- Email: [email protected]
RQTL THAT AFFECT THE RELATIONSHIP BETWEEN Aß42, TAU AND PTAU, AND LOCI THAT INTERACT WITH THEM (GXG)
Poster Presentations: Wednesday, July 27, 2016
and the Proteasome. Molecular & Cellular Proteomics, 14(11), pp.3000-3014.
P4-291
ASSESSING THE IMPACT OF A CENTRALIZED DATA REVIEW ON THE RELIABILITY OF THE ALZHEIMER’S DISEASE ASSESSMENT SCALECOGNITIVE (ADAS-COG)
P1145
between data sources demonstrates that centralized review of ADAS-Cog can detect rater errors and increase reliability of the scale. Findings emphasize the value of centralized review in maintaining scale reliability across longitudinal studies, and suggest that targeted rater education and within-trial surveillance can improve data quality.
Anzalee Khan1,2, Alexandra S. Atkins3, Ioan Stroescu3, Vicki Davis3, Tiffany Williamson3, Lyn Harper Mozley4, Tiffini Voss5, Kerry Budd McMahon6, Richard SE. Keefe3,7, 1Neurocog Trials, Durham, NC, USA; 2Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA; 3NeuroCog Trials, Durham, NC, USA; 4 Merck & Co., Inc., Kenilworth, NJ, USA; 5Merck & Co., Inc., Kenilworth, NJ, USA; 6Merck & Co., Inc., Kenilworth, NJ, USA; 7Duke University Medical Center, Durham, NC, USA. Contact e-mail: anzalee.khan@ neurocogtrials.com
Taylor J. Maxwell1, Keoni Kauwe2, Christopher Corcoran3, 1The George Washington University, Ashburn, VA, USA; 2Brigham Young University, Provo, UT, USA; 3Utah State University, Logan, UT, USA. Contact e-mail: [email protected]
Background: The ADAS-Cog is the most commonly used neuro-
Background: Relationship loci (rQTL) exist when the correlation
cognitive endpoint in Alzheimer’s disease (AD) clinical trials. Variations in administration practices, misinterpretation regarding scoring rules, and intra-rater drift decreases reliability. Addressing these issues via rater education and centralized surveillance may increase reliability and sensitivity to treatment effects. The goal was to quantify and compare variability in ADAS-Cog scores in the Critical Path Online Data Repository (CODR), and in the run-in phase of an industry trial that incorporated centralized data surveillance, in order to assess the impact of centralized video/audio review on reliability across visits. Methods: Subjects had mild-moderate AD with MMSE scores from 12-22. Data Source 1: 14 studies in CODR, n¼2257, that included ADAS-Cog placebo arm data and were > six months in duration. Data Source 2: Pre-treatment data (screening, runin, baseline), n¼355, from a multicenter, randomized, placebo-controlled trial. Raters received training and certification prior to data collection, and the ADAS-Cog underwent central video/audio review and revisions. Scaling assumptions, targeting and test-retest reliability were assessed between the first visit and 2 subsequent pre-treatment visits. Results: For CODR, Absolute Agreement ICCs (0.810 (Visit 2), 0.760 (Visit 3)) showed a progressive decrease in correlations across time. The dataset that underwent data surveillance showed higher and increased Absolute Agreement ICCs (0.832 (Visit 2), 0.840 (Visit 3)). For CODR, item analysis revealed a decrease in item correlations, with the lowest for Spoken Language (ICC ¼ 0.42). For the comparison dataset, item analysis remained consistent, with increases in Commands (ICC ¼ 0.72 - 0.78) and Word Recall (0.60 – 0.64), and decrease in Spoken Language (ICC ¼ 0.62). For CODR, 10/11 items (90.91%) of the ADAS-Cog showed decrease in ICCs of > 0.02, compared to 4/11 items (36.36%) for the centralized reviewed dataset. Conclusions: Results have important implications for clinical research, rater education and centralized surveillance. The difference in ICCs
