Multiple sclerosis subgroups: Data-driven clusters based on patient-reported outcomes and a large clinical sample.

BACKGROUND: While standard clinical assessments provide great value for people with multiple sclerosis (PwMS), they are limited in their ability to characterize patient perspectives and individual-level symptom heterogeneity. OBJECTIVES: To identify PwMS subgroups based on patient-reported outcomes (PROs) of physical, cognitive, and emotional symptoms. We also sought to connect PRO-based subgroups with demographic variables, functional impairment, hypertension and smoking status, traditional qualitative multiple sclerosis (MS) symptom groupings, and neuroperformance measurements. METHODS: Using a cross-sectional design, we applied latent profile analysis (LPA) to a large database of PROs; analytic sample N = 6619). RESULTS: We identified nine distinct MS subtypes based on PRO patterns. The subtypes were primarily categorized into low, moderate, and high mobility impairment clusters. Approximately 70% of participants were classified in a low mobility impairment group, 10% in a moderate mobility impairment group, and 20% in a high mobility impairment group. Within these subgroups, several unexpected patterns were observed, such as high mobility impairment clusters reporting low non-mobility impairment. CONCLUSIONS: The present study highlights an opportunity to advance precision medicine approaches in MS. Combining PROs with data-driven methodology allows for a cost-effective and personalized characterization of symptom presentations. that can inform clinical practice and future research designs.

Risk Factors for Bacterial Keratitis and Severe Disease in Hydrogel Contact Lens Users: A Multicenter Case-Control Study and Case-Only Analysis.

PURPOSE: To assess risk factors for contact lens (CL)-related bacterial keratitis, cases and high-risk controls were enrolled. Using high-risk controls can help elucidate whether certain CL types or modalities are attributable to disease burden if risky wear patterns are similar between the cases and controls. This analysis identified whether such CL factors were associated with the occurrence of bacterial keratitis. In addition, a case-only analysis determined CL factors associated with severe disease. METHODS: From 2018 to 2021, 158 controls were enrolled at University Hospitals of Cleveland Eye Institute, and 153 bacterial keratitis cases were enrolled across 14 sites in the United States. Cases were soft CL wearers with either culture-proven bacterial keratitis or a corneal infiltrate with an overlying epithelial defect within the central 4 mm of the cornea, uveitis, or significant pain. Fungal, protozoan, or nonsoft CL wear-related microbial keratitis cases were excluded. Controls were recruited from high-risk CL wearers with no history of disease. All participants completed a questionnaire related to demographics, type of CL used, wearing schedule, lens handling practices, and storage case handling. Cases with ulcer/infiltrate size ≥2 mm in size, presence of hypopyon, or had fortified antibiotics prescribed were classified as severe keratitis. Univariate and multivariable logistic regression was used to assess association of CL variables with the occurrence of bacterial keratitis as well as occurrence of severe disease among the cases only. RESULTS: Compared with the control cohort, cases were older (mean age 45.6 vs. 38.9 years), had more males (42.5% vs. 23.6%), and had more current or former smokers (41.7% vs. 12.9%). There were no significant associations between CL material (silicone hydrogel vs. not) or CL type (daily disposable vs. reusable) and occurrence of bacterial keratitis. More than two-thirds (67.3%) of cases were classified as severe. Among cases only, univariate analyses found current smokers to have increased risk of severe disease (OR=2.87; 95% CI 1.13-7.26, P=0.03). Adjusting for age, sex, and smoking among the cases only, daily disposable lenses were protective against severe disease (OR=0.32; 95% CI 0.11-0.89, P=0.03). Reusable lenses increased risk of severe microbial keratitis between 3.0- and 4.4-fold compared with compliant daily disposability. DISCUSSION/CONCLUSION: Compared with a high-risk control cohort, no specific lens factors were associated with occurrence of CL-associated bacterial keratitis. Among cases only, current smokers and patients wearing reusable lenses are at increased risk of severe keratitis. Daily disposable lenses were protective even when noncompliance to daily disposability was considered.

