31 research outputs found
Candidate-Pathway Gene Environment Interactions on Colon and Rectal Cancer Risk and Survival: Methodological Frameworks for Interaction in Genetic Association Studies
No full textGenetic association studies have adopted for a long time a traditional analytic approach that focuses on individual genetic markers, usually single nucleotide polymorphisms (SNPs), in association with disease or phenotype. A standard single-SNP analysis that ignores combined effects of multiple SNPs and furthermore their interactions with environmental exposures, explains a small portion of disease heritability: an often cited issue of ‘missing heritability’. A comprehensive approach that accounts for these interactions carries the potential for identifying novel susceptibility loci and is more suited to decipher causal relationships and underlying molecular mechanisms of disease. The overall goal of this dissertation is to develop a methodologically sound framework that examines interactions in genetic association studies that is able to represent the biologic underpinnings of disease and yield interpretations that are statistically valid and of clinical and/or public health relevance. We first examined interactions between genetic variants at the gene level in genome-wide association study (GWAS) data of six common chronic diseases of the Wellcome-Trust-Case-Control-Consortium (WTCCC): bipolar disorder (BD); coronary artery disease (CAD); hypertension (HT); rheumatoid arthritis (RA); type 2 diabetes (T2D); and type 1 diabetes (T1D). We used logic regression to search for biologically plausible forms of SNP-set interactions within genes. Next, we extended our approach to test for gene-environment interaction (GEI) effects at the pathway level and applied it to the population-based case-control data of the Diet, Activity and Lifestyle as a Risk Factor for Colorectal Cancer Study. We focused on the candidate pathway of angiogenesis and three hypothesized environmental exposures: dietary protein intake; smoking; and alcohol consumption. Our approach consisted of 3-steps: the first two summarized the within gene effects and the full pathway effects; and the third step modelled the GEI effects on colon and rectal cancer risk and survival. Our interaction analysis was able to detect an appreciable number of susceptibility loci showing strong evidence of association with the six diseases in WTCCC, including novel signals supported by biologically plausible links to the diseases. The number of genes with strong evidence of association was: 13 for BD; 16 for CAD; 15 for HT; 72 for RA; 105 for T1D; and 19 for T2D. The top significant genes were: NFIA with BD, CDKN2B with CAD, COL4A4 with HT, BTNL2 with RA, and TCF7L2 with T2D. The majority of strong single-SNP signals of WTCCC and on average 46% of recent GWAS meta-analyses signals were confirmed in our analysis. The results of the GEI pathway analysis also yielded an appreciable number of significant and novel interactions. Overall the magnitudes of gene interaction odds and hazard ratios increased with increasing levels of the interacting environmental exposure. This observed positive gradient supported the plausibility of the interactions. We found five statistically significant GEIs associated with colon cancer risk and three GEIs with colon cancer survival involving all three environmental exposures. For rectal cancer, we found eight significant GEIs in association with risk involving six genes and five GEIs with survival. This dissertation showed how exploring interactions of all measured SNPs within each gene can identify appreciable numbers of novel susceptibility loci in GWAS. We also showed that GEI effects on colorectal cancer risk and survival can be identified by adopting a comprehensive candidate pathway approach that emphasizes the biologic hypothesis in the selection of the pathway genes and environmental exposures and carries that logic through the analysis
Multiple Gene-Environment Interactions on the Angiogenesis Gene-Pathway Impact Rectal Cancer Risk and Survival
No full textCharacterization of gene-environment interactions (GEIs) in cancer is limited. We aimed at identifying GEIs in rectal cancer focusing on a relevant biologic process involving the angiogenesis pathway and relevant environmental exposures: cigarette smoking, alcohol consumption, and animal protein intake. We analyzed data from 747 rectal cancer cases and 956 controls from the Diet, Activity and Lifestyle as a Risk Factor for Rectal Cancer study. We applied a 3-step analysis approach: first, we searched for interactions among single nucleotide polymorphisms on the pathway genes; second, we searched for interactions among the genes, both steps using Logic regression; third, we examined the GEIs significant at the 5% level using logistic regression for cancer risk and Cox proportional hazards models for survival. Permutation-based test was used for multiple testing adjustment. We identified 8 significant GEIs associated with risk among 6 genes adjusting for multiple testing: TNF (OR = 1.85, 95% CI: 1.10, 3.11), TLR4 (OR = 2.34, 95% CI: 1.38, 3.98), and EGR2 (OR = 2.23, 95% CI: 1.04, 4.78) with smoking; IGF1R (OR = 1.69, 95% CI: 1.04, 2.72), TLR4 (OR = 2.10, 95% CI: 1.22, 3.60) and EGR2 (OR = 2.12, 95% CI: 1.01, 4.46) with alcohol; and PDGFB (OR = 1.75, 95% CI: 1.04, 2.92) and MMP1 (OR = 2.44, 95% CI: 1.24, 4.81) with protein. Five GEIs were associated with survival at the 5% significance level but not after multiple testing adjustment: CXCR1 (HR = 2.06, 95% CI: 1.13, 3.75) with smoking; and KDR (HR = 4.36, 95% CI: 1.62, 11.73), TLR2 (HR = 9.06, 95% CI: 1.14, 72.11), EGR2 (HR = 2.45, 95% CI: 1.42, 4.22), and EGFR (HR = 6.33, 95% CI: 1.95, 20.54) with protein. GEIs between angiogenesis genes and smoking, alcohol, and animal protein impact rectal cancer risk. Our results support the importance of considering the biologic hypothesis to characterize GEIs associated with cancer outcomes
