Hierarchical likelihood inference on clustered competing risks data.

The frailty model, an extension of the proportional hazards model, is often used to model clustered survival data. However, some extension of the ordinary frailty model is required when there exist competing risks within a cluster. Under competing risks, the underlying processes affecting the events of interest and competing events could be different but correlated. In this paper, the hierarchical likelihood method is proposed to infer the cause-specific hazard frailty model for clustered competing risks data. The hierarchical likelihood incorporates fixed effects as well as random effects into an extended likelihood function, so that the method does not require intensive numerical methods to find the marginal distribution. Simulation studies are performed to assess the behavior of the estimators for the regression coefficients and the correlation structure among the bivariate frailty distribution for competing events. The proposed method is illustrated with a breast cancer dataset.

Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity.

IMPORTANCE: Severe obesity (body mass index [BMI] ≥35) is associated with a broad range of health risks. Bariatric surgery induces weight loss and short-term health improvements, but little is known about long-term outcomes of these operations. OBJECTIVE: To report 3-year change in weight and select health parameters after common bariatric surgical procedures. DESIGN AND SETTING: The Longitudinal Assessment of Bariatric Surgery (LABS) Consortium is a multicenter observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers. PARTICIPANTS AND EXPOSURE: Adults undergoing first-time bariatric surgical procedures as part of routine clinical care by participating surgeons were recruited between 2006 and 2009 and followed up until September 2012. Participants completed research assessments prior to surgery and 6 months, 12 months, and then annually after surgery. MAIN OUTCOMES AND MEASURES: Three years after Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB), we assessed percent weight change from baseline and the percentage of participants with diabetes achieving hemoglobin A1c levels less than 6.5% or fasting plasma glucose values less than 126 mg/dL without pharmacologic therapy. Dyslipidemia and hypertension resolution at 3 years was also assessed. RESULTS: At baseline, participants (N = 2458) were 18 to 78 years old, 79% were women, median BMI was 45.9 (IQR, 41.7-51.5), and median weight was 129 kg (IQR, 115-147). For their first bariatric surgical procedure, 1738 participants underwent RYGB, 610 LAGB, and 110 other procedures. At baseline, 774 (33%) had diabetes, 1252 (63%) dyslipidemia, and 1601 (68%) hypertension. Three years after surgery, median actual weight loss for RYGB participants was 41 kg (IQR, 31-52), corresponding to a percentage of baseline weight lost of 31.5% (IQR, 24.6%-38.4%). For LAGB participants, actual weight loss was 20 kg (IQR, 10-29), corresponding to 15.9% (IQR, 7.9%-23.0%). The majority of weight loss was evident 1 year after surgery for both procedures. Five distinct weight change trajectory groups were identified for each procedure. Among participants who had diabetes at baseline, 216 RYGB participants (67.5%) and 28 LAGB participants (28.6%) experienced partial remission at 3 years. The incidence of diabetes was 0.9% after RYGB and 3.2% after LAGB. Dyslipidemia resolved in 237 RYGB participants (61.9%) and 39 LAGB participants (27.1%); remission of hypertension occurred in 269 RYGB participants (38.2%) and 43 LAGB participants (17.4%). CONCLUSIONS AND RELEVANCE: Among participants with severe obesity, there was substantial weight loss 3 years after bariatric surgery, with the majority experiencing maximum weight change during the first year. However, there was variability in the amount and trajectories of weight loss and in diabetes, blood pressure, and lipid outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00465829.

4-Year Changes in Sex Hormones, Sexual Functioning, and Psychosocial Status in Women Who Underwent Bariatric Surgery.

BACKGROUND: Initial weight loss after bariatric surgery has been associated with improvements in reproductive hormones and sexual functioning in women. Few studies have investigated the durability of these changes. OBJECTIVES: The objective of this paper is to investigate changes in sex hormones, sexual functioning, and relevant psychosocial constructs over 4 years in women who underwent bariatric surgery. SETTING: The setting is a prospective cohort of 106 women from the Longitudinal Assessment of Bariatric Surgery consortium. METHODS: Changes in sex hormones were assessed by blood assay. Sexual functioning, quality of life (QOL), body image, depressive symptoms, and marital adjustment were assessed by psychometric measures. RESULTS: Women lost on average (95% confidence interval) 32.3% (30.4%, 34.3%) at postoperative year 3 and 30.6% (28.5%, 32.8%) at postoperative year 4. Compared to baseline, women experienced significant changes at 4 years in all hormones assessed, except estradiol. Women reported significant improvements in sexual functioning (i.e., arousal, desire, and satisfaction) through year 3, but these changes were not maintained through year 4. Changes in relationship quality followed a similar pattern. Improvements in physical aspects of QOL, body image, and depressive symptoms were maintained through 4 years. CONCLUSIONS: Improvements in reproductive hormones and physical aspects of QOL, body image, and depressive symptoms were maintained 4 years after bariatric surgery. Improvements in sexual functioning, relationship satisfaction, and mental components of QOL eroded over time.