Physical comorbidities of older age bipolar disorder (OABD) patients: A global replication analysis of prevalence and sex differences.

OBJECTIVES: To compare the prevalence of physical morbidities between older aged patients with bipolar disorder (OABD) and non-psychiatric comparisons (NC), and to analyze sex differences in prevalence. METHODS: OABD was defined as bipolar disorder among adults aged ≥50 years. Outcomes analyzed were the prevalence of diseases affecting the cardiovascular, respiratory, gastrointestinal, genitourinary, renal, musculoskeletal, and endocrine systems. The analysis used cross-sectional data of OABD participants (n = 878; mean age 60.9 ± 8.0 years, n = 496 (56%) women) from the collaborative Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) dataset and NC participants recruited at the same sites (n = 355; mean age 64.4 ± 9.7 years, n = 215 (61%) women). RESULTS: After controlling for sex, age, education, and smoking history, the OABD group had more cardiovascular (odds ratio [95% confidence interval]: 2.12 [1.38-3.30]), renal (5.97 [1.31-43.16]), musculoskeletal (2.09 [1.30-3.43]) and endocrine (1.90 [1.20-3.05]) diseases than NC. Women with OABD had more gastrointestinal (1.56 [0.99-2.49]), genitourinary (1.72 [1.02-2.92]), musculoskeletal (2.64 [1.66-4.37]) and endocrine (1.71 [1.08-2.73]) comorbidities than men with OABD, when age, education, smoking history, and study site were controlled. CONCLUSIONS: This replication GAGE-BD study confirms previous findings indicating that OABD present more physical morbidities than matched comparison participants, and that this health burden is significantly greater among women.

Beta-defensin index: A functional biomarker for oral cancer detection.

There is an unmet clinical need for a non-invasive and cost-effective test for oral squamous cell carcinoma (OSCC) that informs clinicians when a biopsy is warranted. Human beta-defensin 3 (hBD-3), an epithelial cell-derived anti-microbial peptide, is pro-tumorigenic and overexpressed in early-stage OSCC compared to hBD-2. We validate this expression dichotomy in carcinoma in situ and OSCC lesions using immunofluorescence microscopy and flow cytometry. The proportion of hBD-3/hBD-2 levels in non-invasively collected lesional cells compared to contralateral normal cells, obtained by ELISA, generates the beta-defensin index (BDI). Proof-of-principle and blinded discovery studies demonstrate that BDI discriminates OSCC from benign lesions. A multi-center validation study shows sensitivity and specificity values of 98.2% (95% confidence interval [CI] 90.3-99.9) and 82.6% (95% CI 68.6-92.2), respectively. A proof-of-principle study shows that BDI is adaptable to a point-of-care assay using microfluidics. We propose that BDI may fulfill a major unmet need in low-socioeconomic countries where pathology services are lacking.

The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate.

Genes associated with increased susceptibility to multiple sclerosis (MS) have been identified, but their functions are incompletely understood. One of these genes codes for the RNA helicase DExD/H-Box Polypeptide 39B (DDX39B), which shows genetic and functional epistasis with interleukin-7 receptor-α gene (IL7R) in MS-risk. Based on evolutionary and functional arguments, we postulated that DDX39B enhances immune tolerance thereby decreasing MS risk. Consistent with such a role we show that DDX39B controls the expression of many MS susceptibility genes and important immune-related genes. Among these we identified Forkhead Box P3 (FOXP3), which codes for the master transcriptional factor in CD4+/CD25+ T regulatory cells. DDX39B knockdown led to loss of immune-regulatory and gain of immune-effector expression signatures. Splicing of FOXP3 introns, which belong to a previously unrecognized type of introns with C-rich polypyrimidine tracts, was exquisitely sensitive to DDX39B levels. Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as an important guardian of immune tolerance.

The impact of cigarette smoking on cognitive processing speed and brain atrophy in multiple sclerosis.

