Multilevel Models for Longitudinal Data

Longitudinal data arise when individuals are measured several times during an ob- servation period and thus the data for each individual are not independent. There are several ways of analyzing longitudinal data when different treatments are com- pared. Multilevel models are used to analyze data that are clustered in some way. In this work, multilevel models are used to analyze longitudinal data from a case study. Results from other more commonly used methods are compared to multilevel models. Also, comparison in output between two software, SAS and R, is done. Finally a method consisting of fitting individual models for each individual and then doing ANOVA type analysis on the estimated parameters of the individual models is proposed and its power for different sample sizes and effect sizes is studied by simulation

Statistical Approaches for Functional Annotation Tree Guided Prioritization of Genome-wide Association Studies (GWAS) Results

Genome-wide association studies (GWAS) have successfully identified over two hundred thousand trait risk-associated genetic variants; however, several challenges remain. First, a complex trait is associated with many single nucleotide polymorphisms (SNPs), each with small or moderate effect sizes that are hard to detect with limited sample size due to a phenomenon called polygenicity. Additionally, currently available statistical methods are limited in explaining the functional mechanisms through which genetic variants are associated with complex traits. In the first dissertation aim, we address these challenges by proposing a statistical approach called GPA-Tree. GPA-Tree integratesGWAS summary statistics and functional annotation information for a single trait within a unified framework. Specifically, by combining a decision tree algorithm with a hierarchical modeling framework, GPA-Tree simultaneously implements association mapping and identifies key combinations of functional annotations related to the trait risk-associated SNPs. We evaluate the proposed GPA-Tree approach using simulation studies and demonstrate that, in most scenarios, GPA-Tree shows greater area under the curve (AUC) and power relative to existing statistical approaches in detecting risk-associated SNPs and greater accuracy in identifying the true combinations of functional annotations. We applied GPA-Tree to a systemic lupus erythematosus (SLE) GWAS and functional annotation data including GenoSkyline and GenoSkylinePlus. The results from GPA-Tree highlight the dysregulation of blood immune cells, including but not limited to primary B, memory helper T, regulatory T, neutrophils and CD8+ memory T cells. The second dissertation aim exploits the phenomenon called pleiotropy, shared genetic basis among multiple traits, to improve statistical power to detect SNPs associated with one or more traits. We extend GPA-Tree to develop Multi-GPA-Tree so that GWAS summary statistics for multiple traits and functional annotation information can be integrated within a unified framework. Specifically, by combining a multivariate decision tree algorithm with a hierarchical modeling framework, Multi-GPA-Tree simultaneously implements association mapping and identifies key combinations of functional annotations related to the SNPs associated with one or more traits. We evaluate the proposed Multi-GPA-Tree approach using simulation studies and demonstrate that, in most scenarios, Multi-GPA-Tree outperforms existing statistical approaches in detecting SNPs associated with one or more traits and identifying the true combinations of functional annotations with high accuracy. We utilize Multi-GPA-Tree to integrate GWAS from two rheumatic diseases, SLE and Rheumatoid Arthritis (RA), and GWAS from two inflammatory bowel diseases, Crohn’s trait (CD) and ulcerative colitis (UC), with GenoSkyline and GenoSkylinePlus annotations. The results from Multi-GPA-Tree highlight the dysregulation of blood immune cells for both joint analysis, including dysregulation of primary B cells for SLE and RA, and dysregulation of primary T regulatory cells for UC and CD. In the third dissertation aim, we develop the R package GPATree and the R Shiny app ShinyGPATree. The R package and Shiny app facilitate users’ convenience and make the GPA-Tree and Multi-GPA-Tree approach easily accessible. The package includes an example data and a vignette to facilitate seamless step-by-step implementation of the proposed methods. In addition, the Shiny app allows interactive and dynamic investigation of association mapping results and functional annotation trees

Effects of open dumping site on surrounding air, soil, and water: a case study of Biratnagar metropolitan city

Managing solid waste is one of the emerging challenges in urban areas, and open dumping and burning is common practices mostly in developing countries like Nepal. Which affects the overall surroundings. The study has investigated the effects of open dumping and burning in nearby air, soil, and river water in dumping site of Biratnagar metropolitan city. For studying the effects on air, the three samples of air were taken, at center and 100m upstream and downstream to the direction of wind flow. Soil samples were taken at 10m from the dumping site center, at 25m from the first sample and at 60m from the second sample, and the water samples were taken at leachate and 100 m upstream and downstream to the leachate. Soil and water were subjected to the physiochemical test, heavy metals test and microbes test whereas PM 2.5, and PM 10 were tested for air  quality. The results showed that the air from upstream has been seen carrying particulate matter from the dumping site to downstream. Similarly, it is found that the quality of water at leachate and downstream is degraded compared to upstream. The soil quality has been found to have degraded due to the harmful and toxic material of the dumping site. Thus, this study shows that open dumping and burning have affected the nearby air, water, and soil

Predictors of Sinonasal Improvement After Highly Effective Modulator Therapy in Adults with Cystic Fibrosis

The 22-question SinoNasal Outcome Test (SNOT-22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT-22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT-22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF)

multi-GPA-Tree: Statistical approach for pleiotropy informed and functional annotation tree guided prioritization of GWAS results.

