Papers by Nallakkandi Rajeevan
Human Genomics, Jun 2, 2023
Background The Million Veteran Program (MVP) participants represent 100 years of US history, incl... more Background The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]). Results Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen's d < 0.259, p < 7.80 × 10 −4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics.
Social Cognitive and Affective Neuroscience, Dec 1, 2009
Psychological Science, Apr 30, 2010
Australian and New Zealand Journal of Psychiatry, Feb 1, 2011
Objective-This study indirectly tested the hypothesis that individuals with autism spectrum disor... more Objective-This study indirectly tested the hypothesis that individuals with autism spectrum disorders (ASDs) have impaired neural connections between the amygdala, fusiform face area, and superior temporal sulcus, key processing nodes of the "social brain." This would be evidenced by abnormalities in the major fibre tracts known to connect these structures, including the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus. Method-Magnetic resonance diffusion tensor imaging was performed on 20 right-handed males (ASD = 10, controls = 10) with a mean age 13.5 ± 4.0 years. Subjects were group-matched according to age, full-scale IQ, handedness, and ethnicity. Fractional anisotropy was used to assess structural integrity of major fibre tracts. Voxel-wise comparison of white matter fractional anisotropy was conducted between groups using ANCOVA adjusting for age, full-scale IQ, and brain volume. Volumes of interest were identified using predetermined probability and cluster thresholds. Follow-up tractography was performed to confirm the anatomic location of all volumes of interest. Results-All volumes of interest were regions of lower FA and were observed primarily in pericallosal regions and temporal lobes. As confirmed by tractography, affected white matter structures included the inferior longitudinal fasciculus/inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and corpus callosum/cingulum. Notably, some volumes of interest were adjacent to the fusiform face area, bilaterally, corresponding to involvement of the inferior longitudinal fasciculus. The largest effect sizes were noted for volumes of interest in the right anterior radiation of the corpus callosum/cingulum and right fusiform face area (inferior longitudinal fasciculus).
Insight Journal, Aug 5, 2005
BioImage Suite is an integrated image analysis software suite developed at Yale. It uses a combin... more BioImage Suite is an integrated image analysis software suite developed at Yale. It uses a combination of C++ and Tcl in the same fashion as that pioneered by the Visualization Toolkit (VTK) and it leverages both VTK and the Insight Toolkit. It has extensive capabilities for both neuro/cardiac and abdominal image analysis and state of the art visualization. It is currently in use at Yale; a first public release is expected before the end of 2005.
Objective: Develop models to predict 30-day COVID-19 hospitalization and death in the Omicron era... more Objective: Develop models to predict 30-day COVID-19 hospitalization and death in the Omicron era for clinical and research applications.Material and Methods: We used comprehensive electronic health records from a national cohort of patients in the Veterans Health Administration (VHA) who tested positive for SARS-CoV-2 between March 1, 2022, and March 31, 2023. Full models incorporated 84 predictors , including demographics, comorbidities, and receipt of COVID-19 vaccinations and anti-SARS-CoV-2 treatments. Parsimonious models included 19 predictors. We created models for 30-day hospitalization or death, 30-day hospitalization, and 30-day all-cause mortality. We used the Super Learner ensemble machine learning algorithm to model risks. Model performance was assessed with the area under the receiver operating characteristic curve (AUC), Brier scores, and calibration intercepts and slopes in a 20% holdout dataset.Results: Models were trained and tested on 198,174 patients, of whom 8% ...
European Neuropsychopharmacology, 2019
effects of these variants on MCPH1 function. Cell viability and cell count assays indicated that ... more effects of these variants on MCPH1 function. Cell viability and cell count assays indicated that the variant allele of rs199422124 had a larger impact on cell survival compared to the variant allele of rs61749465, however neither of the variant alleles significantly altered DNA damage or mRNA stability. Gene expression analysis for rs61749465 using RNAseq shows that the expression of a number of heat shock protein have been affected. Gene network and pathway analysis indicated that the variant alleles may impact cellular aging and protein translation. Discussion: Further in vitro and in vivo characterization of the rs61749465 variant in MCPH1 may provide insight into the molecular pathogenesis of psychosis.