Analysis of clustered competing risks data using subdistribution hazard models with multivariate frailties.

Competing risks data often exist within a center in multi-center randomized clinical trials where the treatment effects or baseline risks may vary among centers. In this paper, we propose a subdistribution hazard regression model with multivariate frailty to investigate heterogeneity in treatment effects among centers from multi-center clinical trials. For inference, we develop a hierarchical likelihood (or h-likelihood) method, which obviates the need for an intractable integration over the frailty terms. We show that the profile likelihood function derived from the h-likelihood is identical to the partial likelihood, and hence it can be extended to the weighted partial likelihood for the subdistribution hazard frailty models. The proposed method is illustrated with a dataset from a multi-center clinical trial on breast cancer as well as with a simulation study. We also demonstrate how to present heterogeneity in treatment effects among centers by using a confidence interval for the frailty for each individual center and how to perform a statistical test for such heterogeneity using a restricted h-likelihood.

Postoperative Behavioral Variables and Weight Change 3 Years After Bariatric Surgery.

IMPORTANCE: Severe obesity (body mass index ≥35 [calculated as weight in kilograms divided by height in meters squared]) is associated with significant medical comorbidity and increased mortality. Bariatric surgery induces weight loss, the extent of which can vary. Postoperative predictors of weight loss have not been adequately examined. OBJECTIVE: To describe postoperative eating behaviors and weight control and their effects on 3-year change in weight. DESIGN, SETTING, AND PARTICIPANTS: The Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study is a multicenter observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers. Adults undergoing first-time bariatric surgical procedures as part of routine clinical care were recruited between 2006 and 2009 and followed up until September 2012. Participants completed detailed surveys regarding eating and weight control behaviors prior to surgery and then annually after surgery for 3 years. MAIN OUTCOMES AND MEASURES: Twenty-five postoperative behaviors related to eating behavior, eating problems, weight control practices, and the problematic use of alcohol, smoking, and illegal drugs. Behaviors examined were divided into those that were never present (preoperatively or postoperatively), those that were always present (preoperatively and postoperatively), and those that underwent a healthy change after surgery (development of a positive behavior or omission of a negative behavior). RESULTS: The sample included a total of 2022 participants (median age, 47 years [interquartile range, 38-55 years]; median BMI, 46 [interquartile range, 42-51]; 78% women): 1513 who had undergone Roux-en-Y gastric bypass and 509 who had undergone laparoscopic adjustable gastric banding. If we consider the cumulative effects of the 3 behaviors that explain most of the variability (16%) in 3-year percent weight change following Roux-en-Y gastric bypass, ie, weekly self-weighing, continuing to eat when feeling full more than once a week, and eating continuously during the day, a participant who postoperatively started to self-weigh, stopped eating when feeling full, and stopped eating continuously during the day after surgery would be predicted to lose a mean (SE) of 38.8% (0.8%) of their baseline weight. This average is about 14% greater weight loss compared with participants who made no positive changes in these variables (mean [SE], -24.6% [1.6%]; mean difference, -14.2%; 95% CI, -18.7% to -9.8%; P < .001) and 6% greater weight loss compared with participants who always reported positive on these healthy behaviors (mean [SE], -33.2% [0.6%]; mean difference, -5.7%; 95% CI, -7.8% to -3.5%; P < .001). CONCLUSIONS AND RELEVANCE: The results suggest the importance of assessing behaviors related to eating behavior, eating problems, weight control practices, and the problematic use of alcohol, smoking, and illegal drugs in bariatric surgery candidates and patients who have undergone bariatric surgery, and they suggest that the utility of programs to modify problematic eating behaviors and eating patterns should be addressed in research.

Sexual functioning and sex hormones in men who underwent bariatric surgery.

