Covariate-adjusted Regression Research Articles

Distortion Diagnostics for Covariate-adjusted Regression: Graphical Techniques Based on Local Linear Modeling

Linear regression models are often useful tools for exploring the relationship between a response and a set of explanatory (predictor) variables. When both the observed response and the predictor variables are contaminated/distorted by unknown functions of an observable confounder, inferring the underlying relationship between the latent (unobserved) variables is more challenging. Recently, S¸ent¨urk and M¨uller (2005) proposed the method of covariate-adjusted regression (CAR) analysis for this distorted data setting. In this paper, we describe graphical techniques for assessing departures from or violations of specific assumptions regarding the type and form of the data distortion. The type of data distortion consists of multiplicative, additive or no-distortion. The form of the distortion encompasses a class of general smooth distorting functions. However, common confounding adjustment methods in regression analysis implicitly make distortion assumptions, such as assuming additive or multiplicative linear distortions. We illustrate graphical detection of departures from such assumptions on the distortion. The graphical diagnostic techniques are illustrated with numeri cal and real data examples. The proposed graphical assessment of distortion assumptions is feasible due to the CAR estimation method, which utilizes a local regression technique to estimate a set of transformed distorting functions (S¸ent¨urk and Nguyen, 2006).

Impact of acute lymphoblastic leukemia induction therapy: findings from metabolomics on non-fasted plasma samples from a biorepository.

Acute lymphoblastic leukemia (ALL) is among the most common cancers in children. With improvements in combination chemotherapy regimens, the overall survival has increased to over 90%. However, the current challenge is to mitigate adverse events resulting from the complex therapy. Several chemotherapies intercept cancer metabolism, but little is known about their collective role in altering host metabolism. We profiled the metabolomic changes in plasma of ALL patients initial- and post- induction therapy. We exploited a biorepository of non-fasted plasma samples derived from the Dana Farber Cancer Institute ALL Consortium; these samples were obtained from 50 ALL patients initial- and post-induction therapy. Plasma metabolites and complex lipids were analyzed by high resolution tandem mass spectrometry and differential mobility tandem mass spectrometry. Data were analyzed using a covariate-adjusted regression model with multiplicity adjustment. Pathway enrichment analysis and co-expression network analysis were performed to identify unique clusters of molecules. More than 1200 metabolites and complex lipids were identified in the total of global metabolomics and lipidomics platforms. Over 20% of those molecules were significantly altered. In the pathway enrichment analysis, lipids, particularly phosphatidylethanolamines (PEs), were identified. Network analysis indicated that the bioactive fatty acids, docosahexaenoic acid (DHA)-containing (22:6) triacylglycerols (TAGs), were decreased in the post-induction therapy. Metabolomic profiling in ALL patients revealed a large number of alterations following induction chemotherapy. In particular, lipid metabolism was substantially altered. The changes in metabolites and complex lipids following induction therapy could provide insight into the adverse events experienced by ALL patients.

A Benchmark Dose Analysis for Maternal Pregnancy Urine-Fluoride and IQ in Children.

As a guide to establishing a safe exposure level for fluoride exposure in pregnancy, we applied benchmark dose modeling to data from two prospective birth cohort studies. We included mother-child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Maternal urinary fluoride concentrations (U-F, in mg/L, creatinine-adjusted) were measured in urine samples obtained during pregnancy. Children were assessed for intelligence quotient (IQ) at age 4 (n = 211) and between six and 12 years (n = 287) in the ELEMENT cohort, and three to four years (n = 407) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to assess the association of maternal U-F concentrations with children's IQ measures. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) and benchmark concentration levels (BMCLs). No deviation from linearity was detected in the dose-response relationships, but boys showed lower BMC values than girls. Using a linear slope for the joint cohort data, the BMC for maternal U-F associated with a 1-point decrease in IQ scores was 0.31 mg/L (BMCL, 0.19 mg/L) for the youngest boys and girls in the two cohorts, and 0.33 mg/L (BMCL, 0.20 mg/L) for the MIREC cohort and the older ELEMENT children. Thus, the joint data show a BMCL in terms of the adjusted U-F concentrations in the pregnant women of approximately 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in pregnant women.

