The impact of correlated exposures and missing data on multiple informant models used to identify critical exposure windows.

There has been heightened interest in identifying critical windows of exposure for adverse health outcomes; that is, time points during which exposures have the greatest impact on a person's health. Multiple informant models implemented using generalized estimating equations (MIM GEEs) have been applied to address this research question because they enable statistical comparisons of differences in associations across exposure windows. As interest rises in using MIMs, the feasibility and appropriateness of their application under settings of correlated exposures and partially missing exposure measurements requires further examination. We evaluated the impact of correlation between exposure measurements and missing exposure data on the power and differences in association estimated by the MIM GEE and an inverse probability weighted extension to account for informatively missing exposures. We assessed these operating characteristics under a variety of correlation structures, sample sizes, and missing data mechanisms considering various exposure-outcome scenarios. We showed that applying MIM GEEs maintains higher power when there is a single critical window of exposure and exposure measures are not highly correlated, but may result in low power and bias under other settings. We applied these methods to a study of pregnant women living with HIV to explore differences in association between trimester-specific viral load and infant neurodevelopment.

Absorbance Measurements From Normal-hearing Ears in the National Health and Nutrition Examination Survey, 2015-2016 and 2017-2020.

OBJECTIVE: To summarize absorbance and impedance angles from normal-hearing ears within the 2015-2016 and 2017-2020 US National Health and Nutrition Examination Surveys (NHANES). DESIGN: Two publicly available NHANES datasets were analyzed. Ears meeting criteria for normal hearing and valid absorbance and impedance angle measurements were identified. Measurements were summarized via descriptive statistics within categories of age cohort, race/ethnicity cohort, sex (male, female), and ear (left, right). RESULTS: A total of 7029 ears from 4150 subjects, ages 6 to 80 years, met inclusion criteria. Differences between subgroups within all categories (age, race/ethnicity, sex, and ear) were fractions of the sample SDs. The largest differences occurred between age cohorts younger than 20 years. CONCLUSIONS: The NHANES absorbance and impedance angle measurements are consistent with published literature. These results demonstrate that trained professionals, using the Titan instrument in a community setting inclusive of all demographics, produce comparable measurements to those in laboratory settings.

Three-photon imaging of mouse brain structure and function through the intact skull.

Optical imaging through the intact mouse skull is challenging because of skull-induced aberrations and scattering. We found that three-photon excitation provided improved optical sectioning compared with that obtained with two-photon excitation, even when we used the same excitation wavelength and imaging system. Here we demonstrate three-photon imaging of vasculature through the adult mouse skull at >500-µm depth, as well as GCaMP6s calcium imaging over weeks in cortical layers 2/3 and 4 in awake mice, with 8.5 frames per second and a field of view spanning hundreds of micrometers.

In vivo three-photon imaging of activity of GCaMP6-labeled neurons deep in intact mouse brain.

High-resolution optical imaging is critical to understanding brain function. We demonstrate that three-photon microscopy at 1,300-nm excitation enables functional imaging of GCaMP6s-labeled neurons beyond the depth limit of two-photon microscopy. We record spontaneous activity from up to 150 neurons in the hippocampal stratum pyramidale at ∼1-mm depth within an intact mouse brain. Our method creates opportunities for noninvasive recording of neuronal activity with high spatial and temporal resolution deep within scattering brain tissues.

Measurements of ear-canal cross-sectional areas from live human ears with implications for wideband acoustic immittance measurements.

Wideband acoustic immittance (WAI) measures are noninvasive diagnostic measurements that require an estimate of the ear canal's area at the measurement location. Yet, physical measurements of the area at WAI probe locations are lacking. Methods to measure ear-canal areas from silicone molds were developed and applied to 169 subjects, ages 18-75 years. The average areas at the canal's first bend and at 12 mm insertion depth, which are likely WAI probe locations, were 63.4 ± 13.5 and 61.6 ± 13.5 mm2, respectively. These areas are substantially larger than those assumed by current FDA-approved WAI measurement devices as well as areas estimated with acoustical methods or measured on cadaver ears. Left and right ears from the same subject had similar areas. Sex, height, and weight were not significant factors in predicting area. Age cohort was a significant predictor of area, with area increasing with decade of life. A subset of areas from the youngest female subjects did not show an effect of race on area (White or Chinese). Areas were also measured as a function of insertion depth of 4.8-13.2 mm from the canal entrance; area was largest closest to the canal entrance and systematically decreased with insertion depth.