Single Nucleotide Polymorphisms on Toll-like Receptor-4 and the Risk of Developing Skin Cancer
No full textExposure to solar ultraviolet (UV) radiation is an established risk factor for skin cancer. Toll-like receptor-4 (TLR4)-mediated immune dysregulation has emerged as a key mechanism for the detrimental effects of acute and chronic UV exposure and skin cancer in mice. Single nucleotide polymorphisms (SNPs) on the TLR4 gene have been reported to increase or decrease susceptibility to various cancers in other organs. There is limited information on TLR4 SNPs and susceptibility to human keratinocyte carcinomas. The study’s objective is to test the association between TLR4 SNPs and the risk of developing keratinocyte carcinomas. Skin cancer patients and controls at the University of Alabama at Birmingham completed a cross-sectional survey on personal and family history of skin cancer as well as on sunscreen use and tanning proneness. Peripheral blood samples were obtained from participants, and DNA was extracted to genotype the TLR4 SNPs. Descriptive analytics were used to describe the cohort. Multivariable logistic regression models were used to assess the association between TLR4 SNPs and skin cancer risk. The sample consisted of a cohort of 93 skin cancer patients over the age of 50 and 94 controls; 33.3% of cases and 44.7% of controls were females; 12.9% of cases and 17% of controls had a TLR4 SNP. The most common SNP was D299G/T399I in 9.7% of skin cancer patients and 13.8% of controls. We did not find a statistically significant association between the D299G/T399I SNP and skin cancer (odds ratio (OR) = 0.34, 95% CI: 0.11, 1.07, p = 0.065) adjusting for age, sex, eye color, actinic keratosis, sunscreen use and reapplication, and family history of skin cancer. Based on our findings from our limited cohort of participants, we found some protective effect for the TLR4 SNP for skin cancer, which was not statistically significant. Validation of these findings in a larger cohort is warranted
Tele-Ophthalmology for Age-Related Macular Degeneration and Diabetic Retinopathy Screening: A Systematic Review and Meta-Analysis
No full textBackground: To synthesize high-quality evidence to compare traditional in-person screening and tele-ophthalmology screening.Methods: Only randomized controlled trials (RCTs) were included in this systematic review and meta-analysis. The intervention of interest was any type of tele-ophthalmology, including screening of diseases using remote devices. Studies involved patients receiving care from any trained provider via tele-ophthalmology, compared with those receiving equivalent face-to-face care. A search was executed on the following databases: Medline, EMBASE, EBM Reviews, Global Health, EBSCO-CINAHL, SCOPUS, ProQuest Dissertations and Theses Global, OCLC Papers First, and Web of Science Core Collection. Six outcomes of care for age-related macular degeneration (AMD), diabetic retinopathy (DR), or glaucoma were measured and analyzed.Results: Two hundred thirty-seven records were assessed at the full-text level; six RCTs fulfilled inclusion criteria and were included in this review. Four studies involved participants with diabetes mellitus, and two studies examined choroidal neovascularization in AMD. Only data of detection of disease and participation in the screening program were used for the meta-analysis. Tele-ophthalmology had a 14% higher odds to detect disease than traditional examination; however, the result was not statistically significant (n = 2,012, odds ratio: 1.14, 95% confidence interval (CI): 0.52-2.53, p = 0.74). Meta-analysis results show that odds of having DR screening in the tele-ophthalmology group was 13.15 (95% CI: 8.01-21.61; p \u3c 0.001) compared to the traditional screening program.Conclusions: The current evidence suggests that tele-ophthalmology for DR and age-related macular degeneration is as effective as in-person examination and potentially increases patient participation in screening
Review of economic evaluations of teleophthalmology as a screening strategy for chronic eye disease in adults
No full textBackground/aimsTeleophthalmology is well positioned to play a key role in screening of major chronic eye diseases. Economic evaluation of cost-effectiveness of teleophthalmology, however, is lacking. This study provides a systematic review of economic studies of teleophthalmology screening for diabetic retinopathy (DR), glaucoma and macular degeneration.MethodsStructured search of electronic databases and full article review yielded 20 cost-related articles. Sixteen articles fulfilled the inclusion criteria and were retained for a narrative review: 12 on DR, 2 on glaucoma and 2 on chronic eye disease.ResultsTeleophthalmology for DR yielded the most cost savings when compared with traditional clinic examination. The study settings varied among urban, rural and remote settings, community, hospital and health mobile units. The most important determinant of cost-effectiveness of teleophthalmology was the prevalence of DR among patients screened, indicating an increase of cost savings with the increase of screening rates. The required patient pool size to be screened varied from 110 to 3500 patients. Other factors potentially influencing cost-effectiveness of teleophthalmology were older patient age, regular screening and full utilisation of the equipment. Teleophthalmology for glaucoma was more cost-effective compared with in-person examination. Similarly, increasing number of glaucoma patients targeted for screening yielded more cost savings.ConclusionsThis economic review provides supportive evidence of cost-effectiveness of teleophthalmology for DR and glaucoma screening potentially increasing screening accessibility especially for rural and remote populations. Special selection of the targeted screening population will optimise the cost-effectiveness of teleophthalmology.</jats:sec