Does the timing of kindergarten absences matter for children's early school success?

Although we know that children who are more frequently absent from school do less well academically, we know little about whether absences matter for other domains of development and whether the timing of their absences matter. In order to address these gaps in knowledge, we examined the experiences of 1,131 kindergartners (64% Hispanic, 7% Black, 17% Asian/other, 12% White) from a mid-Atlantic state. Covariate-adjusted regression analyses showed that children who missed school more frequently did less well in terms of their academic achievement and executive function skills both in kindergarten and through the end of first grade. Importantly, however, there were no consistent differences in children's social behavior nor did outcomes vary as a function of whether their absences occurred in the fall as compared with spring. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Knowledge of Infant Development and Parent Well-Being: Cross-Sectional Analysis of Toddlers.

Knowledge about child development is associated with parenting and children's outcomes. Parents with less accurate knowledge about developmental milestones may have unrealistic expectations for their child's behavior, which may affect parent well-being. Limited research has examined this topic relative to depression, but other aspects of parent well-being (e.g., parenting stress) are unexplored. Cross-sectional analysis of an ongoing prospective cohort study of 300 families in central Ohio enrolled when children were a mean (SD) calendar age of 18.2 (0.7) months. Children of all gestational ages at birth are included, and 37% were born preterm (<37 weeks' gestation.) Primary caregivers (93% mothers) completed the 20-item Knowledge of Infant Development Index (KIDI) and questionnaires for child temperament and 3 aspects of parent well-being (depressive and anxious symptoms, parenting stress, and general health). Covariate-adjusted regression models assessed relationships between the KIDI score and each well-being outcome. We hypothesized that parents with less knowledge would have more symptoms of depression and anxiety, greater parenting stress, and poorer health. Whether associations were stronger for parents of children born preterm or who had high negative affect was explored. Knowledge of Infant Development Index scores were associated with sociodemographic characteristics, child temperament, and gestational age (more knowledge: higher socioeconomic position, less child negative affect, and full-term birth). KIDI scores did not predict any aspect of parent well-being, and there was no evidence that child temperament or preterm birth altered these findings. In this sample of parents of toddlers assessed in 2018/19, greater knowledge of infant development was not associated with parent well-being.

Treatment outcomes of psychotherapy for binge-eating disorder in a randomized controlled trial: Examining the roles of childhood abuse and post-traumatic stress disorder.

To examine childhood abuse and post-traumatic stress disorder (PTSD) as predictors and moderators of binge-eating disorder (BED) treatment outcomes in a randomized controlled trial comparing Integrative Cognitive-Affective Therapy with cognitive-behavioural therapy administered using guided self-help. In 112 adults with BED, childhood abuse was defined as any moderate/severe abuse as assessed by the Childhood Trauma Questionnaire, lifetime PTSD was assessed via the Structured Clinical Interview for DSM-IV, and outcomes were assessed via the Eating Disorder Examination (EDE). Covariate-adjusted regression models predicting binge-eating frequency and EDE global scores at end of treatment and 6-month follow-up were conducted. Lifetime PTSD predicted greater binge-eating frequency at end of treatment (B=1.32, p=0.009) and childhood abuse predicted greater binge-eating frequency at follow-up (B=1.00, p=0.001). Lifetime PTSD moderated the association between childhood abuse and binge-eating frequency at follow-up (B=2.98, p=0.009), such that childhood abuse predicted greater binge-eating frequency among participants with a history of PTSD (B=3.30, p=0.001) but not among those without a PTSD history (B=0.31, p=0.42). No associations with EDE global scores or interactions with treatment group were observed. Results suggest that a traumatic event history may hinder treatment success and that PTSD may be more influential than the trauma exposure itself.