Using generalized estimating equations and extensions in randomized trials with missing longitudinal patient reported outcome data.

OBJECTIVE: Patient reported outcomes (PROs) are important in oncology research; however, missing data can pose a threat to the validity of results. Psycho-oncology researchers should be aware of the statistical options for handling missing data robustly. One rarely used set of methods, which includes extensions for handling missing data, is generalized estimating equations (GEEs). Our objective was to demonstrate use of GEEs to analyze PROs with missing data in randomized trials with assessments at fixed time points. METHODS: We introduce GEEs and show, with a worked example, how to use GEEs that account for missing data: inverse probability weighted GEEs and multiple imputation with GEE. We use data from an RCT evaluating a web-based brain training for cancer survivors reporting cognitive symptoms after chemotherapy treatment. The primary outcome for this demonstration is the binary outcome of cognitive impairment. Several methods are used, and results are compared. RESULTS: We demonstrate that estimates can vary depending on the choice of analytical approach, with odds ratios for no cognitive impairment ranging from 2.04 to 5.74. While most of these estimates were statistically significant (P < 0.05), a few were not. CONCLUSIONS: Researchers using PROs should use statistical methods that handle missing data in a way as to result in unbiased estimates. GEE extensions are analytic options for handling dropouts in longitudinal RCTs, particularly if the outcome is not continuous.

Depressive and anxious symptoms and 20-year mortality: Evidence from the Stirling County study.

BACKGROUND: Depression and anxiety disorders are highly comorbid, and share significant symptom overlap. Whereas depression has been consistently associated with excess mortality, the association between anxiety and mortality is less clear. Our aim was to identify constellations of anxious and depressive symptoms and examine their associations with mortality. METHOD: This study considers respondents from the 1970 (n = 1203) and 1992 (n = 1402) cohorts of the Stirling County study. Symptoms of depression and anxiety were assessed using structured at-home interviews. Vital status of participants through 2011 was determined using probabilistic linkages to the Canadian Mortality Database. RESULTS: Exploratory factor analysis yielded three correlated factors in each cohort. Items loading on each factor varied slightly between cohorts, but roughly corresponded to (1) depressive symptoms, (2) anxious symptoms, and (3) somatic symptoms. The depressive factor was associated with increased risk of mortality in both the 1970 (HR: 1.35, 95% CI: 1.12, 1.62) and 1992 (HR: 1.25, 95% CI: 1.05, 1.48) cohorts. Anxious symptoms were associated with a reduced risk of mortality in the 1992 sample (HR: 0.72; 95% CI: 0.53, 0.90). Somatic symptoms were associated with a reduced risk of mortality in the 1970 sample (HR: 0.83, 95% CI: 0.69, 0.99), but an elevated risk of mortality in the 1992 sample (HR: 1.29; 95% CI: 1.11, 1.51). CONCLUSIONS: This study provides evidence that symptoms of depression and anxiety may have differential associations with early mortality. Somatic symptoms such as upset stomach and loss of appetite may be protective against mortality, perhaps through increased use of health care services. Conversely, symptoms such as weakness and cold sweats may be indicative of failing health.

A mean score method for sensitivity analysis to departures from the missing at random assumption in randomised trials.