BACKGROUND: Smoking is associated with an increased risk of multiple sclerosis (MS) and disability worsening. The relationship between smoking, cognitive processing speed, and brain atrophy remains uncertain. OBJECTIVE: To quantify the impact of smoking on processing speed and brain volume in MS and to explore the longitudinal relationship between smoking and changes in processing speed. METHODS: A retrospective study of MS patients who completed the processing speed test (PST) between September 2015 and March 2020. Demographics, disease characteristics, smoking history, and quantitative magnetic resonance imaging (MRI) were collected. Cross-sectional associations between smoking, PST performance, whole-brain fraction (WBF), gray matter fraction (GMF), and thalamic fraction (TF) were assessed using multivariable linear regression. The longitudinal relationship between smoking and PST performance was assessed by linear mixed modeling. RESULTS: The analysis included 5536 subjects of whom 1314 had quantitative MRI within 90 days of PST assessment. Current smokers had lower PST scores than never smokers at baseline, and this difference persisted over time. Smoking was associated with reduced GMF but not with WBF or TF. CONCLUSION: Smoking has an adverse relationship with cognition and GMF. Although causality is not demonstrated, these observations support the importance of smoking cessation counseling in MS management.

Characterizing relapsing remitting multiple sclerosis patients burdened with hypertension, hyperlipidemia, and asthma.

BACKGROUND: Hypertension, hyperlipidemia, and asthma are common in multiple sclerosis (MS) patients and adversely impact physical and mental health independent of sociodemographic and clinical attributes. Characterizing MS patients with these comorbidities is necessary for informing comorbidity screening and managed care in vulnerable patient subgroups; however, there is sparse data currently available. METHODS: We conducted cross-sectional analyses of 2,012 relapsing remitting (RR) MS patients. Separate multivariable logistic regression models were conducted for the presence of hypertension, hyperlipidemia, and asthma. Independent variables included age, sex, race, MS duration, body mass index classification, insurance payer, smoking status, median income by residence ZIP code, disease modifying therapies, and the other comorbidities. RESULTS: Hypertension was more common in RRMS patients who were older, obese/severely obese, had hyperlipidemia, were asthmatics, living in neighborhoods with the lowest income, and who were Black Americans. RRMS patients with hyperlipidemia were more likely to be male, older, overweight/obese/severely obese, hypertensive, asthmatics, and White American. Asthmatic RRMS patients were more likely to be female, obese, hypertensive, and living in neighborhood of medium/low income, and less likely to be on interferons or glatiramer acetate. CONCLUSION: We identified factors independently associated with common comorbidity burden in RRMS patients, which will inform risk-stratification efforts aimed at mitigating the adverse impact of these conditions in MS patients. Our results are consistent with what is known about the determinants of hypertension, hyperlipidemia, and asthma in the non-MS patient population, and therefore disparities that exist in screening and management in the general U.S. population may likely exist in U.S. MS patients. It is also possible that there may be unique differences in specific MS patient subgroups, which warrants further investigation and detailed characterization.

Integrating patient-reported outcomes and quantitative timed tasks to identify relapsing remitting multiple sclerosis patient subgroups: a latent profile analysis.

BACKGROUND: Multiple sclerosis (MS) patients experience wide-ranging symptoms with varied severity, and approaches that integrate patient-reported outcomes and objective quantitative measures will present opportunities for advancing clinical profiling. The primary objective of the current study was to conduct exploratory data analysis using latent variable modeling to empirically identify clusters of relapsing remitting (RR) MS patients with shared impairment patterns across three patient-reported outcomes and two timed task measures. METHODS: Latent profile analyses and impairment data for 2,012 RRMS patients identified distinct patient clusters using timed task measures of upper and lower limb performance, and patient-reported outcomes measuring quality of life, depression symptom severity, and perceived global disability. Multinomial logistic regression models were used to characterize associations between socio-demographic attributes and assignment to the patient clusters. RESULTS: There were 6 distinct clusters of RRMS patients that differed by symptom patterns, and by their socio-demographic attributes. Most notable were were no differences in age, sex, or disease duration between the least and most impaired classes, representing 14% and 4% of patients, respectively. Patients in the most impaired class were much more likely to be Black American, have a history of smoking, have a higher body mass index, and be of lower socioeconomic status than the least impaired class. There were positive relationships between age and classification to clusters of increasing moderately severe impairment but not the most severe clusters. CONCLUSION: We present a framework for discerning phenotypic impairment clusters in RRMS. The results demonstrate opportunities for advancing clinical profiling, which is necessary for optimizing personalized MS care models and clinical research.