Outlier detection under a covariate-adjusted exponential regression model with censored data

Exponential regression models with censored data are most widely used in practice. In the modeling process, there exist situations where the covariates are not directly observed but are observed after being contaminated by unknown functions of an observable confounder in a multiplicative manner. The problem of outlier detection is a fundamental and important problem in applied statistics. In this paper, we use a nonparametric regression method to adjust the covariates and recast the outlier detection issue into a high-dimensional regularization regression issue in the covariate-adjusted exponential regression model with censored data. We propose a smoothly clipped absolute deviation (SCAD) penalized likelihood method to detect the possible outliers, which features that the proposed method can simultaneously deal with outlier detection and estimations for the regression coefficients. The coordinate descent algorithm is employed to facilitate computation. Simulation studies are conducted to evaluate the finite-sample performance of our proposed method. An application to a German breast cancer study demonstrates the utility of the proposed method in practice.

The Relationship Between Personality and Perceived Mental Fatigability

Several personality traits are known to be protective against global fatigue, however perceived mental fatigability (PMF, Pittsburgh Fatigability Scale 0-50) specifically measures an individual’s susceptibility to cognitive tiredness and is associated with mobility decline. We assessed whether optimism, conscientiousness, goal reengagement and goal disengagement contributed to greater PMF in 1,812 men (mean±SD age 84.4±4.2 years, 90.4% white) in the Osteoporotic Fractures in Men Study 4th visit (2014-2016). Covariates included demographic, psychological/behavioral factors, health conditions, physical activity and function. Prevalence of higher PMF (score ≥13) was 25% (n=448). In a covariate-adjusted regression model, each SD lower conscientiousness and lower optimism were associated with 0.93 and 0.61 SDs greater PMF, each p<0.01. Goal disengagement and goal reengagement were not associated with PMF. These findings warrant further investigation into how personality traits may help clinicians design targeted and effective interventions to reduce fatigability, and consequently lower the risk of adverse aging-related health outcomes.

Abstract 16749: Prevalence, Predictors, and Prognostic Implications of Left Ventricular Systolic Dysfunction Among Patients With STEMI in India: The Prospective NORIN-STEMI Registry

Introduction: Left ventricular (LV) systolic dysfunction (LVSD) and HF are important complications of ST-elevation myocardial infarction (STEMI). The prevalence and prognostic implications of LVSD in patients with STEMI in low/middle-income countries such as India are not well established. Methods: The present analysis was performed using data from the ongoing , prospective NORIN-STEMI registry of patients presenting with STEMI to 2 tertiary care medical centers in New Delhi, India from January to November 2019. LV ejection fraction (EF) was assessed at STEMI presentation using transthoracic echocardiography. Covariate-adjusted logistic regression models were constructed to evaluate the association of LVSD (mild: EF = 40-50%; moderate/severe: EF&lt;40%; ref: EF&gt;50%) with risk of in-hospital and 30-day mortality. Results: Among 3,635 patients with STEMI (age: 55[45-62], 33%≤50 years, 16% women), 1,489 (41%) had mild and 1,675 (46%) had moderate/severe LVSD on presentation. Patients with greater LVSD more commonly presented with anterior wall STEMI and had more frequent involvement of the left anterior descending artery as the culprit vessel. Among those with no, mild or moderate/severe LVSD, PCI was performed in 70% and 62% of patients, respectively. Hypertension, prior myocardial infarction, physical inactivity, greater time since symptom onset, and lower literacy levels were each independently associated with higher likelihood of LVSD. In adjusted analysis, LVSD was significantly associated with higher likelihood of in-hospital but not 30-day mortality ( See Table ). Conclusion: Among patients presenting to tertiary care centers in India with STEMI, LVSD is common, with 87% demonstrating LVEF&lt;50%. LVSD was significantly associated with higher risk of in-hospital and 30-day mortality. Future studies are needed to determine if quality improvement efforts to standardize pathways for primary PCI may lessen occurrence of LVSD.

