Fig. 36.1
LABS map of centers. Map of the participating centers in the LABS study. The LABS consortium is comprised of investigators from the six clinical centers, the Data Coordinating Center (located at the University of Pittsburgh Graduate School of Public Health), and the NIDDK/ORWH
Goals of the LABS Consortium
Ultimately, the LABS consortium is seeking to develop an information continuum that will help to advance the understanding of both the mechanisms of bariatric surgery and the responses to bariatric surgery. Furthermore, LABS will attempt to define potential predictors of response to surgical procedures. To do so, a detailed research protocol has been developed to answer questions about bariatric procedures and their effects on energy regulation and obesity-related comorbid conditions. To ensure consistency across LABS sites, the consortium developed standardized definitions and procedures, which include predetermined data collection points, common data collection devices, and standardized methods for data entry. The collected data is retained in a detailed and comprehensive database from which the information can be analyzed. This extensive database will enable investigators to determine predictive factors for both positive and negative outcomes following surgery that will assist in selecting appropriate patients and procedures. In addition, the LABS data will allow for a thorough investigation of the impact of bariatric surgery on important outcomes including medical, physiologic, psychosocial, and economic [13].
Rationale for Research Design
The LABS Steering Committee initially considered several potential study designs to address the unanswered and important questions in bariatric surgery and determined that, within the constraints of the available time and resources, an observational study was the most efficient means to test a multitude of important hypotheses. LABS was designed as a multicenter, observational database of prospectively collected detailed patient and operative characteristics, short- and longer-term clinical outcomes, and behavioral- and health-related outcomes. Because relatively little is known about the factors involved in both favorable and adverse outcomes in bariatric surgery, a well-designed and implemented database that includes substantial data in a variety of content areas was considered necessary to test a multitude of hypotheses. The use of a nonrandomized comparator group that would include subjects who did not undergo bariatric surgery was also considered. However, it was decided that several limitations of that approach would make it difficult to interpret the results. These include differences between those who did and did not undergo surgery, including physical and mental health issues, differences in socioeconomic status, and underlying physician or patient motivation, all of which could affect the results and limit the ability to generalize the findings. Although randomized clinical trials provide higher-order evidence of efficacy than do observational studies, the number of questions that can be addressed by a randomized clinical trial (RCT) is more limited. In addition, there were concerns about the feasibility and ethical issues involved in undertaking an RCT to best study numerous questions related to bariatric surgery.
The LABS consortium determined that the high-priority scientific questions could be most efficiently addressed by creating a longitudinal cohort study with an extensive database to test and to explore hypotheses related to bariatric surgical outcomes. The limitations of such an observational approach were also considered. Under best circumstances, the data should be collected prospectively and in sufficient detail to measure known and currently unknown factors related to outcomes. LABS investigators attempted to standardize the definitions of the data items and data collection procedures. An Adjudication Committee was formed to review and classify all deaths and reoperations. In addition, unplanned post-discharge anticoagulation therapies for which the reason could not be confirmed were and are examined. Common protocols were designed to include specific data collection points, data collection instruments, and methods for computerizing data collection, entry, and analysis. Manuals of operations and procedures were created that defined each data element and provided instructions for collection. Data collectors, including study coordinators and surgeons, underwent training and certification with respect to protocols and data collection definitions before collecting any data for the LABS database. The data elements included breaking down each of the surgical procedures into its component parts (e.g., length of intestinal limbs, pouch size) and structuring a measuring scheme for each. Extensive quality control procedures were put into place and procedures to identify and correct faulty data were implemented. Finally, there was and is a strong focus on long-term subject retention for accurate follow-up evaluation of outcome status.2
Structure and Working Organization of LABS
The governing body of LABS, or Steering Committee, is comprised of the Principal Investigators and one other investigator from each clinical site, the Data Coordinating Center Principal Investigator, and the NIDDK project scientist. The Steering Committee provides oversight in LABS planning and execution and also votes on all important decisions related to the development and conduct of the LABS study. Furthermore, there are a number of committees, subcommittees, and working groups that help to make decisions and develop study protocols.
An Executive Committee meets weekly by conference call to oversee study conduct between in-person Steering Committee meetings and to set the Steering Committee meeting agendas. The chair of the Steering Committee, the Coordinating Center Principal Investigator, and the NIDDK project scientist form this committee. Various subcommittees were developed to aid the Steering Committee in some areas including safety, website development, publication, ancillary studies to LABS, adjudication of events, and others.