BACKGROUND: The relationship between obesity and impairments in male sexual functioning is well documented. Relatively few studies have investigated changes in sexual functioning and sex hormones in men who achieve significant weight loss with bariatric surgery. The objective of this study was to assess changes in sexual functioning, sex hormones, and relevant psychosocial constructs in men who underwent bariatric surgery. METHODS: A prospective cohort study of 32 men from the Longitudinal Assessment of Bariatric Surgery-2 (LABS) investigation who underwent a Roux-en-Y gastric bypass (median body mass index [25th percentile, 75th percentile] 45.1 [42.0, 52.2]) and completed assessments between 2006 and 2012. Bariatric surgery was performed by a LABS-certified surgeon. Sexual functioning was assessed by the International Index of Erectile Functioning (IIEF). Hormones were assessed by blood assay. Quality of life (QoL), body image, depressive symptoms and marital adjustment were assessed by questionnaire. RESULTS: Men lost, on average, (95% confidence interval) 33.3% (36.1%, 30.5%) of initial weight at postoperative year 1, 33.6% (36.8%, 30.5%) at year 2, 31.0% (34.1%, 27.9%) at year 3, and 29.4% (32.7%, 26.2%) at year 4. Participants experienced significant increases in total testosterone (P<.001) and sex hormone binding globulin (SHBG) (P<.001) through postoperative year 4. Although men reported improvements in sexual functioning after surgery, these changes did not significantly differ from baseline, with the exception of overall satisfaction at postoperative year 3 (P = .008). Participants reported significant improvements in physical domains of health-related quality of life (HRQoL), all domains of weight-related QOL, and body image, but not in the mental health domains of HRQoL or relationship satisfaction. CONCLUSIONS: Men who lost approximately one third of their weight after Roux-en-Y gastric bypass experienced significant increases in total testosterone and SHBG. They did not, however, report significant improvements in sexual functioning, relationship satisfaction, or mental health domains of HRQoL. This pattern of results differs from that of women who have undergone bariatric surgery, who reported almost uniform improvements in sexual functioning and psychosocial status.

Preoperative factors and 3-year weight change in the Longitudinal Assessment of Bariatric Surgery (LABS) consortium.

BACKGROUND: Limited data guide the prediction of weight loss success or failure after bariatric surgery according to presurgery factors. There is significant variation in weight change after bariatric surgery and much interest in identifying preoperative factors that may contribute to these differences. This report evaluates the associations of a comprehensive set of baseline factors and 3-year weight change. SETTING: Ten hospitals in 6 geographically diverse clinical centers in the United States. METHODS: Adults undergoing a first bariatric surgical procedure as part of clinical care by participating surgeons were recruited between 2006 and 2009. Participants completed research assessments utilizing standardized and detailed data collection on over 100 preoperative and operative parameters for individuals undergoing Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB). Weight was measured 3 years after surgery. Percent weight change for RYGB or LAGB from baseline to 3 years was analyzed as both a continuous and dichotomous outcome with cut points at 25% for RYGB and 10% for LAGB. Multivariable linear and logistic regression models were used to identify independent baseline predictors of the continuous and categorical outcomes, respectively. RESULTS: The median weight loss 3 years after surgery for RYGB (n = 1513) participants was 31.5% (IQR: 24.6%-38.4%; range, 59.2% loss to .9% gain) of baseline weight and 16.0% (IQR: 8.1%-23.1%; range, 56.1% loss to 12.5% gain) for LAGB (n = 509) participants. The median age was 46 years for RYGB and 48 years for LAGB; 80% of RYGB participants and 75% of LAGB participants were female; and the median baseline body mass index (BMI) was 46 kg/m(2) for RYGB and 44 kg/m(2) for LAGB. For RYGB, black participants lost 2.7% less weight compared with whites and participants with diabetes at baseline had 3.7% less weight loss at year 3 than those without diabetes at baseline. There were small but statistically significant differences in weight change for RYGB in those with abnormal kidney function and current or recent smoking. For LAGB participants, those with a large band circumference had 75% greater odds of experiencing less than 10% weight loss after adjusting for BMI and sex. CONCLUSIONS: Few baseline variables were associated with 3-year weight change and the effects were small. These results indicate that baseline variables have limited predictive value for an individual's chance of a successful weight loss outcome after bariatric surgery. TRIAL REGISTRATION: NCT00465829, ClinicalTrials.gov.

Changes in sexual functioning and sex hormone levels in women following bariatric surgery.