Nicotinic acetylcholine receptors α7 and α9 modifies tobacco smoke risk for multiple sclerosis.

INTRODUCTION: Tobacco smoke exposure is an established risk factor for multiple sclerosis (MS), yet how it confers risk is not known. Evidence from observational studies suggests nicotine may be a protective component. Animal studies further support this hypothesis, demonstrating nicotine's protective effect in MS is mediated by the presence and absence of α7 and α9 nicotinic acetylcholine receptors (nAChRs), respectively. OBJECTIVE: To determine if variation in the genes encoding α7 and α9 nAChRs (cholinergic receptor nicotinic alpha 7 (CHRNA7) and alpha 9 (CHRNA9)) will modify MS risk conferred by tobacco smoking. METHODS: A multi-stage gene-environment (G×E) framework was utilized, including a case-control analysis (286 cases, 176 controls) with haplotype- and gene-based analyses, followed by an extension case-only (1053 cases) analysis for overlapping variants. RESULTS: The results suggest that CHRNA7 and CHRNA9 modifies MS risk conferred by tobacco smoke, where risk among smokers was increased in carriers of the minor CHRNA9 haplotype and in non-carriers the minor CHRNA7 haplotype. The findings are consistent with the pharmacology of these receptors and animal studies of MS. CONCLUSION: This study implicates novel processes in MS initiation and demonstrate the need for further G×E studies to advancing our understanding of the missing heritability of MS.

Opportunistic Infections Are More Prevalent in Crohn's Disease and Ulcerative Colitis: A Large Population-Based Study.

BACKGROUND: Opportunistic infections (OIs) are more common in patients with inflammatory bowel disease (IBD); however, there have been limited large-scale studies of OIs in IBD. We investigated the epidemiological characteristics of OI in Crohn's disease (CD) and ulcerative colitis (UC) using a large population-based database. METHODS: Data were collected from a commercial database (Explorys Inc., Cleveland, OH, USA) that provided electronic health records from 26 major integrated US health care systems from 1999 to March 2018. In this data set, we identified all CD and UC patients, based on Systemized Nomenclature of Medicine-Clinical Terms. Within these cohorts, we identified a variety of OIs and compared the prevalence rate of OI in individuals with IBD with that of controls (patients in the database between March 2013 and March 2018 without the diagnosis of IBD). RESULTS: Explorys included 153,290 patients with CD and 128,540 patients with UC between March 2013 and March 2018. The prevalence of OIs was 17.8% in CD, 19.2% in UC, and 7% in non-IBD controls. When compared with non-IBD controls, all OIs were more common in CD (prevalence ratio [PR], 2.54; 95% confidence interval [CI], 2.51-2.57) and UC (PR, 2.74; 95% CI, 2.71-2.77). Overall, viral infections were numerically more common, whereas bacterial infections had the highest PRs in CD and UC when compared with controls without IBD. CONCLUSIONS: We found significantly higher rates of OI in IBD. Our study suggests the need for close follow-up of IBD patients to diagnose and provide vaccinations where applicable for prevention of infections.

Prognostic factors of disability in relapsing remitting multiple sclerosis.