Genome-wide association studies (GWAS) have successfully identified over two hundred thousand genotype-trait associations. Yet some challenges remain. First, complex traits are often associated with many single nucleotide polymorphisms (SNPs), most with small or moderate effect sizes, making them difficult to detect. Second, many complex traits share a common genetic basis due to 'pleiotropy' and and though few methods consider it, leveraging pleiotropy can improve statistical power to detect genotype-trait associations with weaker effect sizes. Third, currently available statistical methods are limited in explaining the functional mechanisms through which genetic variants are associated with specific or multiple traits. We propose multi-GPA-Tree to address these challenges. The multi-GPA-Tree approach can identify risk SNPs associated with single as well as multiple traits while also identifying the combinations of functional annotations that can explain the mechanisms through which risk-associated SNPs are linked with the traits. First, we implemented simulation studies to evaluate the proposed multi-GPA-Tree method and compared its performance with existing statistical approaches. The results indicate that multi-GPA-Tree outperforms existing statistical approaches in detecting risk-associated SNPs for multiple traits. Second, we applied multi-GPA-Tree to a systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and to a Crohn's disease (CD) and ulcertive colitis (UC) GWAS, and functional annotation data including GenoSkyline and GenoSkylinePlus. Our results demonstrate that multi-GPA-Tree can be a powerful tool that improves association mapping while facilitating understanding of the underlying genetic architecture of complex traits and potential mechanisms linking risk-associated SNPs with complex traits

Face-to-face training as an effective approach for instructing rotahaler technique in newly diagnosed cases of asthma and COPD: a pilot study

Introduction: This study aimed to evaluate the effectiveness of face-to-face training for instructing rotahaler technique in newly diagnosed cases of asthma and chronic obstructive pulmonary disease (COPD). Methods: A hospital-based study was conducted on twenty patients who were prescribed rotahaler for the first time. Patients received face-to-face training on rotahaler technique from pharmacist using GINA guidelines. The patients rotahaler technique was assessed after two weeks of training and scored one for correct and zero for incorrect steps. Descriptive statistics was performed. Results: The mean age of the study population was 48.85±20.49 years. Eleven (55%) patients were females and 13 (65%) were formally uneducated. Fourteen patients (70%) were able to perform all the steps correctly giving overall median score of 8 (7-8). Conclusions: Face-to-face training seems to be effective approach for instructing rotahaler technique in asthma and COPD patients

Effects of open dumping site on surrounding air, soil, and water: a case study of Biratnagar metropolitan city

Managing solid waste is one of the emerging challenges in urban areas, and open dumping and burning is common practices mostly in developing countries like Nepal. Which affects the overall surroundings. The study has investigated the effects of open dumping and burning in nearby air, soil, and river water in dumping site of Biratnagar metropolitan city. For studying the effects on air, the three samples of air were taken, at center and 100m upstream and downstream to the direction of wind flow. Soil samples were taken at 10m from the dumping site center, at 25m from the first sample and at 60m from the second sample, and the water samples were taken at leachate and 100 m upstream and downstream to the leachate. Soil and water were subjected to the physiochemical test, heavy metals test and microbes test whereas PM 2.5, and PM 10 were tested for air  quality. The results showed that the air from upstream has been seen carrying particulate matter from the dumping site to downstream. Similarly, it is found that the quality of water at leachate and downstream is degraded compared to upstream. The soil quality has been found to have degraded due to the harmful and toxic material of the dumping site. Thus, this study shows that open dumping and burning have affected the nearby air, water, and soil

Remission of lupus nephritis: the trajectory of histological response in successfully treated patients

Objective This study investigated changes in kidney histology over time in patients with lupus nephritis (LN) undergoing immunosuppressive treatment.Methods Patients with proliferative±membranous LN were studied. After a diagnostic kidney biopsy (Bx1), patients had protocol biopsy 2 (Bx2) at 9 (6–15) months and protocol biopsy 3 (Bx3) at 42 (28–67) months. Kidney histological activity and chronicity indices (AI, CI) were measured.Results AI declined in a biphasic fashion, falling rapidly between Bx1 and Bx2 and then more slowly between Bx2 and Bx3. Patients were divided into those who achieved histological remission, defined as an AI=0 at Bx3 (group 1), and those with persistent histological activity (AI >0) at Bx3 (group 2). The early decline in AI was 1.6 times greater (95% CI 1.30, 1.91) in group 1 than group 2 (p=0.01). Between Bx2 and Bx3, the AI decline was 2.19-fold greater (95% CI 2.09, 2.29) in group 1 versus group 2 (p=7.34×10−5). Individual histological components of the AI resolved at different rates. Inflammatory lesions like glomerular crescents, karyorrhexis and necrosis mostly resolved by Bx2, whereas endocapillary hypercellularity, subendothelial hyaline deposits and interstitial inflammation resolved slowly, accounting for residual histological activity at biopsy 3 in group 2. In contrast, CI increased rapidly, by 0.15 units/month between Bx1 and Bx2, then plateaued. There were no differences in the rate of accumulation of chronic damage between group 1 and group 2. The increase in CI was significantly related to the severity of glomerular crescents (p=0.044), subendothelial hyaline deposits (p=0.002) and interstitial inflammation (p=0.015) at Bx1.Conclusions LN histological activity takes months to years to resolve, providing a rationale for the need of long-term, well-tolerated maintenance immunosuppression. Despite responding, LN kidneys accrue chronic damage early during treatment. This finding provides an explanation for the association of chronic progressive kidney disease with recurrent episodes of LN