Most analyses of randomised trials with incomplete outcomes make untestable assumptions and should therefore be subjected to sensitivity analyses. However, methods for sensitivity analyses are not widely used. We propose a mean score approach for exploring global sensitivity to departures from missing at random or other assumptions about incomplete outcome data in a randomised trial. We assume a single outcome analysed under a generalised linear model. One or more sensitivity parameters, specified by the user, measure the degree of departure from missing at random in a pattern mixture model. Advantages of our method are that its sensitivity parameters are relatively easy to interpret and so can be elicited from subject matter experts; it is fast and non-stochastic; and its point estimate, standard error and confidence interval agree perfectly with standard methods when particular values of the sensitivity parameters make those standard methods appropriate. We illustrate the method using data from a mental health trial.

Depression and mortality in a longitudinal study: 1952-2011.

BACKGROUND: Many studies have shown that depression increases mortality risk. We aimed to investigate the duration of time over which depression is associated with increased risk of mortality, secular trends in the association between depression and mortality, and sex differences in the association between depression and mortality. METHODS: We conducted a cohort study of 3410 adults enrolled in 3 representative samples of a county in Atlantic Canada in 1952 (n = 1003), 1970 (n = 1203) or 1992 (n = 1402) (the Stirling County Study). Depression was measured using a diagnostic algorithm based on the presence of depressed mood and associated symptoms, duration of more than 1 month, and substantial impairment. Vital status of participants through 2011 was determined using probabilistic linkages to the Canadian Mortality Database. RESULTS: Depression was associated with a heightened risk of mortality among men during the 3 time periods of the study, with hazard ratios (HRs) of 2.90 (95% confidence interval [CI] 1.69-4.98) between 1952 and 1967, 1.97 (CI 1.34-2.89) between 1968 and 1990, and 1.52 (CI 1.09-2.13) between 1991 and 2011. Elevated risk of mortality was noted among women only between 1990 and 2011 (HR = 1.51; CI = 1.11-2.05). INTERPRETATION: The association between depression and mortality persists over long periods of time and has emerged among women in recent decades, despite contemporaneous improvements in the treatment of depression and reduction of stigma associated with depression. Further research is needed to better understand the mechanisms involved.

Impact of Single- vs. Split-Dose Low-Volume Bowel Preparations on Bowel Movement Kinetics, Patient Inconvenience, and Polyp Detection: A Prospective Trial.

OBJECTIVES: There are little data on bowel movement (BM) kinetics induced by bowel preparation. Whether single-dose (SID) or split-dose (SPD) regimens differ in terms of patient convenience is unclear. We compared BM kinetics, sleep and travel disruptions, and polyp detection rates in patients undergoing colonoscopy assigned to SID vs. SPDs. METHODS: Patients were randomly assigned to 2-L SID or SPD (SPD1 and SPD2) bowel preparations. Surveys were completed querying the onset, duration, cessation, and intensity of BMs, along with sleep and travel disruption en route to the endoscopy center. Colon cleansing quality and polyp histology were recorded. RESULTS: A total of 341 patients were enrolled, 51% in SPD and 49% in SID. Over half of patients had their first BM within 60 min of starting the preparation. After dosing, 92% of SID and 66% of SPD1 patients achieved clear effluent (P<0.001), whereas it was reported in 97% of SPD2 patients (P=0.028 vs. SID). Total duration (P=0.041) and intensity (P<0.001) of BMs were greater in SID. More patients in SID woke up for BMs (65.9 vs. 48.8%, P<0.003). No differences in the need to stop driving en route to colonoscopy were noted. Bowel prep quality was better in SPD (P<0.001). Although no difference in the adenoma detection rate was noted, the sessile-serrated polyp detection rate was greater in SPD than in SID (9.9 vs. 2.4%, P=0.004). CONCLUSIONS: Our data demonstrate that SPD bowel preparation results in decreased intensity and duration of BMs, less patient inconvenience, improved bowel preparation, and increased sessile-serrated polyp detection rates.

Family functioning and quality of parent-adolescent relationship: cross-sectional associations with adolescent weight-related behaviors and weight status.

