Bayesian joint modeling of multivariate longitudinal and survival outcomes using Gaussian copulas.

There is an increasing interest in the use of joint models for the analysis of longitudinal and survival data. While random effects models have been extensively studied, these models can be hard to implement and the fixed effect regression parameters must be interpreted conditional on the random effects. Copulas provide a useful alternative framework for joint modeling. One advantage of using copulas is that practitioners can directly specify marginal models for the outcomes of interest. We develop a joint model using a Gaussian copula to characterize the association between multivariate longitudinal and survival outcomes. Rather than using an unstructured correlation matrix in the copula model to characterize dependence structure as is common, we propose a novel decomposition that allows practitioners to impose structure (e.g., auto-regressive) which provides efficiency gains in small to moderate sample sizes and reduces computational complexity. We develop a Markov chain Monte Carlo model fitting procedure for estimation. We illustrate the method's value using a simulation study and present a real data analysis of longitudinal quality of life and disease-free survival data from an International Breast Cancer Study Group trial.

Interactions between Bifidobacterium and Bacteroides and human milk oligosaccharides and their associations with infant cognition.

While ample research on independent associations between infant cognition and gut microbiota composition and human milk (HM) oligosaccharides (HMOs) has been reported, studies on how the interactions between gut microbiota and HMOs may yield associations with cognitive development in infancy are lacking. We aimed to determine how HMOs and species of Bacteroides and Bifidobacterium genera interact with each other and their associations with cognitive development in typically developing infants. A total of 105 mother-infant dyads were included in this study. The enrolled infants [2.9-12 months old (8.09 ± 2.48)] were at least predominantly breastfed at 4 months old. A total of 170 HM samples from the mothers and fecal samples of the children were collected longitudinally. Using the Mullen Scales of Early Learning to assess cognition and the scores as the outcomes, linear mixed effects models including both the levels of eight HMOs and relative abundance of Bacteroides and Bifidobacterium species as main associations and their interactions were employed with adjusting covariates; infant sex, delivery mode, maternal education, site, and batch effects of HMOs. Additionally, regression models stratifying infants based on the A-tetrasaccharide (A-tetra) status of the HM they received were also employed to determine if the associations depend on the A-tetra status. With Bacteroides species, we observed significant associations with motor functions, while Bif. catenulatum showed a negative association with visual reception in the detectable A-tetra group both as main effect (value of p = 0.012) and in interaction with LNFP-I (value of p = 0.007). Additionally, 3-FL showed a positive association with gross motor (p = 0.027) and visual reception (p = 0.041). Furthermore, significant associations were observed with the interaction terms mainly in the undetectable A-tetra group. Specifically, we observed negative associations for Bifidobacterium species and LNT [breve (p = 0.011) and longum (p = 0.022)], and positive associations for expressive language with 3'-SL and Bif. bifidum (p = 0.01), 6'-SL and B. fragilis (p = 0.019), and LNFP-I and Bif. kashiwanohense (p = 0.048), respectively. Our findings suggest that gut microbiota and HMOs are both independently and interactively associated with early cognitive development. In particular, the diverse interactions between HMOs and Bacteroides and Bifidobacterium species reveal different candidate pathways through which HMOs, Bifidobacterium and Bacteroides species potentially interact to impact cognitive development in infancy.

Joint analyses of human milk fatty acids, phospholipids, and choline in association with cognition and temperament traits during the first 6 months of life.

Early dietary exposure via human milk nutrients offers a window of opportunity to support cognitive and temperament development. While several studies have focused on associations of few pre-selected human milk nutrients with cognition and temperament, it is highly plausible that human milk nutrients synergistically and jointly support cognitive and behavioral development in early life. We aimed to discern the combined associations of three major classes of human milk nutrients with cognition and temperament during the first 6 months of life when human milk is the primary source of an infant's nutrition and explore whether there were persistent effects up to 18 months old. The Mullen Scales of Early Learning and Infant Behavior Questionnaires-Revised were used to assess cognition and temperament, respectively, of 54 exclusively/predominantly breastfed infants in the first 6 months of life, whose follow-ups were conducted at 6-9, 9-12, and 12-18 months old. Human milk samples were obtained from the mothers of the participants at less than 6 months of age and analyzed for fatty acids [total monounsaturated fatty acids, polyunsaturated fatty acid, total saturated fatty acid (TSFA), arachidonic acid (ARA), docosahexaenoic acid (DHA), ARA/DHA, omega-6/omega-3 polyunsaturated fatty acids ratio (n-6/n-3)], phospholipids [phosphatidylcholine, phosphatidylethanolamine (PE), phosphatidylinositol (PI), sphingomyelin], and choline [free choline, phosphocholine (PCho), glycerophosphocholine]. Feature selection was performed to select nutrients associated with cognition and temperament. The combined effects of selected nutrients were analyzed using multiple regression. A positive association between the arachidonic acid (ARA) and surgency was observed (p = 0.024). A significant effect of DHA, n-6/n-3, PE, and TSFA concentrations on receptive language (R 2 = 0.39, p = 0.025) and the elevated ARA, PCho, and PI with increased surgency (R 2 = 0.43, p = 0.003) was identified, suggesting that DHA and ARA may have distinct roles for temperament and language functions. Furthermore, the exploratory association analyses suggest that the effects of human milk nutrients on R.L. and surgency may persist beyond the first 6 months of life, particularly surgency at 12-18 months (p = 0.002). Our study highlighted that various human milk nutrients work together to support the development of cognition and temperament traits during early infancy.