BACKGROUND: The clinical manifestation of multiple sclerosis (MS) is highly variable. Factors influencing phenotypic heterogeneity are not well known since most studies have relied on the Expanded Disability Status Scale which has modest inter/intra-rater reliability. We therefore sought to investigate other reliable and valid measures of impairment. METHODS: We constructed a retrospective cohort of 2083 relapsing remitting MS patients using electronic health records to identify prognostic factors of Timed 25-Foot Walk (lower limb disability), Performance Scales Sum (perceived global disability), and Patient Health Questionnaire 9 (a depression tool). Patients had a clinical visit between 1/1/2008 and 5/29/2012, and at least one additional visit within approximately 3 years; the cohort consisted of 16,538 visits. The outcomes and predictors were extracted from the records. Longitudinal models were conducted, and sex- and race-specific differences were explored. RESULTS: Walking speeds were slower in females, black patients, ever smokers, and Medicaid/Medicare beneficiaries. Higher body mass index (BMI), older age, longer disease duration, lower median income, and higher depression scores also predicted slower walking speeds. Older age, higher BMI, lower median income, higher depression scores, ever smokers and Medicaid/Medicare beneficiaries were associated with higher global disability. Those who were of younger age, higher BMI, lower median income, ever smoked, and on Medicaid had higher depressive scores. The effect of age and BMI on depressive scores were restricted to female and white patients, respectively. CONCLUSION: We identified multiple longitudinal predictors of disability in relapsing remitting patients. Modifiable factors (including smoking and BMI) and adverse socioeconomic conditions were independently, and negatively associated with walking speed, global disability, and depression.

Multiple sclerosis risk factors contribute to onset heterogeneity.

BACKGROUND: The phenotypic presentation of multiple sclerosis (MS) may predict long-term outcomes and little is known about factors contributing to heterogeneity at MS onset. Given temporality, it is likely MS risk factors also influence presentation of the disease near onset. METHODS: Using a retrospective cross-sectional study of MS cases, we investigated: age of onset (AOO), number of impaired functional domains (NIFDs), time to second relapse (TT2R), and early relapse activity (ERA). Machine learning variable selection was applied to epidemiologic data for each outcome, followed by multivariable regression models. The models were further adjusted for HLA-DRB1*15:01 carrier status and a MS genetic risk score (GRS). The TT2R and ERA analyses were restricted to relapsing remitting MS cases. RESULTS: HLA-DRB1*15:01, GRS, and smoking were associated with earlier AOO. Cases who were male, obese, had lower education, or had primary progressive MS were older at onset. For NIFDs, those with relapsing remitting MS and of lower SES had increased NIFDs. Among relapsing remitting cases, those who were older at onset, obese, and had polyfocal presentation had shorter TT2R, while ERA was greater among those younger at onset and who were obese. CONCLUSION: Individual characteristics including age, genetic profiles, obesity, and smoking status contribute to heterogeneity in disease presentation and modulate early disease course evolution.

Cardiovascular conditions in persons with multiple sclerosis, neuromyelitis optica and transverse myelitis.

BACKGROUND: Cardiovascular conditions are associated with poorer outcomes in multiple sclerosis (MS). Whether the burden of cardiovascular conditions differs between those with demyelinating disease and unaffected controls is not clear. The objective of this study is to investigate the burden and age of onset of cardiovascular conditions in a US population with MS, neuromyelitis optica spectrum disorder (NMOSD), or transverse myelitis (TM) to unaffected controls adjusting for likely confounders. METHODS: Using a case-control study design, we compared the burden of self-reported diabetes mellitus type 2, heart disease, hyperlipidemia, and hypertension in cases with MS (N = 1,548), NMOSD (N = 306), and TM (N = 145) to controls (N = 677), adjusting for demographics, smoking history, obesity, family history of individual cardiovascular conditions, and presence of other cardiovascular conditions. The age of onset for individual cardiovascular conditions were also compared between cases and controls. RESULTS: MS cases were 48% more likely to have ever had hypertension than controls (p = 0.01). The prevalence of other cardiovascular conditions did not differ across cases and controls. There were also no differences in the age of cardiovascular disease onset between cases and controls. CONCLUSION: Cardiovascular conditions are as common in those with demyelinating diseases compared to unaffected individuals, with hypertension being more common among those with MS.

In-patient outcomes of Hematopoietic Stem Cell Transplantation in Patients with Immune Mediated Inflammatory Diseases: A Nationwide Study.