BACKGROUND: Little is known about how factors within the general family environment are associated with weight and related behaviors among adolescents/young adults. METHODS: We studied 3768 females and 2614 males, 14-24 years old in 2011, participating in the Growing Up Today Study 2. We used generalized mixed models to examine cross-sectional associations of family functioning and quality of mother- and father-adolescent relationship with adolescent/young adult weight status, disordered eating, intake of fast food and sugar-sweetened beverages, screen time, physical activity, and sleep duration. In all models, we included participant's age and family structure. RESULTS: Eighty percent of participants reported high family functioning and 60% and 50% of participants reported high-quality mother and father relationship, respectively. Among both males and females, high family functioning was associated with lower odds of disordered eating (adjusted odds ratio [AOR] females = 0.53; 95% Confidence Interval [CI] = 0.45-0.63; AOR males = 0.48; CI = 0.39-0.60), insufficient physical activity, i.e., less than 1 h/day, (AOR females = 0.74; CI = 0.61-0.89; AOR males = 0.73; CI = 0.58-0.92), and insufficient sleep, i.e., less than 7 h/day, (AOR females = 0.56; CI = 0.45-0.68; AOR males = 0.65; CI 0.5-0.85). High family functioning was also associated with lower odds of being overweight/obese (AOR = 0.73; CI = 0.60-0.88) and eating fast food one or more times/week (AOR = 0.74; CI = 0.61-0.89) among females only. Among females, high-quality mother and father relationship were both associated with lower odds of being overweight/obese and disordered eating, eating fast food, and insufficient sleep and the magnitude of associations were similar for mother and father relationship quality (AOR range 0.61-0.84). Among males, high-quality mother and father relationship were both associated with lower odds of disordered eating, insufficient physical activity and insufficient sleep, but only father relationship quality was associated with lower odds of overweight/obesity. CONCLUSIONS: Adolescents/young adults reporting high family functioning and more positive relationships with their parents reported better weight-related behaviors. For weight status, females appear to be affected equally by the quality of their relationship with both parents, whereas males may be more affected by their relationship with fathers.

Reflectance Measures from Infant Ears With Normal Hearing and Transient Conductive Hearing Loss.

OBJECTIVE: The objective is to develop methods to utilize newborn reflectance measures for the identification of middle-ear transient conditions (e.g., middle-ear fluid) during the newborn period and ultimately during the first few months of life. Transient middle-ear conditions are a suspected source of failure to pass a newborn hearing screening. The ability to identify a conductive loss during the screening procedure could enable the referred ear to be either (1) cleared of a middle-ear condition and recommended for more extensive hearing assessment as soon as possible, or (2) suspected of a transient middle-ear condition, and if desired, be rescreened before more extensive hearing assessment. DESIGN: Reflectance measurements are reported from full-term, healthy, newborn babies in which one ear referred and one ear passed an initial auditory brainstem response newborn hearing screening and a subsequent distortion product otoacoustic emission screening on the same day. These same subjects returned for a detailed follow-up evaluation at age 1 month (range 14 to 35 days). In total, measurements were made on 30 subjects who had a unilateral refer near birth (during their first 2 days of life) and bilateral normal hearing at follow-up (about 1 month old). Three specific comparisons were made: (1) Association of ear's state with power reflectance near birth (referred versus passed ear), (2) Changes in power reflectance of normal ears between newborn and 1 month old (maturation effects), and (3) Association of ear's newborn state (referred versus passed) with ear's power reflectance at 1 month. In addition to these measurements, a set of preliminary data selection criteria were developed to ensure that analyzed data were not corrupted by acoustic leaks and other measurement problems. RESULTS: Within 2 days of birth, the power reflectance measured in newborn ears with transient middle-ear conditions (referred newborn hearing screening and passed hearing assessment at age 1 month) was significantly greater than power reflectance on newborn ears that passed the newborn hearing screening across all frequencies (500 to 6000 Hz). Changes in power reflectance in normal ears from newborn to 1 month appear in approximately the 2000 to 5000 Hz range but are not present at other frequencies. The power reflectance at age 1 month does not depend significantly on the ear's state near birth (refer or pass hearing screening) for frequencies above 700 Hz; there might be small differences at lower frequencies. CONCLUSIONS: Power reflectance measurements are significantly different for ears that pass newborn hearing screening and ears that refer with middle-ear transient conditions. At age 1 month, about 90% of ears that referred at birth passed an auditory brainstem response hearing evaluation; within these ears the power reflectance at 1 month did not differ between the ear that initially referred at birth and the ear that passed the hearing screening at birth for frequencies above 700 Hz. This study also proposes a preliminary set of criteria for determining when reflectance measures on young babies are corrupted by acoustic leaks, probes against the ear canal, or other measurement problems. Specifically proposed are "data selection criteria" that depend on the power reflectance, impedance magnitude, and impedance angle. Additional data collected in the future are needed to improve and test these proposed criteria.