The working groups are made up of multidisciplinary investigators from all sites and have been responsible for proposing and defining measures included in the core database and suggesting short- and long-term sub-studies to be carried out on a subset of LABS participants (LABS-3 studies). There are a multitude of specific bariatric surgery-related areas for which the working groups are responsible; these include surgical measures and operative risk, behavioral assessment, nutrition, laboratory measures, body composition, diabetes, cardiovascular disease, liver disease, health services and economics, quality of life, and biospecimens [13].
During the first year and a half of the LABS study funding period, the core database was developed, protocols were written, and appropriate regulatory documents were created for the conduct of the study by way of this above-described structure. The LABS study is organized into three phases: LABS-1, LABS-2, and LABS-3. LABS-1 includes all subjects greater than or equal to 18 years of age who have undergone bariatric surgery at participating centers by LABS-certified surgeons. The primary goal of LABS-1 is the evaluation of the short-term safety of bariatric surgery. The primary endpoints include important adverse outcomes, such as death and percutaneous or operative reintervention, which occur within 30 days of surgery. For LABS-1, limited data set of the patient and operative characteristics was gathered to describe the frequency of these events in different subgroups and to assess the relationship between adverse outcomes and patient and operative characteristics. The sample size for LABS-1 was calculated to be able to obtain precise estimates of safety events (e.g., 30-day mortality) and to have greater than or equal to 80 % power to identify a greater than or equal to twofold increase in the combined risk of 30-day mortality, reintervention, deep vein thrombosis/pulmonary embolism, or failure to be discharged from the hospital within 30 days after surgery between important subgroups (e.g., men versus women, BMI less than 50 kg/m2 versus greater than or equal to 50 kg/m2) [12].
The primary goal of LABS-2 is to evaluate the longer-term safety and efficacy of bariatric surgery and to more comprehensively evaluate patient characteristics as they relate to short- and longer-term outcomes. The sample size for LABS-2, approximately 2,400 patients, was determined to be able to detect “small” effect sizes [14] for continuous outcomes (e.g., change in excess body weight) and a greater than or equal to twofold increase or decrease in the incidence or prevalence for categorical efficacy outcomes (e.g., resolution of diabetes). To address the aims of LABS-2, the extensive collection of demographic, anthropometric, clinical, behavioral, surgical, and postoperative care variables will be used to determine their associations with the outcomes. The data are and will be collected before surgery, during surgery, and postoperatively (at the 30-day, 6-months, 1-year, and annual follow-up visits).
LABS-3 includes additional smaller subsets of LABS-2 subjects, determined in composition and size by the hypotheses underlying the specific mechanisms that are being studied. There are two LABS-3 studies: one which will measure the psychosocial and behavioral aspects of obesity in more detail and a second LABS-3 study that is looking at the mechanisms underlying diabetes remission. Other aspects of bariatric surgery and obesity-related diseases will be studied through the LABS ancillary studies mechanism. Ancillary studies to LABS are funded by sources other than LABS, required resources that exceeded those available within LABS, and extend the research of LABS. Ancillary study subjects are LABS-2 participants and LABS investigators are involved in these additional projects. Nine ancillary studies are funded by NIDDK and will explore in more detail the following specific topics:
Body composition and energy expenditure responses
Physical activity and energy expenditure
Changes in sexual functioning
Psychological issues and eating disorders
Cognitive effects of bariatric surgery
Effect of weight loss on fatty acid metabolism
MC4R mutations
Other genetic mutations
Adolescent bariatric surgery patients (Teen LABS)
A biospecimen repository consisting of frozen samples of serum, plasma, and urine, as well as DNA extracted from white blood cells, was established at baseline and continues to accept annual samples. The samples, as well as appropriate data, are available to investigators outside the LABS consortium by way of a defined mechanism. Guidelines to submit an ancillary study proposal (with or without specimens) to LABS can be found at http://www.edc.gsph.pitt.edu/labs/Public/ancillarystudies.html.3
Outcome Domains in Bariatric Surgery
The goals of the LABS study are to assess the risks and health benefits associated with bariatric surgery and to identify the aspects of the procedures and patients associated with outcomes. To achieve these goals, LABS investigators defined a range of relevant outcome domains in bariatric surgery. Whenever possible, LABS included objective measures of patient status and comorbid disease burden. When objective measures of disease were not feasible, validated and standardized data collection/survey instruments were used. Investigators sought to identify existing data collection instruments that were psychometrically sound. When validated data collection instruments were not available, LABS investigators created new instruments appropriate for patients undergoing bariatric surgery or adapted questionnaires from other clinical studies. Table 36.1 outlines the standard forms and measures used in LABS-2 to assess each of these domains, as well as the contact points at which they are administered [12].