IMPORTANCE: Obesity has been associated with impairments in sexual function and untoward changes in reproductive hormones in women. Relatively few studies have investigated changes in these domains following bariatric surgery. OBJECTIVE: To investigate changes in sexual functioning, sex hormone levels, and relevant psychosocial constructs in women who underwent bariatric surgery. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 106 women from phase 2 of the Longitudinal Assessment of Bariatric Surgery who underwent bariatric surgery (median [interquartile range] body mass index, 44.5 [41.4-49.7]). Assessments were completed between 2006 and 2012. INTERVENTIONS: Bariatric surgery was performed by a surgeon certified by the Longitudinal Assessment of Bariatric Surgery (85 women underwent a Roux-en-Y gastric bypass, and 21 women underwent laparoscopic adjustable gastric banding). MAIN OUTCOMES AND MEASURES: Sexual functioning was assessed by use of the Female Sexual Function Index. Hormones were assessed by use of a blood assay. Quality of life, body image, depressive symptoms, and marital adjustment were assessed by use of validated questionnaires. RESULTS: Women lost a mean 32.7% (95% CI, 30.7%-34.7%) of initial body weight at postoperative year 1 and a mean 33.5% (95% CI, 31.5%-35.6%) at postoperative year 2. Two years following surgery, women reported significant improvements in overall sexual functioning and specific domains of sexual functioning: arousal, lubrication, desires, and satisfaction. They also experienced significant changes at 2 years in all hormones of interest. Women reported significant improvements in most domains of quality of life, as well as body image and depressive symptoms, within the first year after surgery, with these improvements being maintained through the second postoperative year. CONCLUSIONS AND RELEVANCE: Women who underwent bariatric surgery had significant improvements in overall sexual functioning, in most reproductive hormones of interest, and in psychosocial status. Improvements in sexual health can be added to the list of health benefits associated with bariatric surgery. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00670098.

Sexual functioning and sex hormones in persons with extreme obesity and seeking surgical and nonsurgical weight loss.

BACKGROUND: Many individuals with obesity are motivated to lose weight to improve weight-related co-morbidities or psychosocial functioning, including sexual functioning. Few studies have documented rates of sexual dysfunction in persons with obesity. This study investigated sexual functioning, sex hormones, and relevant psychosocial constructs in individuals with obesity who sought surgical and nonsurgical weight loss. METHODS: One hundred forty-one bariatric surgery patients (median BMI [25th percentile, 75th percentile] 44.6 [41.4, 50.1]) and 109 individuals (BMI = 40.0 [38.0, 44.0]) who sought nonsurgical weight loss participated. Sexual functioning was assessed by the Female Sexual Function Index (FSFI) and the International Index of Erectile Function (IIEF). Hormones were assessed by blood assay. Quality of life, body image, depressive symptoms, and marital adjustment were assessed by validated questionnaires. RESULTS: Fifty-one percent of women presenting for bariatric surgery reported a sexual dysfunction; 36% of men presenting for bariatric surgery reported erectile dysfunction (ED). This is in contrast to 41% of women who sought nonsurgical weight loss and reported a sexual dysfunction and 20% of men who sought nonsurgical weight loss and reported ED. These differences were not statistically significant. Sexual dysfunction was strongly associated with psychosocial distress in women; these relationships were less strong and less consistent among men. Sexual dysfunction was unrelated to sex hormones, except for sex hormone binding globulin (SHGB) in women. CONCLUSION: Women and men who present for bariatric surgery, compared with individuals who sought nonsurgical weight loss, were not significantly more likely to experience a sexual dysfunction. There were few differences in reproductive hormones and psychosocial constructs between candidates for bariatric surgery and individuals interested in nonsurgical weight loss.

Psychopathology before surgery in the longitudinal assessment of bariatric surgery-3 (LABS-3) psychosocial study.

BACKGROUND: Current and previous psychopathology in bariatric surgery candidates is believed to be common. Accurate prevalence estimates, however, are difficult to obtain given that bariatric surgery candidates often wish to appear psychiatrically healthy when undergoing psychiatric evaluation for approval for surgery. Also, structured diagnostic assessments have been infrequently used. METHODS: The present report concerned 199 patients enrolled in the longitudinal assessment of bariatric surgery study, who also participated in the longitudinal assessment of bariatric surgery-3 psychopathology substudy. The setting was 3 university hospitals, 1 private not-for-profit research institute, and 1 community hospital. All the patients were interviewed independently of the usual preoperative psychosocial evaluation process. The patients were explicitly informed that the data would not be shared with the surgical team unless certain high-risk behaviors, such as suicidality, that could lead to adverse perioperative outcomes were reported. RESULTS: Most of the patients were women (82.9%) and white (nonwhite 7.6%, Hispanic 5.0%). The median age was 46.0 years, and the median body mass index was 44.9 kg/m2. Of the 199 patients, 33.7% had ≥1 current Axis I disorder, and 68.8% had ≥1 lifetime Axis I disorder. Also, 38.7% had a lifetime history of a major depressive disorder, and 33.2% had a lifetime diagnosis of alcohol abuse or dependence. All these rates were much greater than the population-based prevalence rates obtained for this age group in the National Comorbidity Survey-Replication Study. Also, 13.1% had a lifetime diagnosis and 10.1% had a current diagnosis of a binge eating disorder. CONCLUSION: The current and lifetime rates of psychopathology are high in bariatric surgery candidates, and the lifetime rates of affective disorder and alcohol use disorders are particularly prominent. Finally, binge eating disorder is present in approximately 1 in 10 bariatric surgery candidates.