Impact of Low Immunoglobulin G Levels on Disease Outcomes in Patients with Inflammatory Bowel Diseases.

BACKGROUND: Inflammatory bowel diseases (IBDs) are considered immune-mediated disorders with dysregulated innate and adaptive immunities. Secondary immunogloblin deficiency can occur in IBD and its impact on the disease course of IBD is not clear. AIMS: We sought to determine associations between low IgG/G1 levels and poor clinical outcomes in IBD patients. METHODS: This historic cohort study was performed on IBD patients with obtained IgG/IgG1 levels. The primary outcome was defined as any IBD-related bowel resection surgery and/or hospitalization. Subgroup analyses assessed particular surgical outcomes in Crohn's disease (CD), ulcerative colitis (UC) or indeterminate colitis (IC), and ileal pouch-anal anastomosis (IPAA). The secondary outcomes included IBD drug escalations and C. difficile or cytomegalovirus infections. RESULTS: A total of 136 IBD patients had IgG/G1 levels checked and adequate follow-up, 58 (42.6 %) with normal IgG/G1 levels and 78 (57.4 %) having low levels. A total of 49 patients (62.8 %) with low immunoglobulin levels had IBD-related surgeries or hospitalizations, compared to 33 patients (56.9 %) with normal levels [odds ratio (OR) 1.28, 95 % confidence interval (CI) 0.64-2.56; p = 0.49]. Low IgG/G1 levels were associated with IBD-related surgery in CD in univariate analysis [hazard ratio (HR) 4.42, 95 % CI 1.02-19.23; p = 0.048] and in Kaplan-Meier survival curve analysis (p = 0.03), with a trend toward significance on multivariate analysis (HR 3.07, 95 % CI 0.67-14.31; p = 0.15). IBD patients with low IgG/G1 levels required more small bowel resections (12.8 vs. 1.7 %, p = 0.024) and 5-aminosalicylate initiations (28.2 vs. 13.8 %, p = 0.045). CONCLUSIONS: Our study demonstrated a possible association between low IgG/G1 levels and poor outcomes in CD including surgery. Future implications include using immunoglobulin levels in IBD patients as a prognostic indicator or boosting humoral immunity as a treatment in this subset.

Prevalence of purging at age 16 and associations with negative outcomes among girls in three community-based cohorts.