The impact of personality traits on medication adherence and self-care in patients with type 2 diabetes mellitus: The moderating role of gender and age

ObjectivesThis study aimed to investigate the role of the five-factor model of personality (FFM) and the moderating role of gender and age in predicting medication adherence (MA) and self-care behaviors (SCB) among Iranian patients with type 2 diabetes mellitus (T2DM). MethodsThis study was conducted on 495 patients with T2DM (73.5% female; n = 364) from two major cities of Iran (Tehran and Qom) in 2019. Pearson's correlation coefficient, multiple regression analysis, and conditional process analysis were performed. P < .05 and P < .10 were considered significant for the relationships and moderation analysis, respectively. ResultsNeuroticism indicated a negative association with MA and SCB. Positive associations were found between MA and personality traits, including extraversion, agreeableness, and conscientiousness, whereas extraversion showed a weak correlation with SCB. According to the covariate-adjusted regression model, neuroticism had a negative effect on MA and SCB. Agreeableness had a positive effect on MA and a negative effect on SCB. However, extraversion exerted a negative effect on MA and a positive effect on SCB. Also, the negative effect of neuroticism on MA was highlighted in women, indicating marginally significant moderation effect. The positive effects of extraversion and conscientiousness on MA were moderated by age. The effect of conscientiousness on SCB was positive in young patients and negative in old patients. No interaction effect was observed between age and gender. ConclusionThis study indicated that neuroticism, extraversion, and agreeableness significantly contributed to MA, but not to SCB. However, the effects were conditioned by age for extraversion and conscientiousness to some extent.

0373 Blacks with Obstructive Sleep Apnea Report Greater Nighttime Insomnia Symptoms than Whites, but Don’t Endorse Daytime Impairment

Abstract Introduction Few studies have assessed insomnia severity in racial/ethnic minority patients with OSA. In recognition of the burden of OSA in blacks compared to whites, the current study sought to examine insomnia symptoms in a sample of black and white patients newly diagnosed with OSA, prior to treatment, at 3 and 6 months. Methods 94 patients newly diagnosed with OSA provided demographics (age, sex, race/ethnicity), socioeconomic status, and completed the well-known and validated Insomnia Severity Index (ISI). To assess insomnia complaints, we ascertained total ISI score, nighttime sleep complaints, and daytime impairment. Linear regression and repeated measures analysis were conducted. Results Mean age was 57.43 years ±13.55; 63.8% were men and 35% were black. Mean BMI was 32.35±7.04and 35% were diagnosed with hypertension. The mean ISI score for the total sample was 13.06±7.06. The total ISI was significantly higher in blacks than whites, respectively (M=15.00±7.17; M=12.02±6.83, p&amp;lt;0.05) indicating moderate clinical insomnia in blacks, but not whites. In covariate-adjusted linear regression, nighttime complaints were statistically more pronounced in blacks (b=1.71, SE=0.82, p&amp;lt;0.05) and women (b=2.05, SE=0.72, p&amp;lt;0.01). There were no significant racial/ethnic differences with daytime impairment, but gender differences in daytime impairment remained (b=2.93, SE=1.04 p&amp;lt;0.01). Results from repeated measures effects of race over time revealed that blacks had higher nighttime complaints across all time-points (b=2.51, SE=1.10, p&amp;lt;0.05), but we did not observe a race-by-time interaction effect (b=-0.89, SE=0.50). Conclusion For the first time, we observed that overall ISI score and nighttime complaints are more pronounced in blacks than whites. Notably, only women endorsed complaints of daytime impairment. Findings from the study may contribute to understanding who will need treatment for relief of insomnia complaints. Support K23HL125939

