A9>2B7, with coefficient of variation values ranging from 92 to 45%. Liver donor age, sex, enzyme inducers, and genetic polymorphism are factors that have been implicated as sources of this Variability in UGT activity. The expression of UGTs prior to, and immediately following, birth is quite limited, explaining the susceptibility of neonates to certain drug toxicities. Old age appears to have minimal effect on UGT function. Sex differences in UGT activity are relatively small and are confined to several UGTs, including UGT2B15, which shows higher activity in males, compared with females. Enzyme inducers, including coadministered drugs, smoking, and alcohol, may increase hepatic UGT levels. Human liver bank phenotype-genotype studies, using UGT-isoform-selective probes have identified common genetic polymorphisms that are predictive of glucuronidation activity in vitro and that were subsequently verified as predictors of probe-drug clearance by glucuronidation in vivo.
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pharmacogenetic determinants of Interindividual Variability in bupropion hydroxylation by cytochrome p450 2b6 in human liver microsomes
2004Co-Authors: Leah M Hesse, Lisa L Von Moltke, David J Greenblatt, Soundararajan Krishnaswamy, Qin Hao, Kirk Hogan, Michael H CourtAbstract:Bupropion is primarily metabolized in human liver by cytochrome P450 (CYP) 2B6, an isoform that shows high Interindividual Variability in expression and catalysis. The aim of this study was to identify mechanisms underlying this Variability through comprehensive phenotype-genotype analysis of a well-characterized human liver bank (n = 54). There was substantial Variability in microsomal bupropion hydroxylation activities (over 45-fold) and CYP2B6 protein content (over 288-fold), with excellent correlation between protein and activity values (rs = 0.88). CYP2B6 mRNA levels showed less Variability (13-fold) and poorer correlation (rs = 0.44) to CYP2B6 protein resulting from 20-30% of livers that contained substantial CYP2B6 mRNA, but low CYP2B6 protein. Livers were genotyped for the common coding polymorphisms (Q172H, K262R and R487C) and 14 additional variations identified by sequencing of the gene promoter to -3000 bp. Of 14 haplotypes that were inferred, *1A (reference), *1H (-2320t>c; -750t>c) and *6B (-1456t>c; -750t>c; Q172H; K262R) were most common with frequencies of 0.28, 0.20 and 0.26, respectively. Alcohol use history (P = 0.011) and *6B haplotype (P = 0.011) were identified as significant predictors of bupropion hydroxylation. A consideration of the effects of these variables on CYP2B6 mRNA and protein levels suggests that alcohol use is associated with enhanced CYP2B6 gene transcription, but the presence of at least one *6B allele reduces this effect on bupropion hydroxylation at the post-transcriptional level. In conclusion, the results of this study indicate that Interindividual Variability in bupropion hydroxylation is a consequence of interactions between environmental and genetic influences on CYP2B6 gene function.
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Interindividual Variability in acetaminophen glucuronidation by human liver microsomes identification of relevant acetaminophen udp glucuronosyltransferase isoforms
2001Co-Authors: Michael H Court, John O Miners, Lisa L Von Moltke, David J Greenblatt, Christopher J Patten, Su X Duan, Peter I. MackenzieAbstract:Interindividual Variability in acetaminophen (APAP) glucuronidation may contribute to differences in susceptibility to APAP intoxication in humans. The purpose of this study was to identify the relevant UDP-glucuronosyltransferase (UGT) isoforms mediating APAP-UGT activity in human liver microsomes (HLMs). APAP-UGT activities and enzyme kinetics were determined using HLMs from 56 donors and nine recombinant human UGTs. Activities mediated by UGT1A1, UGT1A4, UGT1A9, and UGT2B7, and relative UGT1A6 protein content were quantified using 20 livers. More than 15-fold variation in liver microsomal APAP-UGT activities was observed with a distribution skewed toward lower activities. Although most UGTs could glucuronidate APAP, UGT1A1, UGT1A6, and UGT1A9 were most active. UGT1A6 was a relatively high-affinity ( K m = 2.2 mM), low-capacity enzyme; UGT1A1 was intermediate in affinity ( K m = 9.4 mM) and capacity; and UGT1A9 was a low-affinity ( K m = 21 mM), high-capacity enzyme. K m values were similar to UGT1A1 in high- and intermediate-activity HLMs (6–10 mM) and UGT1A9 in low-activity HLMs (10–55 mM). APAP-UGT activities correlated best with propofol-UGT ( r = 0.85; UGT1A9) and bilirubin-UGT ( r = 0.66; UGT1A1) activities, but poorly with UGT1A6 protein ( r = 0.30). A kinetic model was constructed from these data that identified UGT1A9 as the predominant APAP-UGT (>55% total activity) in HLMs over a clinically relevant APAP concentration range (50 μM-5 mM). UGT1A1 was also predicted to contribute substantially at toxic concentrations (>1 mM; >28% activity), whereas UGT1A6 was most active at relatively low concentrations ( 29% activity).
Daniel T Corp - One of the best experts on this subject based on the ideXlab platform.