Human milk 3'-Sialyllactose is positively associated with language development during infancy.

BACKGROUND: Genetic polymorphisms leading to variations in human milk oligosaccharide (HMO) composition have been reported. Alpha-Tetrasaccharide (A-tetra), an HMO, has been shown to only be present (>limit of detection; A-tetra+) in the human milk (HM) of women with blood type A, suggesting genetic origins determining the presence or absence (A-tetra-) of A-tetra in HM. OBJECTIVES: This study aimed to determine whether associations exist between HMO concentrations and cognitive development, and whether the associations vary between A-tetra+ and A-tetra- groups in children (<25 months old). METHODS: We enrolled typically developing children (2-25 months old; mean, 10 months old) who were at least partially breastfed at the study visit. The Mullen Scales of Early Learning (MSEL) were used as the primary outcome measure to assess early cognitive development. Linear mixed effects models were employed by stratifying children based on A-tetra levels (A-tetra+ or A-tetra-) to assess associations between age-removed HMO concentrations and both MSEL composite scores and the 5 subdomain scores. RESULTS: A total of 99 mother-child dyads and 183 HM samples were included (A-tetra+: 57 samples, 33 dyads; A-tetra-: 126 samples, 66 dyads). No significant association was observed between HMOs and MSEL when all samples were analyzed together. The composite score and 3'-sialyllactose (3'-SL) levels were positively associated [P = 0.002; effect size (EF), 13.12; 95% CI, 5.36-20.80] in the A-tetra + group. This association was driven by the receptive (adjusted P = 0.015; EF, 9.95; 95% CI, 3.91-15.99) and expressive (adjusted P = 0.048; EF, 7.53; 95% CI, 2.51-13.79) language subdomain scores. Furthermore, there was an interaction between 3'-SL and age for receptive language (adjusted P = 0.03; EF, -14.93; 95% CI, -25.29 to -4.24). CONCLUSIONS: Our study reports the association of 3'-SL and cognition, particularly language functions, in typically developing children who received HM containing detectable A-tetra during infancy.

Impact of Personal Health Records and Wearables on Health Outcomes and Patient Response: Three-Arm Randomized Controlled Trial.

BACKGROUND: Although using the technologies for a variety of chronic health conditions such as personal health record (PHR) is reported to be acceptable and useful, there is a lack of evidence on the associations between the use of the technologies and the change of health outcome and patients' response to a digital health app. OBJECTIVE: This study aimed to examine the impact of the use of PHR and wearables on health outcome improvement and sustained use of the health app that can be associated with patient engagement. METHODS: We developed an Android-based mobile phone app and used a wristband-type activity tracker (Samsung Charm) to collect data on health-related daily activities from individual patients. Dietary record, daily step counts, sleep log, subjective stress amount, blood pressure, and weight values were recorded. We conducted a prospective randomized clinical trial across 4 weeks on those diagnosed with obstructive sleep apnea (OSA) who had visited the outpatient clinic of Seoul National University Bundang Hospital. The trial randomly assigned 60 patients to 3 subgroups including 2 intervention groups: (1) mobile app and wearable device users (n=20), (2) mobile app-only users (n=20), and (3) controls (n=20). The primary outcome measure was weight change. Body weights before and after the trial were recorded and analyzed during clinic visits. Changes in OSA-related respiratory parameters such as respiratory disturbance, apnea-hypopnea, and oxygenation desaturation indexes and snoring comprised the secondary outcome and were analyzed for each participant. RESULTS: We collected the individual data for each group during the trial, specifically anthropometric measurement and laboratory test results for health outcomes, and the app usage logs for patient response were collected and analyzed. The body weight showed a significant reduction in the 2 intervention groups after intervention, and the mobile app-only group showed more weight loss compared with the controls (P=.01). There were no significant changes in sleep-related health outcomes. From a patient response point of view, the average daily step counts (8165 steps) from the app plus wearable group were significantly higher than those (6034 steps) from the app-only group because they collected step count data from different devices (P=.02). The average rate of data collection was not different in physical activity (P=.99), food intake (P=.98), sleep (P=.95), stress (P=.70), and weight (P=.90) in the app plus wearable and app-only groups, respectively. CONCLUSIONS: We tried to integrate PHR data that allow clinicians and patients to share lifelog data with the clinical workflow to support lifestyle interventions. Our results suggest that a PHR-based intervention may be successful in losing body weight and improvement in lifestyle behavior. TRIAL REGISTRATION: ClinicalTrials.gov NCT03200223; https://clinicaltrials.gov/ct2/show/NCT03200223 (Archived by WebCite at http://www.webcitation.org/74baZmnCX).