Review of economic evaluations of teleophthalmology as a screening strategy for chronic eye disease in adults
No full textBackground/aims: Teleophthalmology is well positioned to play a key role in screening of major chronic eye diseases. Economic evaluation of cost-effectiveness of teleophthalmology, however, is lacking. This study provides a systematic review of economic studies of teleophthalmology screening for diabetic retinopathy (DR), glaucoma and macular degeneration.Methods: Structured search of electronic databases and full article review yielded 20 cost-related articles. Sixteen articles fulfilled the inclusion criteria and were retained for a narrative review: 12 on DR, 2 on glaucoma and 2 on chronic eye disease.Results: Teleophthalmology for DR yielded the most cost savings when compared with traditional clinic examination. The study settings varied among urban, rural and remote settings, community, hospital and health mobile units. The most important determinant of cost-effectiveness of teleophthalmology was the prevalence of DR among patients screened, indicating an increase of cost savings with the increase of screening rates. The required patient pool size to be screened varied from 110 to 3500 patients. Other factors potentially influencing cost-effectiveness of teleophthalmology were older patient age, regular screening and full utilisation of the equipment. Teleophthalmology for glaucoma was more cost-effective compared with in-person examination. Similarly, increasing number of glaucoma patients targeted for screening yielded more cost savings.Conclusions: This economic review provides supportive evidence of cost-effectiveness of teleophthalmology for DR and glaucoma screening potentially increasing screening accessibility especially for rural and remote populations. Special selection of the targeted screening population will optimise the cost-effectiveness of teleophthalmology
Reply to K. Takada et al
No full textSee the letter "Reasons to Consider the COVID-19 Vaccination Status of Patients With Cancer When Analyzing Their COVID-19 Outcomes" in volume 39 on page 3996
Cognitive Functioning After Hematopoietic Cell Transplantation for Hematologic Malignancy: Results From a Prospective Longitudinal Study
No full textPurpose Cognitive impairment is well-recognized after myeloablative allogeneic hematopoietic cell transplantation (HCT). However, cognitive functioning after reduced-intensity allogeneic or autologous HCT remains unclear. Methods A total of 477 HCT recipients (236 autologous, 128 reduced-intensity allogeneic, 113 myeloablative allogeneic) underwent standardized neuropsychologic testing before HCT and at 6 months and 1, 2, and 3 years after HCT. Ninety-nine frequency-matched healthy controls underwent testing at commensurate time points. Primary outcomes of the study were practice effect–adjusted domain-specific T scores and global deficit scores. Piecewise generalized estimating equation models were used to compare groups and to identify associated variables and post-HCT trends of cognitive impairment. Results Median age was 52 years (range, 18 to 74 years) for HCT recipients and 55 years (range, 19 to 73 years) for controls. Post-HCT scores were comparable between controls and autologous and reduced-intensity HCT recipients. Myeloablative HCT recipients had significantly lower ( P < .001) post-HCT scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity. Pre-HCT to 6 months post-HCT scores did not change after reduced-intensity HCT but declined significantly for fine motor dexterity ( P < .001) after myeloablative HCT. However, pre-HCT to 3 years post-HCT scores declined significantly ( P < .003) in reduced-intensity HCT recipients for executive function, verbal fluency, and working memory. Older age, male sex, and lower education, income, and cognitive reserve were associated with post-HCT cognitive impairment. At 3 years post-HCT, global cognitive impairment was present in 18.7% of autologous and 35.7% of allogeneic HCT recipients. Conclusion Myeloablative allogeneic HCT recipients showed significant cognitive decline compared with healthy controls. Reduced-intensity allogeneic HCT recipients showed evidence of delayed decline. Cognitive functioning in autologous HCT recipients generally was spared. The study identified vulnerable subpopulations that could benefit from targeted interventions. </jats:sec
Self‐endorsed cognitive problems versus objectively assessed cognitive impairment in blood or bone marrow transplantation recipients: A longitudinal study
No full textCharacterizing Artificial Intelligence Applications in Cancer Research: A Latent Dirichlet Allocation Analysis
No full text10.2196/14401JMIR Medical Informatics74e1440