Cigarette smoking, obesity, physical activity, and alcohol use as predictors of chemoprevention adherence in the National Surgical Adjuvant Breast and Bowel Project P-1 Breast Cancer Prevention Trial.

The double-blind, prospective, National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) showed a 50% reduction in the risk of breast cancer for tamoxifen versus placebo, yet many women at risk of breast cancer do not adhere to the 5-year course. This first report of the rich BCPT drug adherence data examines predictors of adherence. Between June, 1992 and September, 1997 13,338 women at high risk of breast cancer were randomly assigned to 20 mg/d tamoxifen versus placebo; we analyzed the 11,064 enrolled more than 3 years before trial unblinding. Primary endpoint was full drug adherence (100% of assigned pills per staff report, excluding protocol-required discontinuation) at 1 and 36 months; secondary was adequate adherence (76%-100%). Protocol-specified multivariable logistic regression tested lifestyle factors, controlling for demographic and medical predictors. About 13% were current smokers; 60% were overweight/obese; 46% had moderate/heavy physical activity; 21%, 66%, 13% drank 0, 0-1, 1+ drinks per day, respectively; 91% were adequately adherent at 1 month; and 79% were at 3 years. Alcohol use was associated with reduced full adherence at 1 month (P = 0.016; OR = 0.79 1+ vs. 0), as was college education (P <0.001; OR = 0.78 vs. high school); age (P < 0.001; OR = 1.4 age 60+) and per capita household annual income (P < 0.001; OR = 1.2 per $30,000) with increased adherence. Current smoking (P = 0.003; OR = 0.75), age (P = 0.024, OR = 1.1), college education (P = 0.037; OR = 1.4), tamoxifen assignment (P = 0.031; OR = 0.84), and breast cancer risk (P <.001; OR = 1.5 high vs. low) predicted adequate adherence at 36 months. There were no significant associations with obesity or physical activity. Alcohol use and smoking might indicate a need for greater adherence support.

Patient-reported outcomes in sentinel node-negative adjuvant breast cancer patients receiving sentinel-node biopsy or axillary dissection: National Surgical Adjuvant Breast and Bowel Project phase III protocol B-32.

PURPOSE: Sentinel lymph node resection (SNR) may reduce morbidity while providing the same clinical utility as conventional axillary dissection (AD). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 is a randomized phase III trial comparing SNR immediately followed by AD (SNAD) to SNR and subsequent AD if SN is positive. We report the definitive patient-reported outcomes (PRO) comparisons. PATIENTS AND METHODS: Eligible patients had clinically node-negative, operable invasive breast cancer. The PRO substudy included all SN-negative participants enrolled May 2001 to February 2004 at community institutions in the United States (n = 749; 78% age > or = 50; 87% clinical tumor size < or = 2.0 cm; 84% lumpectomy; 87% white). They completed questionnaires presurgery, 1 and 2 to 3 weeks postoperatively, and every 6 months through year 3. Arm symptoms, arm use avoidance, activity limitations, and quality of life (QOL) were compared with intent-to-treat two-sample t-tests and repeated measures analyses. RESULTS: Arm symptoms were significantly more bothersome for SNAD compared with SNR patients at 6 months (mean, 4.8 v 3.0; P < .001) and at 12 months (3.6 v 2.5; P = .006). Longitudinally, SNAD patients were more likely to experience ipsilateral arm and breast symptoms, restricted work and social activity, and impaired QOL (P < or = .002 all items). From 12 to 36 months, fewer than 15% of either SNAD or SNR patients reported moderate or greater severity of any given symptom or activity limitation. CONCLUSION: Arm morbidity was greater with SNAD than with SNR. Despite considerable fears about complications from AD for breast cancer, this study demonstrates that initial problems with either surgery resolve over time.