Table 36.1
Standard forms and measures used in LABS-2
Weight Loss and Body Composition
The primary intent of bariatric procedures is to induce weight loss by limiting intake and to promote behavioral changes in the overall energy balance that result in significant and sustained decreases in weight. LABS-2 measures the patients’ weight at each of the annual follow-up visits using a standard scale (Tanita model TBF-310H01A). The LABS investigators have hypothesized that men will experience greater weight loss than women and that a direct relationship will be found between physical activity and weight loss at the follow-up intervals. We have also hypothesized that diabetic patients will lose less weight and that a longer length of bypassed limb in gastric bypass surgery is associated with greater weight loss maintenance [15, 16].
Diabetes Mellitus and Insulin Resistance
Type 2 diabetes mellitus, the metabolic syndrome, and the insulin resistance syndrome are common metabolic consequences of obesity. Many case series have demonstrated significant and sustained improvements in these parameters after weight loss procedures [6], but the measures of these parameters in large cohorts have been limited. LABS-2 evaluates the longer-term efficacy of bariatric surgery with respect to type 2 diabetes mellitus according to the clinical history of medication use and serial measurements of fasting blood glucose and hemoglobin A1c levels. Assessing the efficacy for preventing or resolving the metabolic syndrome and insulin resistance syndrome will be done using fasting glucose levels, insulin levels, lipoprotein profiles, resting blood pressure, and waist circumference. We have hypothesized that the improvement in type 2 diabetes mellitus, metabolic syndrome, and insulin resistance syndrome will be related to the procedure type, degree of weight loss, degree of loss of fat mass, and level of physical activity at follow-up [17, 18].
Cardiovascular and Pulmonary Disease
Obesity is a major risk factor for cardiovascular diseases and obstructive sleep apnea, which have been increasingly recognized in patients with extreme obesity [6]. The prevalence of sleep apnea and changes from baseline status will be assessed by self-report using the Berlin Sleep Questionnaire [19] and the reported use of positive airway pressure devices. We have hypothesized that weight loss and reductions in neck circumference will be associated with improvements in sleep apnea. To assess the efficacy of bariatric surgery to reduce the risk of cardiovascular disease, LABS-2 measures C-reactive protein, lipoprotein profiles, resting blood pressure, and waist circumference and determines the clinical history of medication use. We have hypothesized that improvement in cardiovascular diseases risk factors will be related to the magnitude of weight loss, loss of fat mass, and lower BMI postoperatively [20]. Furthermore, changes in cardiac function will be measured by the time needed to complete a 400-m corridor walk, with the hypothesis that changes will be related to age, BMI, gender, and other factors.
Renal Disease
Obesity is linked to diabetes and hypertension, the two most common causes of kidney failure [21]. In addition, several mechanisms exist by which obesity may independently and negatively affect renal function, including adipogenic hormones that could have a direct injurious effect on the kidney [22]. However, bariatric surgery itself has been associated with progressive renal disease by a variety of mechanisms [23] and may also contribute to the development of renal stone disease. For these reasons, LABS-2 evaluates renal function by measuring serum creatinine and cystatin and urinary albumin and creatinine and assesses the prevalence of diagnosed nephrolithiasis at baseline and at follow-up. The LABS investigators have hypothesized that albuminuria will diminish after successful bariatric surgery and that renal function as measured by serum creatinine will remain stable after successful surgery.
Liver Function
Another problem of growing public health concern is the increased prevalence of nonalcoholic fatty liver disease in obese populations [24] and the growing identification of nonalcoholic fatty liver disease when evaluated by liver biopsy in patients undergoing a bariatric surgical procedure [25]. Limited data are available defining the prevalence and severity of nonalcoholic steatohepatitis, as assessed by intraoperative liver biopsy, in extremely obese subjects undergoing bariatric surgery [26]. We have hypothesized that the prevalence and severity of nonalcoholic steatohepatitis has been underestimated by traditional clinical measures and that liver disease and its severity will correlate with short-term postoperative morbidity. We have also hypothesized that increased liver size at surgery will be associated with a greater rate of failed laparoscopic approaches to bariatric procedures.
