Maha Karnoub | DSI - Academia.edu (original) (raw)
Papers by Maha Karnoub
Biomarkers in Medicine, 2008
An area of unmet medical need in clinical oncology has been optimizing patient selection for a gi... more An area of unmet medical need in clinical oncology has been optimizing patient selection for a given therapeutic with the goal of getting the right drug to the right patient. Recent studies have developed preclinical approaches to identifying molecular ‘signatures of resistance’ for cytotoxic therapies and prospective validation of this strategy is ongoing in the clinic. New challenges in this setting include identifying approaches to patient selection for cytostatic compounds such as signaling pathway inhibitors and stem cell targets. Here, we discuss the biomarker methodologies developed using traditional cytotoxic drugs and how these approaches can be adapted to identify biomarkers of patient selection for novel signaling inhibitors and other novel targets. It has become increasingly clear that such biomarker discovery and validation needs to begin early and continue throughout the drug development process.
Human Heredity, 2002
Fax + 41 61 306 12 34 E-Mail kar\ ger@kar\ ger.ch www.kar\\ ger.com
Genomics, 2005
Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target... more Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response.
Genetic Epidemiology
Linkage and linkage disequilibrium tests are powerful tools for mapping complex disease genes. We... more Linkage and linkage disequilibrium tests are powerful tools for mapping complex disease genes. We investigated two approaches to identifying markers associated with disease. One method applied linkage analysis and then linkage disequilibrium tests to markers within linked regions. The other method looked for linkage disequilibrium with disease using all markers. Additionally, we investigated using Simes' test to combine p-values from linkage disequilibrium tests for nearby markers. We applied both approaches to all replicates of the Genetic Analysis Workshop 12 problem 2 isolated population data set. We reported results from the 25th replicate as if it were a real problem and assessed the power of our methods using all replicates. Using all replicates, we found that testing all markers for linkage disequilibrium with disease was more powerful than identifying markers that were in linkage with disease and then testing markers within those regions for linkage disequilibrium with t...
Biomarkers in Medicine, 2008
An area of unmet medical need in clinical oncology has been optimizing patient selection for a gi... more An area of unmet medical need in clinical oncology has been optimizing patient selection for a given therapeutic with the goal of getting the right drug to the right patient. Recent studies have developed preclinical approaches to identifying molecular 'signatures of resistance' for cytotoxic therapies and prospective validation of this strategy is ongoing in the clinic. New challenges in this setting include identifying approaches to patient selection for cytostatic compounds such as signaling pathway inhibitors and stem cell targets. Here, we discuss the biomarker methodologies developed using traditional cytotoxic drugs and how these approaches can be adapted to identify biomarkers of patient selection for novel signaling inhibitors and other novel targets. It has become increasingly clear that such biomarker discovery and validation needs to begin early and continue throughout the drug development process.
Pharmacogenomics, 2011
One approach to delivering cost-effective healthcare requires the identification of patients as i... more One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective–retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provi...
Human Molecular Genetics, 2007
This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LO... more This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P 5 6.94E 2 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOE14 and 12/3 variants (0.09 < D 0 < 1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P 5 0.0010-0.00006; odds ratio (OR) 5 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P 5 0.00005, OR 5 1.2, false positive rate 5 0.87).
Genomics, 2005
Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target... more Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response. D
The American Journal of Human Genetics, 2000
Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatme... more Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association's GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999).
Alzheimer's & Dementia, 2006
Biomarkers in Medicine, 2008
An area of unmet medical need in clinical oncology has been optimizing patient selection for a gi... more An area of unmet medical need in clinical oncology has been optimizing patient selection for a given therapeutic with the goal of getting the right drug to the right patient. Recent studies have developed preclinical approaches to identifying molecular ‘signatures of resistance’ for cytotoxic therapies and prospective validation of this strategy is ongoing in the clinic. New challenges in this setting include identifying approaches to patient selection for cytostatic compounds such as signaling pathway inhibitors and stem cell targets. Here, we discuss the biomarker methodologies developed using traditional cytotoxic drugs and how these approaches can be adapted to identify biomarkers of patient selection for novel signaling inhibitors and other novel targets. It has become increasingly clear that such biomarker discovery and validation needs to begin early and continue throughout the drug development process.
Human Heredity, 2002
Fax + 41 61 306 12 34 E-Mail kar\ ger@kar\ ger.ch www.kar\\ ger.com
Genomics, 2005
Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target... more Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response.