between multiple traits varies by genotype. rQTL are often involved in gene-by-gene (GxG) or gene-by-environmental interactions, making them a powerful tool for detecting GxG. Methods: Empirically, we performed screens for rQTL between tau & AB42, ptau & AB42, and Alzheimer’s status and AB42 with over 3000 individuals from the ADGC using age, gender, series, APOE2, APOE4, and two principal components for population structure (PC1, PC2) as covariates. Parametric bootstrapping was used to determine significance with a 5 x 10-8 genome wide threshold. As independent a priori loci for gene-by-gene (GxG) interactions, each significant rQTL was separately screened for interactions with other loci for each trait in the rQTL model with parametric bootstrapping and the same significance threshold. Results: We found four significant tau/AB42 rQTL from three unique locations and six ptau/AB42 rQTL from five unique locations. GxG screens with these rQTL produced seven significant GxG interactions (1 AB42, 3 ptau, 3 tau) with five rQTL where each second locus was from a unique location. Conclusions: The two most significant rQTL (rs8027714 & rs1036819) for ptau/AB42 are on different chromosomes yet both appear to be very strong hits for pelvic organ prolapse. While diseases of the nervous system can cause pelvic organ prolapse, it is unlikely related to the ptau/AB42 relationship, but it may suggest that these two loci share some pathway. Rs103681914 also resides in the ZFAT gene, which is related to autoimmune thyroid disease. For tau, rs9817620 interacts with the tau/AB42 rQTL rs74025622. It is in the CHL1 gene, which is a neural cell adhesion molecule and may be involved in signal transduction pathways. CHL1 is related to BACE1, which is a b-secretase enzyme that initiates production of the b-amyloid peptide involved in Alzheimer disease and is a primary drug target. Overall, there are numerous loci that affect the relationship between these important Alzheimer’s disease endophenotypes and some are due to interactions with other loci. They may also modify their relationship to risk of Alzheimer’s and/or rate of progression.
P4-292
RQTL THAT AFFECT THE RELATIONSHIP BETWEEN Aß42, TAU AND PTAU, AND LOCI THAT INTERACT WITH THEM (GXG)
and the Proteasome. Molecular & Cellular Proteomics, 14(11), pp.3000-3014.
P4-291
ASSESSING THE IMPACT OF A CENTRALIZED DATA REVIEW ON THE RELIABILITY OF THE ALZHEIMER’S DISEASE ASSESSMENT SCALECOGNITIVE (ADAS-COG)
P1145
between data sources demonstrates that centralized review of ADAS-Cog can detect rater errors and increase reliability of the scale. Findings emphasize the value of centralized review in maintaining scale reliability across longitudinal studies, and suggest that targeted rater education and within-trial surveillance can improve data quality.
Anzalee Khan1,2, Alexandra S. Atkins3, Ioan Stroescu3, Vicki Davis3, Tiffany Williamson3, Lyn Harper Mozley4, Tiffini Voss5, Kerry Budd McMahon6, Richard SE. Keefe3,7, 1Neurocog Trials, Durham, NC, USA; 2Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA; 3NeuroCog Trials, Durham, NC, USA; 4 Merck & Co., Inc., Kenilworth, NJ, USA; 5Merck & Co., Inc., Kenilworth, NJ, USA; 6Merck & Co., Inc., Kenilworth, NJ, USA; 7Duke University Medical Center, Durham, NC, USA. Contact e-mail: anzalee.khan@ neurocogtrials.com
Taylor J. Maxwell1, Keoni Kauwe2, Christopher Corcoran3, 1The George Washington University, Ashburn, VA, USA; 2Brigham Young University, Provo, UT, USA; 3Utah State University, Logan, UT, USA. Contact e-mail: [email protected]
Background: The ADAS-Cog is the most commonly used neuro-
Background: Relationship loci (rQTL) exist when the correlation