L_{1}-Estimation for covariate-adjusted regression

We study a covariate-adjusted regression(CAR) model that is proposed for such situations where both predictors and response in a regression model are not directly observable but are distorted by a multiplicative factor that is determined by an unknown function of some observable covariate. By establishing a connection to varying-coefficient models, we present the local linear L_{1}-estimation method when the underlying error distribution deviates from a normal distribution. The robust estimators of parameters are proposed in the underlying regression model. The consistency and asymptotic normality of the robust estimators are investigated. Since the limit distribution depends on the unknown components of the errors, an empirical likelihood ratio method based on L_{1} estimator is proposed. The confidence intervals for the regression coefficients are constructed. Simulation results demonstrate the superiority of the proposed estimators over other classical estimators when the underlying errors have heavy tails. Pima Indian diabetes data set is conducted to illustrate the performance of the proposed method, where the response and predictors are potentially contaminated by body mass index.

Abstract A85: Prediagnostic 25-hydroxyvitamin D concentrations in relation to tumor molecular alterations and risk of breast cancer recurrence

Abstract Although vitamin D inhibits breast tumor growth and development in experimental settings, the findings from population-based studies remain inconclusive. Our goals were to investigate the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] concentration and breast cancer recurrence in prospective epidemiologic studies and to explore the molecular underpinnings linking 25(OH)D to slower progression of breast cancer. Our study included 659 women with invasive breast cancer from the Nurses’ Health Studies (NHS) diagnosed from 1989 to 2010. Plasma 25(OH)D was measured with a high-affinity protein binding assay or a radioimmunoassay. We profiled transcriptome-wide gene expression in breast tumors using microarrays. Hazard ratios (HRs) of breast cancer recurrence were estimated from covariate-adjusted Cox proportional hazards models. We examined differential gene expression regulation in association with 25(OH)D with covariate-adjusted linear regression and employed pathway analysis. We derived a gene expression score for 25(OH)D, and further assessed associations between the standardized score and breast cancer recurrence. Although 25(OH)D was not associated with breast cancer recurrence overall (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.86, 1.08) (median follow-up=12.8 years), the association varied by estrogen receptor (ER) status (p for interaction=0.005). Importantly, among ER-positive stage I to III cancers, every 5 ng/ml increase in prediagnostic plasma 25(OH)D was associated with a 13% lowered risk of recurrence (HR=0.87; 95% CI: 0.76; 0.99). No association was observed in women with stage I to III ER-negative cancers (HR=1.07; 95% CI: 0.91; 1.27). Pathway analysis identified multiple gene sets that were significantly (FDR&amp;lt;5%) downregulated in ER-positive breast tumors of women with high prediagnostic 25(OH)D (≥30 ng/ml), compared to those with low levels (&amp;lt;30 ng/ml). These gene sets are primarily involved in tumor proliferation, apoptosis, migration and invasion, inflammation, and cancer cell metabolism. The standardized score of 25(OH)D signatures derived from these gene sets was marginally significantly associated with reduced risk of recurrence in ER-positive diseases (HR=0.77; 95% CI: 0.59, 1.01). Using TIMER, a mathematical algorithm to deconvolute tumor cellular heterogeneity, we found more infiltrated CD8+ T cells in ER-negative tumors as compared to ER-positive tumors, and this higher immune infiltration in ER-negative tumors may contribute to the observed heterogeneous response. Our findings support an intriguing line of research for future studies to better understand the biologic mechanisms underlying the role of vitamin D in breast tumor progression, particularly for the ER-positive subtype. Citation Format: Yujing Heng, Donghao Lu, Natalie DuPre, Kimberly Glass, Peter Kraft, David Feldman, Susan Hankinson, Kathryn Rexrode, Heather Eliassen, Rulla Tamimi, Cheng Peng. Prediagnostic 25-hydroxyvitamin D concentrations in relation to tumor molecular alterations and risk of breast cancer recurrence [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A85.