Effects of vitamin D supplementation on circulating concentrations of growth factors and immune-mediators in healthy women during pregnancy

OBJECTIVE: For the second aim of the Kellogg Foundation grant, this double-blind RCT investigated the impact of plasma vitamin D metabolite, 25-hydroxyvitamin D (25(OH)D) on plasma immune-mediators during pregnancy. We hypothesized that higher 25(OH)D concentrations would associate with reduced pro-inflammatory and increased tolerogenic immune-mediator concentrations. METHOD: Pregnant women enrolled at 10–14 weeks gestation were randomized to 400 or 4400 IU vitamin D(3)/day. Data on health, safety, circulating 25(OH)D, and 9 immune-mediators were collected at each trimester. Associations between immune-mediators and 25(OH)D at baseline and at 2(nd) and 3(rd) trimesters were examined. RESULTS: Baseline TGF-β and 2(nd) and 3(rd) trimesters IFN-γ and IL-2 were associated with baseline 25(OH)D. Baseline immune-mediators were associated with immune-mediators at 2(nd) and 3(rd) trimesters for all immune-mediators except IL-5 and IL-10. Race was associated with baseline TGF-β, VEGF and IL-10 and with IL-10 at 2(nd) and 3(rd) trimesters. CONCLUSION: Both treatment groups had increased 25(OH)D at 2(nd) and 3(rd) trimesters, greatest in the 4400 IU group. Though associations between baseline 25(OH)D and baseline TGF-β and 2(nd) and 3(rd) trimester IFN-γ and IL-2 were noted, vitamin D supplementation throughout pregnancy did not impact immune-mediators at later trimesters. Supplementing with vitamin D before conception conceivably influences immune-mediator responses during pregnancy

Determining the Minimal Clinically Important Difference for the Questionnaire of Olfactory Disorders in People with Cystic Fibrosis and Factors Associated with Improvement After Highly Effective Modulator Therapy.

Introduction Olfactory dysfunction (OD) is common among people with cystic fibrosis (PwCF). The Questionnaire of Olfactory Disorders (QOD) is a validated instrument that evaluates olfactory-specific quality-of-life. The QOD minimal clinically important difference (MCID) and factors associated with olfactory improvement after elexacaftor/tezacaftor/ivacaftor have not been determined for PwCF. Methods Prospective observational data were pooled from three studies that enrolled adult PwCF with chronic rhinosinusitis (CRS). QOD scores and disease characteristics were assessed. To evaluate internal consistency and calculate the QOD MCID, Cronbach\u27s alpha and four distribution-based methods were employed. For participants who enrolled prior to elexacaftor/tezacaftor/ivacaftor, QOD scores were obtained at baseline and after elexacaftor/tezacaftor/ivacaftor initiation. Multivariable regression was used to identify factors associated with QOD improvement. Results Of 129 PwCF included, 65 had QOD scores before and 3–6 months after starting elexacaftor/tezacaftor/ivacaftor. Mean baseline QOD score was 6.5 ± 7.9. Mean Cronbach\u27s alpha was ≥0.85. The MCID estimates were as follows: Cohen\u27s effect size = 1.6, standard error of measurement = 2.5, ½ baseline standard deviation = 4.0, and minimal detectable change = 6.9. Mean MCID was 3.7. Of those with pre/post elexacaftor/tezacaftor/ivacaftor QOD scores, the mean change in QOD was −1.3 ± 5.4. After elexacaftor/tezacaftor/ivacaftor, QOD improvement surpassed the MCID in 22% of participants (14/65). Worse baseline QOD scores and nasal polyps were associated with improved QOD scores after elexacaftor/tezacaftor/ivacaftor (both p \u3c 0.04). Conclusion The QOD MCID in PwCF was estimated to be 3.7. Elexacaftor/tezacaftor/ivacaftor led to qualitative but not clinically meaningful improvements in QOD score for most PwCF; PwCF with worse baseline QOD scores and nasal polyps improved in a clinically significant manner