Behavioral/Psychosocial Factors
Evidence has suggested that preexisting psychological and behavioral factors could influence the outcomes after bariatric surgery [27]. Therefore, patients who have active, untreated substance abuse, binge eating, or depression at baseline could experience greater rates of postoperative medical complications and less weight loss [28, 29]. Conversely, those subjects who intentionally lose weight before surgery may be more likely to achieve greater weight loss in the short and longer term [30]. Behavioral measures are assessed at baseline and follow-up and include questions on preoperative weight loss practices and eating patterns (including binge eating and eating beyond satiation), tobacco and alcohol use, history of psychiatric disorders, and counselor/therapist contact. Depressive symptoms are assessed using the Beck Depression Inventory, version 1 [31]. Objective measures of physical activity are assessed using the STEPWATCH 3 Step Activity Monitor4 at baseline and follow-up visits.
Musculoskeletal and Functional Status
Osteoarthritis, either caused or aggravated by obesity, is a major limiting comorbid condition among the population of patients undergoing bariatric surgery. Functional limitations resulting from back, hip, and knee joint degeneration are a leading cause of functional decline, use of durable medical goods (e.g., wheelchairs, walkers, electric scooters), and impaired quality of life. LABS investigators will test the hypothesis that patients’ functional status will improve with surgery and that the extent of improvement will be associated with the degree of weight loss. In addition, we investigate whether functional limitations before surgery are linked to poor outcomes after the bariatric procedure. Functional status is assessed in the LABS study through a combination of self-reports (e.g., walking ability, use of assistance devices), as well as a timed corridor walk.
Gender Issues
Obesity affects all aspects of well-being, including those that are gender specific. Also, potential gender differences exist in the longer-term efficacy of bariatric surgery. For example, obesity is a known risk factor for several health conditions specific to, and prevalent among, women, such as menstrual abnormalities, infertility [32], and urinary incontinence [33]. We have hypothesized that menstrual abnormalities, fertility, urinary incontinence, and symptoms of polycystic ovarian diseases will improve after bariatric surgery. These are assessed using several questionnaires.
Nutrient Deficiencies
Another potential long-term risk of bariatric surgery is the possibility of nutrient deficiencies [34]. LABS-2 will be able to investigate micro- and macronutrient deficiencies stratified by surgical procedure (hypothesizing more frequent occurrences with malabsorptive procedures) [15, 35] and by various components of surgery such as Roux limb length and pouch size. Plasma and serum samples are stored in a specimen repository for future analysis of macro- and micronutrients as funding permits.
Economic Impact
Employees who are obese have a high prevalence of work limitations [36], and severe obesity increases the number of work loss days and is an important factor in the workplace [37, 38]. The effects of weight loss surgery on productivity at work, absenteeism, and presenteeism are not well studied. LABS administers several validated questionnaires to assess this impact, including the Work Productivity and Activity Impairment form, version 2.0 [39]. We have hypothesized that patients undergoing surgery will lose fewer days of work and that productivity at work will improve after surgery.
Biospecimens
Blood and urine specimens have been and will continue to be obtained from LABS-2 participants at baseline and postoperatively at 12 months and annually thereafter. Aliquots of plasma, serum, and DNA extracted from white blood cells will be banked in the NIDDK Biospecimen Repository for future investigations into factors such as changes in metabolic parameters and markers of risk. These specimens and the extensive data collection will be a major resource for funded, LABS-associated ancillary studies. Non-LABS investigators will also be able to request access to these biospecimens through application by way of the LABS ancillary studies process (http://www.edc.gsph.pitt.edu/labs/Public/ancillarystudies.html).5
Results from the LABS Consortium
Baseline results from the LABS consortium study have been published in addition to some early outcomes. LABS subjects are currently engaged in longer-term retention and future publications will reflect important outcomes at 3 and 5 years following bariatric surgery. The following is a summary of some of the published results from LABS to date.