BACKGROUND: The comorbidity of purging behaviours, such as vomiting, inappropriate use of laxatives, diuretics or slimming medications, has been examined in literature. However, most studies do not include adolescents, individuals who purge in the absence of binge eating, or those purging at subclinical frequency. This study examines the prevalence of purging among 16-year-old girls across three countries and their association with substance use and psychological comorbidity. METHODS: Data were obtained by questionnaire in 3 population-based cohorts (Avon Longitudinal Study of Parents and Children (ALSPAC), United Kingdom, n = 1,608; Growing Up Today Study (GUTS), USA, n = 3,504; North Finland Birth Cohort (NFBC85/86), Finland, n = 2,306). Multivariate logistic regressions were employed to estimate associations between purging and outcomes. Four models were fit adjusting for binge eating and potential confounders of these associations. RESULTS: In ALSPAC, 9.7% of girls reported purging in the 12-months prior to assessment, 7.3% in GUTS, and 3.5% in NFBC. In all 3 cohorts, purging was associated with adverse outcomes such as binge drinking (ALSPAC: odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1.4-2.9; GUTS: OR = 2.5, 95% CI = 1.5-4.0; NFBC: OR = 1.7, 95% CI = 1.0-2.8), drug use (ALSPAC: OR = 2.9, 95% CI = 1.8-4.7; GUTS: OR = 4.5, 95% CI = 2.8-7.3; NFBC: OR = 4.1, 95% CI = 2.6-6.6), depressive symptoms in ALSPAC (OR = 2.2, 95% CI = 1.5-3.1) and GUTS(OR = 3.7, 95% CI = 2.2-6.3), and several psychopathology measures including clinical anxiety/depression in NFBC (OR = 11.2, 95% CI = 3.9, 31.7). CONCLUSIONS: Results show a higher prevalence of purging behaviours among girls in the United Kingdom compared to those in the United States and Finland. Our findings support evidence highlighting that purging in adolescence is associated with negative outcomes, independent of its frequency and binge eating.

Handling missing data in RCTs; a review of the top medical journals.

BACKGROUND: Missing outcome data is a threat to the validity of treatment effect estimates in randomized controlled trials. We aimed to evaluate the extent, handling, and sensitivity analysis of missing data and intention-to-treat (ITT) analysis of randomized controlled trials (RCTs) in top tier medical journals, and compare our findings with previous reviews related to missing data and ITT in RCTs. METHODS: Review of RCTs published between July and December 2013 in the BMJ, JAMA, Lancet, and New England Journal of Medicine, excluding cluster randomized trials and trials whose primary outcome was survival. RESULTS: Of the 77 identified eligible articles, 73 (95%) reported some missing outcome data. The median percentage of participants with a missing outcome was 9% (range 0 - 70%). The most commonly used method to handle missing data in the primary analysis was complete case analysis (33, 45%), while 20 (27%) performed simple imputation, 15 (19%) used model based methods, and 6 (8%) used multiple imputation. 27 (35%) trials with missing data reported a sensitivity analysis. However, most did not alter the assumptions of missing data from the primary analysis. Reports of ITT or modified ITT were found in 52 (85%) trials, with 21 (40%) of them including all randomized participants. A comparison to a review of trials reported in 2001 showed that missing data rates and approaches are similar, but the use of the term ITT has increased, as has the report of sensitivity analysis. CONCLUSIONS: Missing outcome data continues to be a common problem in RCTs. Definitions of the ITT approach remain inconsistent across trials. A large gap is apparent between statistical methods research related to missing data and use of these methods in application settings, including RCTs in top medical journals.

A latent class analysis to empirically describe eating disorders through developmental stages.

OBJECTIVES: The current standards for classifying eating disorders were primarily informed by adult, clinical study populations, while it is unknown whether an empirically based classification system can be supported across preadolescence through young adulthood. Using latent class analyses, we sought to empirically classify disordered eating in females from preadolescence to young adulthood, and assess the association between classes and adverse outcomes. METHOD: Latent class models were fit using observations from the 9,039 girls participating in the growing up today study, an on-going cohort following participants annually or biennially since 1996 when they were ages 9-14 years. Associations between classes and drug use, binge drinking, and depressive symptoms were assessed using generalized estimating equations. RESULTS: Across age groups, there was evidence of six classes: a large asymptomatic class, a class characterized by shape/weight concerns, a class characterized by overeating without loss of control, and three resembling full and subthreshold binge eating disorder, purging disorder, and bulimia nervosa. Relative prevalences of classes varied across developmental stages, with symptomatic classes increasing in prevalence with increasing age. Symptomatic classes were associated with concurrent and incident drug use, binge drinking, and high depressive symptoms. DISCUSSION: A classification system resembling broader definitions of DSM-5 diagnoses along with two further subclinical symptomatic classes may be a useful framework for studying disordered eating among adolescent and young adult females.

