Shubhabrata Mukherjee - Academia.edu (original) (raw)

Papers by Shubhabrata Mukherjee

¶ Membership of the Alzheimer's Disease Genetics Consortium, the Genetic and Environmental Risk i... more ¶ Membership of the Alzheimer's Disease Genetics Consortium, the Genetic and Environmental Risk in AD (GERAD1) Consortium, and the EPIC-InterAct Consortium is provided in S1 Text. Data used in the preparation of this article were obtained from GERAD1. As such, the investigators within GERAD1 contributed to the design and implementation of GERAD1 and/or provided data but did not participate in the analysis or writing of this report.

Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 12, 2015

Observational research shows that higher body mass index (BMI) increases Alzheimer's disease ... more Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.9...

PLOS Medicine, 2015

Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are as... more Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). project/B6C58A7C-3C3E-41CB-AF10-16DB59962C9E). To promote collaboration and wide use of data in order to further Alzheimer's Disease research, qualified investigators can submit proposals to conduct analyses using results from the Genetic and Environmental Risk in Alzheimer's Disease (GERAD) analysis or, in collaboration with with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10 −3 )

Neurobiology of Aging, 2015

Alzheimer&amp... more Alzheimer's disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimer's Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways.

ACM SIGKDD Explorations Newsletter, 2014

Frontiers in Genetics, 2014

Technometrics, 2008

In this article we propose inferential procedures for a gamma distribution using the Wilson-Hilfe... more In this article we propose inferential procedures for a gamma distribution using the Wilson-Hilferty (WH) normal approximation. Specifically, using the result that the cube root of a gamma random variable is approximately normally distributed, we propose normal-based approaches for a gamma distribution for (a) constructing prediction limits, one-sided tolerance limits, and tolerance intervals; (b) for obtaining upper prediction limits for at least l of m observations from a gamma distribution at each of r locations; and (c) assessing the reliability of a stress-strength model involving two independent gamma random variables. For each problem, a normal-based approximate procedure is outlined, and its applicability and validity for a gamma distribution are studied using Monte Carlo simulation. Our investigation shows that the approximate procedures are very satisfactory for all of these problems. For each problem considered, the results are illustrated using practical examples. Our overall conclusion is that the WH normal approximation provides a simple, easy-to-use unified approach for addressing various problems for the gamma distribution.

Metrika, 2007

The problem of hypothesis testing and interval estimation of the reliability parameter in a stres... more The problem of hypothesis testing and interval estimation of the reliability parameter in a stress-strength model involving two-parameter exponential distributions is considered. Test and interval estimation procedures based on the generalized variable approach are given. Statistical properties of the generalized variable approach and an asymptotic method are evaluated by Monte Carlo simulation. Simulation studies show that the proposed generalized variable approach is satisfactory for practical applications while the asymptotic approach is not satisfactory even for large samples. The results are illustrated using simulated data.

Mathematical and Computer Modelling, 2004

paper deals with some studies pertaining to nonprocessive recombinase viz.

Journal of the International Neuropsychological Society, 2011

Older African Americans tend to perform poorly in comparison with older Whites on episodic memory... more Older African Americans tend to perform poorly in comparison with older Whites on episodic memory tests. Observed group differences may reflect some combination of biological differences, measurement bias, and other confounding factors that differ across groups. Cognitive reserve refers to the hypothesis that factors, such as years of education, cognitive activity, and socioeconomic status, promote brain resilience in the face of pathological threats to brain integrity in late life. Educational quality, measured by reading test performance, has been postulated as an important aspect of cognitive reserve. Previous studies have not concurrently evaluated test bias and other explanations for observed differences between older African Americans and Whites. We combined data from two studies to address this question. We analyzed data from 273 African American and 720 White older adults. We assessed DIF using an item response theory/ordinal logistic regression approach. DIF and factors associated with cognitive reserve did not explain the relationship between race, and age-and sex-adjusted episodic memory test performance. However, reading level did explain this relationship. The results reinforce the importance of considering education quality, as measured by reading level, when assessing cognition among diverse older adults.

The genetic basis of resilience, defined as better cognitive functioning than predicted based on ... more The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD *Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at:

Human molecular genetics, Jan 11, 2015

The CD33 single nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzh... more The CD33 single nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by about 25% and decreases the AD odds ratio by about 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as Lintuzu...