PubMed, Aug 1, 2000
This study evaluated the test-retest reproducibility of D2 receptor quantification in the thalamu... more This study evaluated the test-retest reproducibility of D2 receptor quantification in the thalamus and temporal cortex using [123I]epidepride SPECT. Methods: Ten healthy volunteers (4 men, 6 women; age range, 19-46 y) underwent 2 SPECT studies (interval, 2-26 d) using a bolus-plus-constant-infusion paradigm (bolus-to-infusion ratio = 6 h; infusion time = 9 h). Plasma clearance (in liters per hour) and free fraction (f1) of the parent tracer were measured. Radioactivity (in becquerels per gram) in the thalamus, temporal cortex, and cerebellum were normalized to the infusion rate (in becquerels per hour). Normalized striatal radioactivity was also measured to assess reproducibility in regions with a high density of receptors and better counting statistics. The outcome measures obtained were V3 (receptor density [Bmax]/equilibrium dissociation constant [KD]), V3' (f1 x Bmax/KD), and RT (specific-to-nondisplaceable tissue ratio). Results: Test-retest variability and reliability (intraclass correlation coefficient) were 10.8% and 0.88, respectively, for plasma clearance and 15.3% and 0.77, respectively, for f1. The test-retest variability of brain-specific (target minus nondisplaceable) radioactivity was higher in the thalamus and temporal cortex than in the striatum, although reliability was comparable. Among the outcome measures, V3' showed better test-retest variability and reliability in the thalamus (13.3% and 0.75, respectively) and temporal cortex (13.4% and 0.86, respectively). Conclusion: Brain radioactivity was the main source of variability for quantification of extrastriatal D2 receptors with [123I]epidepride. The reproducibility of outcome measures in extrastriatal regions was good. However, because receptor density was lower in extrastriatal regions than in the striatum, the counting statistics in these regions were low and reproducibility was affected by the higher test-retest variability of brain-specific radioactivity. Compared with V3 and V3', RT showed less test-retest variability in the thalamus and temporal cortex but lower reliability. Moreover, measurement of RT may be affected by the presence of potential lipophilic metabolites entering the brain.
PubMed, Oct 1, 1998
The purposes of this study were to develop a method for nonuniform attenuation correction of 123I... more The purposes of this study were to develop a method for nonuniform attenuation correction of 123I emission brain images based on transmission imaging with a longer-lived isotope (i.e., 57Co) and to evaluate the relative improvement in quantitative SPECT images achieved with nonuniform attenuation correction. Methods: Emission and transmission SPECT scans were acquired on three different sets of studies: a heterogeneous brain phantom filled with 1231 to simulate the distribution of dopamine transporters labeled with 2beta-carbomethoxy-3beta-(4-123I-iodophenyl)tropane (123I-beta-CIT); nine healthy human control subjects who underwent transmission scanning using two separate line sources (57Co and 123I); and a set of eight patients with Parkinson's disease and five healthy control subjects who received both emission and transmission scans after injection of 123I-beta-CIT. Attenuation maps were reconstructed using a Bayesian transmission reconstruction algorithm, and attenuation correction was performed using Chang's postprocessing method. The spatial distribution of errors within the brain was obtained from attenuation correction factors computed from uniform and nonuniform attenuation maps and was visualized on a pixel-by-pixel basis as an error image. Results: For the heterogeneous brain phantom, the uniform attenuation correction had errors of 2%-6.5% for regions corresponding to striatum and background, whereas nonuniform attenuation correction was within 1%. Analysis of 123I transmission images of the nine healthy human control subjects showed differences between uniform and nonuniform attenuation correction to be in the range of 6.4%-16.0% for brain regions of interest (ROIs). The human control subjects who received transmission scans only were used to generate a curvilinear function to convert 57Co attenuation values into those for 123I, based on a pixel-by-pixel comparison of two coregistered transmission images for each subject. These values were applied to the group of patients and healthy control subjects who received transmission 57Co scans and emission 123I scans after injection of 123I-beta-CIT. In comparison to nonuniform attenuation correction as the gold standard, uniform attenuation with the ellipse drawn around the transmission image caused an approximately 5% error, whereas placement of the ellipse around the emission image caused a 15% error. Conclusion: Nonuniform attenuation correction allowed a moderate improvement in the measurement of absolute activity in individual brain ROIs. When images were analyzed as target-to-background activity ratios, as is commonly performed with 123I-beta-CIT, these outcome measures showed only small differences when Parkinson's disease patients and healthy control subjects were compared using nonuniform, uniform or even no attenuation correction.