Assessing eating disorder symptoms in adolescence: is there a role for multiple informants?

OBJECTIVES: Studies of adolescent psychiatric disorders often collect information from adolescents and parents, yet most eating disorder epidemiologic studies only rely on adolescent report. METHOD: We studied the eating disorder symptom reports, from questionnaires sent at participants' ages 14 and 16 years, provided by 7,968 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC), and their parents. Adolescents and parents were asked questions about the adolescent's eating disorder symptoms (binge eating, vomiting, laxative use, fasting, and thinness). We assessed cross-sectional concordance and prevalence using kappa coefficients and generalized estimating equations. Generalized estimating equations were used to assess prospective associations between symptom reports and adolescent weight outcomes measured at a face-to-face assessment at 17.5 years. RESULTS: Parents and adolescents were largely discordant on symptom reports cross-sectionally (kappas < 0.3), with the parent generally less likely to report bulimic symptoms than the adolescent but more likely to report thinness. Female adolescents were more likely to report bulimic symptoms than males (e.g., two to four times more likely to report binge eating), while prevalence estimates according to parent reports of female vs. male adolescents were similar. Both informants' symptom reports were predictive of body mass and composition measures at 17.5 years; compared to adolescent report, parentally reported binge eating was more strongly predictive of body mass index. DISCUSSION: Parent report of eating disorder symptoms seemed to measure different, but potentially important, aspects of these symptoms during adolescence. Epidemiologic eating disorder studies should consider the potential value added from incorporating parental reports, particularly in studies of males.

Analysis of partially observed clustered data using generalized estimating equations and multiple imputation.

Clustered data arise in many settings, particularly within the social and biomedical sciences. As an example, multiple-source reports are commonly collected in child and adolescent psychiatric epidemiologic studies where researchers use various informants (e.g. parent and adolescent) to provide a holistic view of a subject's symptomatology. Fitzmaurice et al. (1995) have described estimation of multiple source models using a standard generalized estimating equation (GEE) framework. However, these studies often have missing data due to additional stages of consent and assent required. The usual GEE is unbiased when missingness is Missing Completely at Random (MCAR) in the sense of Little and Rubin (2002). This is a strong assumption that may not be tenable. Other options such as weighted generalized estimating equations (WEEs) are computationally challenging when missingness is non-monotone. Multiple imputation is an attractive method to fit incomplete data models while only requiring the less restrictive Missing at Random (MAR) assumption. Previously estimation of partially observed clustered data was computationally challenging however recent developments in Stata have facilitated their use in practice. We demonstrate how to utilize multiple imputation in conjunction with a GEE to investigate the prevalence of disordered eating symptoms in adolescents reported by parents and adolescents as well as factors associated with concordance and prevalence. The methods are motivated by the Avon Longitudinal Study of Parents and their Children (ALSPAC), a cohort study that enrolled more than 14,000 pregnant mothers in 1991-92 and has followed the health and development of their children at regular intervals. While point estimates were fairly similar to the GEE under MCAR, the MAR model had smaller standard errors, while requiring less stringent assumptions regarding missingness.

Web-based alcohol screening and brief intervention for university students: a randomized trial.