cognitive endpoint in Alzheimer’s disease (AD) clinical trials. Variations in administration practices, misinterpretation regarding scoring rules, and intra-rater drift decreases reliability. Addressing these issues via rater education and centralized surveillance may increase reliability and sensitivity to treatment effects. The goal was to quantify and compare variability in ADAS-Cog scores in the Critical Path Online Data Repository (CODR), and in the run-in phase of an industry trial that incorporated centralized data surveillance, in order to assess the impact of centralized video/audio review on reliability across visits. Methods: Subjects had mild-moderate AD with MMSE scores from 12-22. Data Source 1: 14 studies in CODR, n¼2257, that included ADAS-Cog placebo arm data and were > six months in duration. Data Source 2: Pre-treatment data (screening, runin, baseline), n¼355, from a multicenter, randomized, placebo-controlled trial. Raters received training and certification prior to data collection, and the ADAS-Cog underwent central video/audio review and revisions. Scaling assumptions, targeting and test-retest reliability were assessed between the first visit and 2 subsequent pre-treatment visits. Results: For CODR, Absolute Agreement ICCs (0.810 (Visit 2), 0.760 (Visit 3)) showed a progressive decrease in correlations across time. The dataset that underwent data surveillance showed higher and increased Absolute Agreement ICCs (0.832 (Visit 2), 0.840 (Visit 3)). For CODR, item analysis revealed a decrease in item correlations, with the lowest for Spoken Language (ICC ¼ 0.42). For the comparison dataset, item analysis remained consistent, with increases in Commands (ICC ¼ 0.72 - 0.78) and Word Recall (0.60 – 0.64), and decrease in Spoken Language (ICC ¼ 0.62). For CODR, 10/11 items (90.91%) of the ADAS-Cog showed decrease in ICCs of > 0.02, compared to 4/11 items (36.36%) for the centralized reviewed dataset. Conclusions: Results have important implications for clinical research, rater education and centralized surveillance. The difference in ICCs
between multiple traits varies by genotype. rQTL are often involved in gene-by-gene (GxG) or gene-by-environmental interactions, making them a powerful tool for detecting GxG. Methods: Empirically, we performed screens for rQTL between tau & AB42, ptau & AB42, and Alzheimer’s status and AB42 with over 3000 individuals from the ADGC using age, gender, series, APOE2, APOE4, and two principal components for population structure (PC1, PC2) as covariates. Parametric bootstrapping was used to determine significance with a 5 x 10-8 genome wide threshold. As independent a priori loci for gene-by-gene (GxG) interactions, each significant rQTL was separately screened for interactions with other loci for each trait in the rQTL model with parametric bootstrapping and the same significance threshold. Results: We found four significant tau/AB42 rQTL from three unique locations and six ptau/AB42 rQTL from five unique locations. GxG screens with these rQTL produced seven significant GxG interactions (1 AB42, 3 ptau, 3 tau) with five rQTL where each second locus was from a unique location. Conclusions: The two most significant rQTL (rs8027714 & rs1036819) for ptau/AB42 are on different chromosomes yet both appear to be very strong hits for pelvic organ prolapse. While diseases of the nervous system can cause pelvic organ prolapse, it is unlikely related to the ptau/AB42 relationship, but it may suggest that these two loci share some pathway. Rs103681914 also resides in the ZFAT gene, which is related to autoimmune thyroid disease. For tau, rs9817620 interacts with the tau/AB42 rQTL rs74025622. It is in the CHL1 gene, which is a neural cell adhesion molecule and may be involved in signal transduction pathways. CHL1 is related to BACE1, which is a b-secretase enzyme that initiates production of the b-amyloid peptide involved in Alzheimer disease and is a primary drug target. Overall, there are numerous loci that affect the relationship between these important Alzheimer’s disease endophenotypes and some are due to interactions with other loci. They may also modify their relationship to risk of Alzheimer’s and/or rate of progression.
P4-292
RQTL THAT AFFECT THE RELATIONSHIP BETWEEN Aß42, TAU AND PTAU, AND LOCI THAT INTERACT WITH THEM (GXG)