The impact of underlying immune-mediated inflammatory diseases (IMID) in patients undergoing hematopoietic stem cell transplant (HSCT) is unclear. Hematopoietic cell transplantation co-morbidity index (HCT-CI) is gaining acceptance as a reliable clinical method to score pre-transplant co-morbidities. Higher HCT-CI from a co-morbid IMID implies higher NRM. However, HCT-CI integrates many IMIDs with different pathogenesis and treatment together which may lead to spurious results. We performed a cross-sectional study using Nationwide Inpatient Sample dataset from 1998 to 2011 to compare the outcomes of HSCT in patients with different co-morbid IMIDs with patients without any co-morbid IMIDs. In both our multivariate and stringent matched-pair analysis, ulcerative colitis (UC) was associated with increased mortality while rheumatoid arthritis and psoriasis were associated with lower mortality as compared to no IMID group. Furthermore, in allogeneic HSCT subgroup, UC was associated with higher mortality and psoriasis was associated with lower mortality. In conclusion, we found that depending on the type of HSCT, each IMID has a different impact on outcomes of HSCT. Furthermore, UC patients had increased mortality if they had primary sclerosing cholangitis and had a higher risk of opportunistic infections like tuberculosis and cytomegalovirus suggesting the need for increased vigilance in this cohort.

Smokers with MS have greater decrements in quality of life and disability than non-smokers.

BACKGROUND: Tobacco smoke plays a pathogenic role in multiple sclerosis (MS) and may accelerate disease progression, yet, some people with MS continue to smoke after disease onset. The average smoker reports diminished health-related quality of life (HRQOL) across many populations. OBJECTIVES: To describe the relationships between smoking status and HRQOL, disease activity, and global disability in a US population with MS. METHODS: We compared smokers to non-smokers in 950 responders to the Spring 2014 update survey completed by North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants. HRQOL was assessed using Short Form-12 version 2 (SF-12v2), disease activity was investigated using eight Performance Scales (PS) and three Functionality Scales (FS). Global disability was evaluated using Patient Determined Disease Steps (PDDS) and an item response theory (IRT) summed score based on the PS and FS. RESULTS: Smokers had lower HRQOL ( p < 0.0001), reported more disease activity ( p < 0.05) and greater deficits in all PS and FS ( p = 6 × 10-7 to 0.05), except mobility. Smokers and non-smokers did not differ by PDDS but had substantially greater IRT global disability ( p = 2 × 10-7). CONCLUSION: Active smoking is meaningfully associated with deficits across multiple domains in people with MS and adds to the growing literature of the need for MS-tailored smoking cessation programs.

Pathway Analysis of Genome-wide Association Study in Childhood Leukemia among Hispanics.

BACKGROUND: The incidence of acute lymphoblastic leukemia (ALL) is nearly 20% higher among Hispanics than non-Hispanic Whites. Previous studies have shown evidence for association between risk of ALL and variation within IKZF1, ARID5B, CEBPE, CDKN2A, GATA3, and BM1-PIP4K2A genes. However, variants identified only account for <10% of the genetic risk of ALL. METHODS: We applied pathway-based analyses to genome-wide association study (GWAS) data from the California Childhood Leukemia Study to determine whether different biologic pathways were overrepresented in childhood ALL and major ALL subtypes. Furthermore, we applied causal inference and data reduction methods to prioritize candidate genes within each identified overrepresented pathway, while accounting for correlation among SNPs. RESULTS: Pathway analysis results indicate that different ALL subtypes may involve distinct biologic mechanisms. Focal adhesion is a shared mechanism across the different disease subtypes. For ALL, the top five overrepresented Kyoto Encyclopedia of Genes and Genomes pathways include axon guidance, protein digestion and absorption, melanogenesis, leukocyte transendothelial migration, and focal adhesion (PFDR < 0.05). Notably, these pathways are connected to downstream MAPK or Wnt signaling pathways which have been linked to B-cell malignancies. Several candidate genes for ALL, such as COL6A6 and COL5A1, were identified through targeted maximum likelihood estimation. CONCLUSIONS: This is the first study to show distinct biologic pathways are overrepresented in different ALL subtypes using pathway-based approaches, and identified potential gene candidates using causal inference methods. IMPACT: The findings demonstrate that newly developed bioinformatics tools and causal inference methods can provide insights to furthering our understanding of the pathogenesis of leukemia. Cancer Epidemiol Biomarkers Prev; 25(5); 815-22. ©2016 AACR.