Genes and Immunity, 2014

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). V... more Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

¶ Membership of the Alzheimer's Disease Genetics Consortium, the Genetic and Environmental Risk i... more ¶ Membership of the Alzheimer's Disease Genetics Consortium, the Genetic and Environmental Risk in AD (GERAD1) Consortium, and the EPIC-InterAct Consortium is provided in S1 Text. Data used in the preparation of this article were obtained from GERAD1. As such, the investigators within GERAD1 contributed to the design and implementation of GERAD1 and/or provided data but did not participate in the analysis or writing of this report.

Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 12, 2015

Observational research shows that higher body mass index (BMI) increases Alzheimer's disease ... more Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.9...

PLOS Medicine, 2015

Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are as... more Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). project/B6C58A7C-3C3E-41CB-AF10-16DB59962C9E). To promote collaboration and wide use of data in order to further Alzheimer's Disease research, qualified investigators can submit proposals to conduct analyses using results from the Genetic and Environmental Risk in Alzheimer's Disease (GERAD) analysis or, in collaboration with with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10 −3 )

Neurobiology of Aging, 2015

Alzheimer&amp... more Alzheimer's disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimer's Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways.

ACM SIGKDD Explorations Newsletter, 2014

Frontiers in Genetics, 2014

Technometrics, 2008

In this article we propose inferential procedures for a gamma distribution using the Wilson-Hilfe... more In this article we propose inferential procedures for a gamma distribution using the Wilson-Hilferty (WH) normal approximation. Specifically, using the result that the cube root of a gamma random variable is approximately normally distributed, we propose normal-based approaches for a gamma distribution for (a) constructing prediction limits, one-sided tolerance limits, and tolerance intervals; (b) for obtaining upper prediction limits for at least l of m observations from a gamma distribution at each of r locations; and (c) assessing the reliability of a stress-strength model involving two independent gamma random variables. For each problem, a normal-based approximate procedure is outlined, and its applicability and validity for a gamma distribution are studied using Monte Carlo simulation. Our investigation shows that the approximate procedures are very satisfactory for all of these problems. For each problem considered, the results are illustrated using practical examples. Our overall conclusion is that the WH normal approximation provides a simple, easy-to-use unified approach for addressing various problems for the gamma distribution.

Metrika, 2007

The problem of hypothesis testing and interval estimation of the reliability parameter in a stres... more The problem of hypothesis testing and interval estimation of the reliability parameter in a stress-strength model involving two-parameter exponential distributions is considered. Test and interval estimation procedures based on the generalized variable approach are given. Statistical properties of the generalized variable approach and an asymptotic method are evaluated by Monte Carlo simulation. Simulation studies show that the proposed generalized variable approach is satisfactory for practical applications while the asymptotic approach is not satisfactory even for large samples. The results are illustrated using simulated data.

Mathematical and Computer Modelling, 2004

paper deals with some studies pertaining to nonprocessive recombinase viz.

Journal of the International Neuropsychological Society, 2011

Older African Americans tend to perform poorly in comparison with older Whites on episodic memory... more Older African Americans tend to perform poorly in comparison with older Whites on episodic memory tests. Observed group differences may reflect some combination of biological differences, measurement bias, and other confounding factors that differ across groups. Cognitive reserve refers to the hypothesis that factors, such as years of education, cognitive activity, and socioeconomic status, promote brain resilience in the face of pathological threats to brain integrity in late life. Educational quality, measured by reading test performance, has been postulated as an important aspect of cognitive reserve. Previous studies have not concurrently evaluated test bias and other explanations for observed differences between older African Americans and Whites. We combined data from two studies to address this question. We analyzed data from 273 African American and 720 White older adults. We assessed DIF using an item response theory/ordinal logistic regression approach. DIF and factors associated with cognitive reserve did not explain the relationship between race, and age-and sex-adjusted episodic memory test performance. However, reading level did explain this relationship. The results reinforce the importance of considering education quality, as measured by reading level, when assessing cognition among diverse older adults.

The genetic basis of resilience, defined as better cognitive functioning than predicted based on ... more The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD *Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at:

Human molecular genetics, Jan 11, 2015

The CD33 single nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzh... more The CD33 single nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by about 25% and decreases the AD odds ratio by about 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as Lintuzu...

Genes and Immunity, 2014

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). V... more Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.