Help-seeking for psychological distress and its association with anxiety in the oldest old – results from the AgeQualiDe cohort study

Objectives: This study aimed to examine aspects of help-seeking for psychological distress and its association with increased anxiety symptoms in the oldest old.Method: Baseline data from AgeQualiDe, a multicenter cohort study of people aged 85 and over recruited in primary care, were analyzed. Help-seeking for psychological distress (items from the Camberwell Assessment of Need for the Elderly) was analyzed using ordinal and logistic regression models as a function of increased anxiety symptoms (Geriatric Anxiety Inventory-Short Form ≥ 3), as well as relevant socio-demographic and health-related covariates.Results: N = 155 (18.1% of the sample) reported having experienced psychological distress recently and were thus included in the analysis. Among those, 26.5% reported experiencing increased anxiety symptoms. On a descriptive level, 76.8% sought informal, 29.0% sought formal, and 18.1% sought no help for psychological distress. In covariate-adjusted regression models, increased anxiety was significantly associated with increased use of informal support (OR: 2.92, 95% CI: 1.31–6.48), but was neither associated with formal (OR: 0.72, 95% CI: 0.26–1.97) nor no help-seeking (OR: 0.28, 95% CI: 0.08–1.05).Conclusion: A large proportion of those experiencing psychological distress sought support from informal sources in this study. Anxiety symptoms in the oldest old were associated with the increased use of informal support, but not formal support or no help-seeking. Training and support for people providing informal help to those with mental health problems should be promoted to reduce a possible burden. However, future research addressing underlying mechanisms is needed.

Glycemic control and self-rated health among ethnically diverse adolescents with type 1 diabetes.

Patient-reported outcomes have received increased attention as treatment outcomes and indicators of wellbeing. A1c has been criticized as lacking patient-centered relevance because individuals are often unaware of their A1c, and studies also often fail to show a benefit of intensive control on quality of life. The goal of the present study was to examine self-rated health (SRH) in relation to diabetes self-care behaviors, socioeconomic factors, treatment regimen characteristics, and glycemic control among predominately Hispanic and African American adolescents with type 1 diabetes (T1D). Adolescents with T1D (N = 84) were recruited for a cross-sectional study evaluating psychosocial factors and identity development. SRH, self-care behaviors, treatment regimen, and demographic variables were collected through self-report while glycemic control (A1c) was determined through chart review. Participants were predominantly racial and ethnic minorities (48% Hispanic, 27% African American; 52% female, M age 15.9, M diabetes duration 6.8, M A1c 10% [86 mmol/mol]). Significant bivariate relationships emerged between SRH and sex, A1c, self-care behavior, and insulin delivery method. Covariate-adjusted regression models showed only A1c was significantly and independently related to SRH. Mediation analyses illustrated a significant indirect effect for A1c between self-care and SRH. These findings suggest glycemic control is associated with self-ratings of health among ethnically diverse adolescents with T1D. SRH appears to be an appropriate patient-reported outcome that is sensitive to glycemic control in this population.

PERIPHERAL ARTERIAL DISEASE AND SEDENTARY TIME IN OLDER ADULTS

Peripheral artery disease (PAD) is associated with increased rates of physical disability in older adults, yet few interventions exist to reduce this risk. Intermittent claudication, exertional calf symptoms that resolve within 10 minutes of rest, is the classic symptom for PAD, but many people with PAD are absent of these symptoms. Ankle brachial index (ABI) is a non-invasive measure that identifies the presence and severity of lower extremity arterial obstruction due to atherosclerosis. We studied whether abnormal ABI is associated with increased time spent in sedentary behavior in a large sample of community-dwelling older men and women (70-89 years) enrolled in the Lifestyle Interventions and Independence for Elders (LIFE) study. Older adults underwent an ABI test and then wore a tri-axial accelerometer on the hip for up to seven days. Total accumulated sedentary time and sedentary time spent in bout lengths of 10minutes or more, 30 minutes or more, and 60 minutes or more were calculated. ABI values, divided into PAD (<.90, n=156) and non-PAD (0.90 - 1.40, n=960), were evaluated in covariate-adjusted regression models adjusting for age, body mass index, comorbidity presence, gender and smoking. Older adults with PAD had significantly higher total accumulated time spent in sedentary behavior than those without PAD (13.1 minutes per day, p<0.02). No associations were found with longer bout lengths of sedentary time. These results suggest that older adults with PAD accumulate more time in shorter bouts of sedentary behavior. Future interventions may consider targeting short sedentary bout-lengths for reducing PAD symptoms.