LABS-1 Baseline Data
The Relationship of BMI with Demographic and Clinical Characteristics in the Longitudinal Assessment of Bariatric Surgery (LABS)
LABS-1 is a report of 30-day safety outcomes in subjects undergoing bariatric surgical procedures. Some of the first publications to come from the LABS consortium examine aspects of baseline data in LABS-1 subjects. A manuscript entitled The Relationship of BMI with Demographic and Clinical Characteristics in LABS was developed to better characterize the relationship between BMI and other risk factors thought to be important in bariatric surgery subjects. It included participants with a BMI greater than or equal to 40 kg/m2 and no history of prior bariatric procedures, and its specific objective is to evaluate the relationship between BMI and demographic and clinical characteristics in patients undergoing a primary bariatric procedure in LABS-1 [40]. Within the LABS-1 cohort, there were 2,559 patients (23 % male, 10 % Black/African-American, 9 % age greater than or equal to 60 years) with a BMI greater than or equal to 40 kg/m2, 29 % had a BMI of 50 to less than 60 kg/m2, and 12 % had a BMI greater than or equal to 60 kg/m2 [40]. Higher BMI correlated with an increased percentage of males and Black/African-Americans and a decreased percentage of older participants (aged 60 years or above). Patients with higher BMI were more likely to have a history of several comorbid conditions (hypertension, diabetes, congestive heart failure, asthma, poor functional status, sleep apnea, pulmonary hypertension, venous thromboembolism, or venous edema with ulcerations) than patients with a BMI of 40 to less than 50 kg/m2 after adjusting for age, race, sex, and ethnicity [40]. So in the LABS-1 cohort at baseline, higher BMI correlated with several demographic and clinical characteristics that have previously been linked to less weight loss, more adverse outcomes, and increased healthcare utilization [41–43]. This finding indicates that future outcome analyses in bariatric surgery must examine and consider the associations of BMI with demographic and clinical characteristics [40].
LABS-1 Results
Perioperative Safety in the Longitudinal Assessment of Bariatric Surgery
The perioperative safety results, the main goal of the LABS-1 study, were published in 2009 and present the short-term risks of bariatric surgery in a geographically broad cohort of subjects [44]. LABS-1 was a prospective, multicenter observational study at six centers (involving ten clinical sites) in the United States between 2005 and 2007 and reports the 30-day surgical outcomes in consecutive patients who underwent a bariatric procedure. There were 4,776 patients who underwent a primary bariatric procedure, and over half had at least two comorbid conditions. The cohort demographics consisted of mean age of 44.5 years, 21 % male, 11 % nonwhite, and median BMI of 46 kg/m2. Of the patients, 3,412 underwent Roux-en-Y gastric bypass (2,975, 87 % by the laparoscopic approach) and 1,198 underwent laparoscopic adjustable gastric banding. Table 36.2 shows the characteristics of the LABS-1 participants by procedure type. A composite endpoint of 30-day major adverse outcomes (death; deep venous thromboembolism (DVT) or pulmonary embolism (PE); percutaneous, endoscopic, or operative reintervention; or no discharge at 30 days) was examined among patients undergoing first-time/primary bariatric surgery [44]. The overall 30-day mortality rate for primary bariatric procedures was 0.3 %. There was no mortality among the laparoscopic adjustable gastric banding subjects, 0.2 % mortality for laparoscopic Roux-en-y gastric bypass, and 2.1 % mortality among open bypass subjects (Table 36.3). Of the participants, 4.3 % had at least one major adverse outcome. A history of deep vein thrombosis or pulmonary embolus, obstructive sleep apnea, and functional status were each independently associated with an increased risk of the composite major adverse endpoint [44]. Extreme values of BMI were significantly associated with an increased risk of the composite endpoint as evidenced by the U-shaped curve in Fig. 36.2, while age, sex, race, ethnicity, and other comorbid conditions were not [44]. In summary, the overall risk of death and adverse outcomes after bariatric surgery in LABS-1 was low, varying considerably with patient and procedure characteristics [44].
Table 36.2
Characteristics of LABS-1 patientsa by procedure type
Characteristic | Totalb (N = 4,776) | Laparoscopic adjustable gastric banding (N = 1,198) | Laparoscopic Roux-en-Y gastric bypass (N = 2,975) | Open Roux-en-Y gastric bypass (N = 437) | Sleeve gastrectomy (N = 117) | Biliopancreatic diversion with or without duodenal switch (N = 47) | p valuec |
|---|---|---|---|---|---|---|---|
Age |