Epilepsia, Oct 1, 1999
To evaluate effects of vigabatrin (VGB) by using [123I]iomazenil single-photon emission computed ... more To evaluate effects of vigabatrin (VGB) by using [123I]iomazenil single-photon emission computed tomography (SPECT) to estimate central gamma-aminobutyric acid (GABA(A))/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]iomazenil concentration to estimate BZR distribution volume (V(T)-p and V&amp;amp;#39;(T), respectively). Wilcoxon&amp;amp;#39;s test was used for VOI differences in GABA levels, BZR V(T)-p or V&amp;amp;#39;(T). SPM96 (either no global normalization or proportional scaling) was used to compare BZR V(T)-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. Occipital GABA levels were increased threefold (without VGB, 1.1+/-0.1 micromol/g; with VGB, 2.9+/-0.5 micromol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V(T)-p (without VGB, 6.00+/-0.91 ml/g; with VGB, 5.86+/-0.44 ml/g; p = 0.92) or V(T) (without VGB, 41.1+/-11.2 ml/g; with VGB, 41.2+/-9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.
Journal of the American Geriatrics Society, Aug 14, 2017
Background/Objectives-Polypharmacy and prescribing potentially inappropriate medications (PIMs) a... more Background/Objectives-Polypharmacy and prescribing potentially inappropriate medications (PIMs) are common among older persons. Appropriate prescribing requires robust communication and shared decision making about medications. This study examines the effect of TRIM (Tool to Reduce Inappropriate Medications), a web tool linking the electronic health record (EHR) to a clinical decision support system, on medication communication and prescribing.
medRxiv (Cold Spring Harbor Laboratory), Dec 6, 2022
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
Personalized Medicine in Psychiatry, Jul 1, 2021
Background.Personalization of psychiatric treatment includes treatment of symptoms, cognition and... more Background.Personalization of psychiatric treatment includes treatment of symptoms, cognition and functional deficits, suicide, and medical co-morbidities. VA Collaborative Study 572 examined a large sample of male and female veterans with schizophrenia (n=3,942) and with bipolar disorder (n=5,414) with phenotyping and genomic analyses. We present the results to date and future directions.Methods.All veterans received a structured diagnostic interview and assessments of suicidal ideation and behavior, PTSD, and health. Veterans with schizophrenia were assessed for negative symptoms and lifetime depression. All were assessed with a cognitive and functional capacity assessment. Data for genome wide association studies were collected. Controls came from the VA Million Veteran Program.Results.Suicidal ideation or behavior was present in 66%. Cognitive and functional deficits were consistent with previous studies. 40% of the veterans with schizophrenia had a lifetime major depressive episode and PTSD was present in over 30%. Polygenic risk score (PRS) analyses indicated that cognitive and functional deficits overlapped with PRS for cognition, education, and intelligence in the general population and PRS for suicidal ideation and behavior correlated with previous PRS for depression and suicidal ideation and behavior, as did the PRS for PTSD.Discussion.Results to date provide directions for personalization of treatment in SMI, veterans with SMI, and veterans in general. The results of the genomic analyses suggest that cognitive deficits in SMI may be associated with general population features. Upcoming genomic analyses will reexamine the issues above, as well as genomic factors associated with smoking, substance abuse, negative symptoms, and treatment response.
JMIR medical informatics, Aug 18, 2014
Recent consensus definitions have made a distinction between EHRs (electronic health records, rec... more Recent consensus definitions have made a distinction between EHRs (electronic health records, records that span organizations), and EMRs (electronic medical records that contain information from a single organization). 6 As technology develops there will likely be more development of EHRs, but since EMRs are more common today the term EMR will be used throughout this paper.
American Journal of Psychiatry, Nov 1, 1998
Biological Psychiatry, May 1, 2023
Biological Psychiatry, May 1, 2022
Biological Psychiatry, May 1, 2020
Full consortium authorship is listed in supplementary acknowledgments.
Cell Host & Microbe, 2014
Arthopods such as Ixodes scapularis ticks serve as vectors for many human pathogens. The arthropo... more Arthopods such as Ixodes scapularis ticks serve as vectors for many human pathogens. The arthropod gut presents a pivotal microbial entry point and determines pathogen colonization and survival. We show that the gut microbiota of I. scapularis, a major vector of the Lyme disease spirochete Borrelia burgdorferi, influence spirochete colonization of ticks. Perturbing the gut microbiota of larval ticks reduced Borrelia colonization, and dysbiosed larvae displayed decreased expression of the transcription factor signal transducer and activator of transcription (STAT). Diminished STAT expression corresponded to lower expression of peritrophin, a key glycoprotein scaffold of the glycan-rich mucus-like peritrophic matrix (PM) that separates the gut lumen from the epithelium. The integrity of the I. scapularis PM was essential for B. burgdorferi to efficiently colonize the gut epithelium. These data elucidate a functional link between the gut microbiota, STATsignaling, and pathogen colonization in the context of the gut epithelial barrier of an arthropod vector.
Journal of Affective Disorders, Apr 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Uploads
Papers by Nallakkandi Rajeevan