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large scale analysis of Interindividual Variability in single and paired pulse tms data
2021Co-Authors: Daniel T Corp, Hannah G K Bereznicki, Gillian M Clark, George J Youssef, Peter J Fried, Ali Jannati, Charlotte B Davies, Joyce Gomesosman, Melissa KirkovskiAbstract:Abstract Objective This study brought together over 60 transcranial magnetic stimulation (TMS) researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response Variability. Methods Authors of previously published studies were contacted and asked to share deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to Variability in response to single and paired-pulse TMS data. Results 687 healthy participant’s data were pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual’s single-pulse TMS amplitude. Baseline motor evoked potential amplitude, motor cortex hemisphere, and motor threshold (MT) significantly predicted short-interval intracortical inhibition response. Baseline motor evoked potential amplitude, test stimulus intensity, interstimulus interval, and MT significantly predicted intracortical facilitation response. Age, hemisphere, and TMS machine significantly predicted MT. Conclusions This large-scale analysis has identified a number of factors influencing participants’ responses to single and paired-pulse TMS. We provide specific recommendations to minimise Interindividual Variability in single and paired-pulse TMS data. Significance This study has used large-scale analyses to give clarity to factors driving variance in TMS data. We hope that this ongoing collaborative approach will increase standardisation of methods and thus the utility of single and paired-pulse TMS.
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large scale analysis of Interindividual Variability in single and paired pulse tms data results from the big tms data collaboration
2021Co-Authors: Daniel T Corp, Gillian M Clark, George J Youssef, Peter J Fried, Ali Jannati, Charlotte B Davies, Bereznicki Hgk, Joyce GomesosmanAbstract:Abstract Objective Interindividual Variability of single and paired-pulse TMS data has limited the clinical and experimental applicability of these methods. This study brought together over 60 TMS researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response Variability. Methods 118 corresponding authors provided deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to Variability in response to single and pp TMS data. Results 687 healthy participant’s TMS data was pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual’s single pulse TMS amplitude. Baseline MEP amplitude, M1 hemisphere, and biphasic AMT significantly predicted SICI response. Baseline MEP amplitude, test stimulus intensity, interstimulus interval, monophasic RMT, monophasic AMT, and biphasic RMT significantly predicted ICF response. Age, M1 hemisphere, and TMS machine significantly predicted motor threshold. Conclusions This large-scale analysis has identified a number of factors influencing participants’ responses to single and paired pulse TMS. We provide specific recommendations to increase the standardisation of TMS methods within and across laboratories, thereby minimising Interindividual Variability in single and pp TMS data. Highlights 687 healthy participant’s TMS data was pooled across 35 studies Significant relationships between age and resting motor threshold Significant relationships between baseline MEP amplitude and SICI/ICF
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large scale analysis of Interindividual Variability in theta burst stimulation data results from the big tms data collaboration
2020Co-Authors: Daniel T Corp, Hannah G K Bereznicki, Gillian M Clark, George J Youssef, Peter J Fried, Ali Jannati, Charlotte B Davies, Joyce Gomesosman, Julie StammAbstract:Abstract Background Many studies have attempted to identify the sources of Interindividual Variability in response to theta-burst stimulation (TBS). However, these studies have been limited by small sample sizes, leading to conflicting results. Objective/Hypothesis This study brought together over 60 TMS researchers to form the ‘Big TMS Data Collaboration’, and create the largest known sample of individual participant TBS data to date. The goal was to enable a more comprehensive evaluation of factors driving TBS response Variability. Methods 118 corresponding authors of TMS studies were emailed and asked to provide deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to iTBS and cTBS response Variability. Results 430 healthy participants’ TBS data was pooled across 22 studies (mean age = 41.9; range = 17–82; females = 217). Baseline MEP amplitude, age, target muscle, and time of day significantly predicted iTBS-induced plasticity. Baseline MEP amplitude and timepoint after TBS significantly predicted cTBS-induced plasticity. Conclusions This is the largest known study of Interindividual Variability in TBS. Our findings indicate that a significant portion of Variability can be attributed to the methods used to measure the modulatory effects of TBS. We provide specific methodological recommendations in order to control and mitigate these sources of Variability.
Regina G Ziegler - One of the best experts on this subject based on the ideXlab platform.
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a liquid chromatography mass spectrometry method for the simultaneous measurement of 15 urinary estrogens and estrogen metabolites assay reproducibility and Interindividual Variability
2008Co-Authors: Roni T Falk, Larry K Keefer, Timothy D Veenstra, Regina G ZieglerAbstract:Background: Accurate, reproducible, and sensitive measurements of endogenous estrogen exposure and individual patterns of estrogen metabolism are needed for etiologic studies of breast cancer. We have developed a high-performance liquid chromatography-tandem mass spectrometry method to quantitate simultaneously 15 urinary estrogens and estrogen metabolites (EM): estrone; estradiol; 3 catechol estrogens; 5 estrogens in the 16α pathway, including estriol; and 5 methoxy estrogens. Methods: Overnight urines were obtained from 45 participants. For the reproducibility study, two blinded, randomized aliquots from 5 follicular and 5 luteal premenopausal women, 5 naturally postmenopausal women, and 5 men were assayed in each of four batches. Assay coefficients of variation and intraclass correlation coefficients were calculated with ANOVA models. Data from the additional 25 participants were added to compare EM levels by menstrual/sex group and assess Interindividual Variability. Results: For each EM, overall coefficients of variation were ≤10%. Intraclass correlation coefficients for each menstrual/sex group were generally ≥98%. Although geometric mean EM concentrations differed among the four groups, rankings were similar, with estriol, 2-hydroxyestrone, estrone, estradiol, and 16-ketoestradiol accounting for 60% to 75% of total urinary EM. Within each group, Interindividual differences in absolute concentrations were consistently high; the range was 10- to 100-fold for nearly all EM. Conclusion: Our high-performance liquid chromatography-tandem mass spectrometry method for measuring 15 urinary EM is highly reproducible, and the range of EM concentrations in each menstrual/sex group is quite large relative to assay Variability. Whether these patterns persist in blood and target tissues awaits further development and application of this method. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3411–8)