IMPORTANCE: Unhealthy alcohol use is a leading contributor to the global burden of disease, particularly among young people. Systematic reviews suggest efficacy of web-based alcohol screening and brief intervention and call for effectiveness trials in settings where it could be sustainably delivered. OBJECTIVE: To evaluate a national web-based alcohol screening and brief intervention program. DESIGN, SETTING, AND PARTICIPANTS: A multisite, double-blind, parallel-group, individually randomized trial was conducted at 7 New Zealand universities. In April and May of 2010, invitations containing hyperlinks to the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening test were e-mailed to 14,991 students aged 17 to 24 years. INTERVENTIONS: Participants who screened positive (AUDIT-C score ≥4) were randomized to undergo screening alone or to 10 minutes of assessment and feedback (including comparisons with medical guidelines and peer norms) on alcohol expenditure, peak blood alcohol concentration, alcohol dependence, and access to help and information. MAIN OUTCOMES AND MEASURES: A fully automated 5-month follow-up assessment was conducted that measured 6 primary outcomes: consumption per typical occasion, drinking frequency, volume of alcohol consumed, an academic problems score, and whether participants exceeded medical guidelines for acute harm (binge drinking) and chronic harm (heavy drinking). A Bonferroni-corrected significance threshold of .0083 was used to account for the 6 comparisons and a sensitivity analysis was used to assess possible attrition bias. RESULTS: Of 5135 students screened, 3422 scored 4 or greater and were randomized, and 83% were followed up. There was a significant effect on 1 of the 6 prespecified outcomes. Relative to control participants, those who received intervention consumed less alcohol per typical drinking occasion (median 4 drinks [interquartile range {IQR}, 2-8] vs 5 drinks [IQR 2-8]; rate ratio [RR], 0.93 [99.17% CI, 0.86-1.00]; P = .005) but not less often (RR, 0.95 [99.17% CI, 0.88-1.03]; P = .08) or less overall (RR, 0.95 [99.17% CI, 0.81-1.10]; P = .33). Academic problem scores were not lower (RR, 0.91 [99.17% CI, 0.76-1.08]; P = .14) and effects on the risks of binge drinking (odds ratio [OR], 0.84 [99.17% CI, 0.67-1.05]; P = .04) and heavy drinking (OR, 0.77 [99.17% CI, 0.56-1.05]; P = .03) were not significantly significant. In a sensitivity analysis accounting for attrition, the effect on alcohol per typical drinking occasion was no longer statistically significant. CONCLUSIONS AND RELEVANCE: A national web-based alcohol screening and brief intervention program produced no significant reductions in the frequency or overall volume of drinking or academic problems. There remains a possibility of a small reduction in the amount of alcohol consumed per typical drinking occasion. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12610000279022.

Associations Between Phenotypes of Childhood and Adolescent Obesity and Incident Hypertension in Young Adulthood.

Objectives: We investigated whether empirically derived childhood obesity phenotypes were differentially associated with risk of hypertension in young adulthood, and whether these associations differed by sex. Methods: Data came from 11,404 participants in the Growing Up Today Study, a prospective cohort study in the US established in 1996. We used a childhood obesity phenotype variable that was previously empirically derived using latent class analysis. The childhood obesity phenotypes included an early puberty phenotype (females only), a mothers with obesity phenotype, a high weight concerns phenotype, and a mixed phenotype. Participants without overweight or obesity in childhood or adolescence were the reference group. We then used logistic regression models with generalized estimating equations to examine associations of childhood obesity phenotypes with incident hypertension between ages 20-35 years. All analyses were stratified by sex. Results: Among females, participants in all of the empirically derived childhood obesity phenotypes were more likely than their peers without childhood overweight/obesity to develop hypertension in young adulthood (early puberty subtype odds ratio (OR) = 2.52; 95% confidence interval (CI) = 1.75, 3.62; mothers with obesity (MO) subtype OR = 2.98; 95% CI = 1.93, 4.59; high weight concerns (WC) subtype OR = 2.33; 95% CI = 1.65, 3.28; mixed subtype OR = 1.66; 95% CI = 1.25, 2.20). Among males, the childhood obesity phenotypes were associated with a higher risk of developing hypertension, although males in the MO (OR = 2.65; 95% CI = 1.82, 3.87) and WC phenotypes (OR = 3.52; 95% CI = 2.38, 5.20) had a greater risk of developing hypertension than the mixed subtype (OR = 1.51; 95% CI = 1.23, 1.86) (p = 0.004). Conclusion: Risk for incident hypertension in young adulthood varied by childhood obesity phenotypes, as well as by biological sex. If replicated, these results may suggest that increased surveillance of specific childhood obesity phenotypes might help in targeting those at highest risk for hypertension.