Sleep Disordered Breathing in Patient with Type 2 Diabetes Mellitus and its Association with Diabetic Retinopathy: Single Center Study

Introduction: Sleep-disordered breathing comprises of obstructive sleep apnea, central sleep apnea, and periodic breathing. There is a link between obesity diabetes and sleep apnea with its association with retinopathy. Therefore this study was done to find out the association of sleep-disordered breathing in uncontrolled diabetes mellitus and association with retinopathy.Materials and Methods: This study was done from 2015 September to 2018 September in Sleep center, Nepal. Patients diagnosed with Type 2 diabetes mellitus were included. Diabetes mellitus was diagnosed as blood sugar fasting ≥ 126mg/dl, or blood sugar postprandial ≥200mg/dl and glycosylated hemoglobin above 6.5%. Obstructive sleep apnea risk was determined using the STOP-BANG questionnaire. Relationships between the risk of Obstructive sleep apnea and clinical variables along with its association with diabetic retinopathy were evaluated using bivariate analyses and covariate-adjusted logistic regression models.Results: A total of 150 diabetic patients were analyzed. Among them 30 (20.0%) patients had mild Obstructive sleep apnea, 14 (9.3%) patients had moderate Obstructive sleep apnea and 15 (10.0%) patients had severe sleep apnea. Among patients with diabetes mellitus on multivariate regression analysis Obstructive sleep apnea was associated with diabetes mellitus OR 2.05, 95% CI (1.69- 8.83) and diabetic retinopathy OR 1.20 (0.67-5.89).Conclusions: This study concludes that those individuals having diabetes may be suffering from obstructive sleep apnea and association with retinopathy these individuals can be considered for the screening of sleep-disordered breathing by polysomnography.

KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD.

To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aβ burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aβ was different among KL-VS heterozygotes compared to noncarriers. APOE4 carriers exhibited greater Aβ burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aβ load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0 .001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aβ burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.

3134 Organophosphate pesticide exposure during pregnancy, gestational weight gain and long-term postpartum weight retention