Genetic Epidemiology
Linkage and linkage disequilibrium tests are powerful tools for mapping complex disease genes. We... more Linkage and linkage disequilibrium tests are powerful tools for mapping complex disease genes. We investigated two approaches to identifying markers associated with disease. One method applied linkage analysis and then linkage disequilibrium tests to markers within linked regions. The other method looked for linkage disequilibrium with disease using all markers. Additionally, we investigated using Simes' test to combine p-values from linkage disequilibrium tests for nearby markers. We applied both approaches to all replicates of the Genetic Analysis Workshop 12 problem 2 isolated population data set. We reported results from the 25th replicate as if it were a real problem and assessed the power of our methods using all replicates. Using all replicates, we found that testing all markers for linkage disequilibrium with disease was more powerful than identifying markers that were in linkage with disease and then testing markers within those regions for linkage disequilibrium with t...
Biomarkers in Medicine, 2008
An area of unmet medical need in clinical oncology has been optimizing patient selection for a gi... more An area of unmet medical need in clinical oncology has been optimizing patient selection for a given therapeutic with the goal of getting the right drug to the right patient. Recent studies have developed preclinical approaches to identifying molecular &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;signatures of resistance&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; for cytotoxic therapies and prospective validation of this strategy is ongoing in the clinic. New challenges in this setting include identifying approaches to patient selection for cytostatic compounds such as signaling pathway inhibitors and stem cell targets. Here, we discuss the biomarker methodologies developed using traditional cytotoxic drugs and how these approaches can be adapted to identify biomarkers of patient selection for novel signaling inhibitors and other novel targets. It has become increasingly clear that such biomarker discovery and validation needs to begin early and continue throughout the drug development process.
Pharmacogenomics, 2011
One approach to delivering cost-effective healthcare requires the identification of patients as i... more One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective–retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provi...
Human Molecular Genetics, 2007
This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LO... more This study sets out to identify novel susceptibility genes for late-onset Alzheimer's disease (LOAD) in a powerful set of samples from the UK and USA (1808 LOAD cases and 2062 controls). Allele frequencies of 17 343 gene-based putative functional single nucleotide polymorphisms (SNPs) were tested for association with LOAD in a discovery case-control sample from the UK. A tiered strategy was used to follow-up significant variants from the discovery sample in four independent sample sets. Here, we report the identification of several candidate SNPs that show significant association with LOAD. Three of the identified markers are located on chromosome 19 (meta-analysis: full sample P 5 6.94E 2 81 to 0.0001), close to the APOE gene and exhibit linkage disequilibrium (LD) with the APOE14 and 12/3 variants (0.09 < D 0 < 1). Two of the three SNPs can be regarded as study-wide significant (expected number of false positives reaching the observed significance level less than 0.05 per study). Sixteen additional SNPs show evidence for association with LOAD [P 5 0.0010-0.00006; odds ratio (OR) 5 1.07-1.45], several of which map to known linkage regions, biological candidate genes and novel genes. Four SNPs not in LD with APOE show a false positive rate of less than 2 per study, one of which shows study-wide suggestive evidence taking account of 17 343 tests. This is a missense mutation in the galanin-like peptide precursor gene (P 5 0.00005, OR 5 1.2, false positive rate 5 0.87).
Genomics, 2005
Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target... more Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response. D
The American Journal of Human Genetics, 2000
Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatme... more Type 2 diabetes is a serious, genetically influenced disease for which no fully effective treatments are available. Identification of biochemical or regulatory pathways involved in the disease syndrome could lead to innovative therapeutic interventions. One way to identify such pathways is the genetic analysis of families with multiple affected members where disease predisposing genes are likely to be segregating. We undertook a genomewide screen (389-395 microsatellite markers) in samples of 835 white, 591 Mexican American, 229 black, and 128 Japanese American individuals collected as part of the American Diabetes Association's GENNID study. Multipoint nonparametric linkage analyses were performed with diabetes, and diabetes or impaired glucose homeostasis (IH). Linkage to diabetes or IH was detected near markers D5S1404 (map position 77 cM, LOD = 2.80), D12S853 (map position 82 cM, LOD = 2.81) and GATA172D05 (X-chromosome map position 130 cM, LOD = 2.99) in whites, near marker D3S2432 (map position 51 cM, LOD = 3.91) in Mexican Americans, and near marker D10S1412 (map position 14 cM, LOD = 2.39) in African Americans mainly collected in phase 1 of the study. Further analyses showed evidence for interactions between the chromosome 5 locus and region on chromosome 12 containing the MODY 3 gene (map position 132 cM) and between the X-chromosome locus and region near D12S853 (map position 82 cM) in whites. Although these results were not replicated in samples collected in phase 2 of the GENNID study, the region on chromosome 12 was replicated in samples from whites described by Bektas et al. (1999).
Alzheimer's & Dementia, 2006