Feasibility study for remote assessment of cognitive function in multiple sclerosis.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), and affects employment and quality of life. Large studies are needed to identify risk factors for cognitive decline. Currently, a MS-validated remote assessment for cognitive function does not exist. Studies to determine feasibility of large remote cognitive function investigations in MS have not been published. OBJECTIVE: To determine whether MS patients would participate in remote cognitive studies. We utilized the Modified Telephone Interview for Cognitive Status (TICS-M), a previously validated phone assessment for cognitive function in healthy elderly populations to detect mild cognitive impairment. We identified factors that influenced participation rates. We investigated the relationship between MS risk factors and TICS-M score in cases, and score differences between cases and control individuals. METHODS: The TICS-M was administered to MS cases and controls. Linear and logistic regression models were utilized. RESULTS: 11.5% of eligible study participants did not participate in cognitive testing. MS cases, females and individuals with lower educational status were more likely to refuse (p<0.001). Cases who did complete testing did not differ in terms of perceived cognitive deficit compared to cases that did participate. More severe disease, smoking, and being male were associated with a lower TICS-M score among cases (p<0.001). The TICS-M score was significantly lower in cases compared to controls (p=0.007). CONCLUSIONS: Our results demonstrate convincingly that a remotely administered cognitive assessment is quite feasible for conducting large epidemiologic studies in MS, and lay the much needed foundation for future work that will utilize MS-validated cognitive measures.

Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children.

BACKGROUND: Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed the variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early-life infections (the presence of older siblings, daycare attendance, and ear infections). METHODS: Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated with each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early-life infections using logistic regression models that included an interaction term. RESULTS: Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified: rs7780012, OR 0.50, 95% confidence interval (CI) 0.35-0.71 (p = 0.004); rs7089424, OR 2.12, 95% CI 1.70-2.65 (p = 1.16 × 10(-9)); rs4982731, OR 1.69, 95% CI 1.37-2.08 (p = 2.35 × 10(-6)), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early-life infections with ALL risk was not observed. CONCLUSIONS: Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Results implicate the ARID5B, CEBPE, and IKZF1 genes in the pathogenesis of childhood ALL.

Interaction between passive smoking and two HLA genes with regard to multiple sclerosis risk.

BACKGROUND: The recently described interaction between smoking, human leukocyte antigen (HLA) DRB1*15 and absence of HLA-A*02 with regard to multiple sclerosis (MS) risk shows that the risk conveyed by smoking differs depending on genetic background. We aimed to investigate whether a similar interaction exists between passive smoking and HLA genotype. METHODS: We used one case-control study with incident cases of MS (736 cases, 1195 controls) and one with prevalent cases (575 cases, 373 controls). Never-smokers with different genotypes and passive smoking status were compared with regard to occurrence of MS, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). The potential interaction between different genotypes and passive smoking was evaluated by calculating the attributable proportion (AP) due to interaction. RESULTS: An interaction was observed between passive smoking and carriage of HLA-DRB1*15 (AP 0.3, 95% CI 0.02-0.5 in the incident study, and AP 0.4, 95% CI 0.1-0.7 in the prevalent study), as well as between passive smoking and absence of HLA-A*02. Compared with non-smokers without any of these two genetic risk factors, non-exposed subjects with the two risk genotypes displayed an OR of 4.5 (95% CI 3.3-6.1) whereas the same genotype for subjects exposed to passive smoking rendered an OR of 7.7 (95% CI 5.5-10.8). CONCLUSIONS: The risk of developing MS associated with different HLA genotypes may be influenced by exposure to passive smoking. The finding supports our hypothesis that priming of the immune response in the lungs may subsequently lead to MS in people with a genetic susceptibility to the disease.