OBJECTIVES/SPECIFIC AIMS: Little is known about potentially obesogenic endocrine-disruptors’ effects on excessive gestational weight gain (GWG) and postpartum weight retention (PPWR), which increase risk of adverse pregnancy and postnatal outcomes. We explored associations between prenatal organophosphate (OP) pesticide exposure and increased weight both during and after pregnancy. METHODS/STUDY POPULATION: Three dimethyl (DM) and three diethyl (DE) OP metabolites were measured in spot urine samples collected at &lt;18, 18-25, and &gt;25 gestational weeks among 688 participants in the Generation R Study. Metabolite levels were expressed as molar concentration/gram creatinine and log10-transformed. GWG and PPWR were calculated as the difference between weight at each prenatal/postnatal visit or maximum gestational weight and pre-pregnancy weight. In covariate-adjusted regression models we assessed associations of metabolite concentrations at each prenatal visit and, where appropriate, averaged across pregnancy with early-to-mid pregnancy, mid-to-late pregnancy, late pregnancy-to-maximum, and total GWG; insufficient and excessive GWG according to Institute of Medicine guidelines; and long-term PPWR at 6 and 10 years postpartum. Based on OP pesticides’ lipophilicity and association with hypomethylation, we investigated interactions with pre-pregnancy body mass index, periconceptional folic acid supplementation, and breastfeeding duration. RESULTS/ANTICIPATED RESULTS: A 10-fold increase in late pregnancy DE metabolite concentration was associated with 1.34 kg [95% confidence interval: 0.55, 2.12] higher late pregnancy-to-maximum GWG. A 10-fold increase in mean DE metabolite concentration across pregnancy was associated with 2.41 kg [0.62, 4.20] lower PPWR at 6 years. Stratified analysis suggested that the prenatal finding was driven by women with pre-pregnancy BMI ≥25 kg/m2, while the postnatal finding was driven by women with pre-pregnancy BMI &lt;25 kg/m2 and with inadequate folic acid supplementation. We found no associations between OP pesticide metabolites and insufficient or excessive weight gain and no interaction with breastfeeding. DISCUSSION/SIGNIFICANCE OF IMPACT: In this longitudinal analysis, we observed a positive association of OP pesticide metabolites with GWG in late pregnancy among overweight/obese women, potentially reflecting inhibition of OP pesticide detoxification by oxidative stress. Postnatally, under/normal weight women with higher OP pesticide metabolites had lower PPWR, possibly due to better metabolic function and a more healthful diet. These results suggest that there may be a critical period during the late phase of pregnancy when OP pesticide exposure may increase GWG, and this association may be amplified in overweight/obese women. Areas for future research include examination of how the interaction between OP pesticides and polymorphisms of the paraoxonase (PON1) gene, which detoxifies OP pesticides, affect GWG/PPWR; exploration of the interplay among maternal pre-pregnancy BMI, oxidative stress, and PON1 levels; and characterization of the variability of OP pesticides exposure across pregnancy using more frequent repeated urine samples.

The association of age with acute toxicities in NRG oncology combined modality lower GI cancer trials.

649 Background: This study sought to compare adverse events (AEs) of older and younger adults with lower gastrointestinal (GI) malignancies treated on NRG studies. Methods: Data from six NRG trials (RTOG 9811/0012/0247/0529/0822 &amp; NSABP R-04), testing combined modality therapy (radiation and chemotherapy) in patients with anal or rectal cancer, were collected to test the hypothesis that older age was associated with increase in acute ( ≤ 90 days from treatment start) AEs. AEs were defined as GI, Genitourinary (GU), hematologic, or skin. AEs and compliance with protocol-directed therapy were compared between patients aged ≥ 70 years and &lt; 70 years. Categorical variables were compared across age groups using the chi-square test. The association of age on AEs was evaluated using a covariate-adjusted logistic regression model, with odds ratio (OR) reported. To adjust for multiple comparisons, a p-value &lt; 0.01 was considered statistically significant. Results: Data from 2525 patients were collected (43% female, 72% rectal cancer). There were 380 patients ≥ 70 years old (15%). Older patients were more likely to have worse baseline performance status (PS 1 or 2) (23% vs. 16%, p &lt;0.01), but otherwise baseline characteristics were similar. Older patients were less likely to have completed their chemotherapy (78% vs. 87%, p &lt; 0.01), but had similar median RT duration. On univariate analysis, patients ≥ 70 were more likely to experience grade ≥ 3 GI AEs (36% vs. 23%, OR 1.82, p &lt; 0.001), and less likely to experience ≥ 3 skin AEs (8% vs. 14%, OR 0.56, p = 0.002). There was no difference between GU or hematologic AEs. On multivariable analysis, age ≥ 70 was associated with grade ≥ 3 GI AE (OR 1.80, 95% CI: 1.40, 2.31; p &lt; 0.001) after adjusting for gender, PS, T stage, disease site, RT duration, and chemotherapy completion. Conclusions: Older patients with curable lower GI cancers who underwent combined-modality therapy were less likely to complete chemotherapy and were more likely to experience serious GI toxicity, whereas younger patients had higher rates of serious skin AEs.