Genetic obesity: next-generation sequencing results of 1230 patients with obesity.

BACKGROUND: Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. METHODS: DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m2; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes. RESULTS: In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance. CONCLUSIONS: NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.

Health-Related Quality of Life in Children and Adolescents with Severe Obesity after Intensive Lifestyle Treatment and at 1-Year Follow-Up.

OBJECTIVE: To examine changes in generic and weight-related, health-related quality of life (HRQoL) in children and adolescents with severe obesity participating in intensive lifestyle treatment, and to examine whether changes in SDS-BMI were associated with changes in HRQoL. METHODS: In this prospective observational study, a referred sample of 120 children and adolescents (8-19 years) with severe obesity (SDS-BMI ≥ 3.0, or ≥ 2.3 in combination with obesity-related comorbidity) received an intensive 1-year lifestyle treatment with an inpatient period in a specialized childhood obesity center. A weight-related (IWQOL-Kids) and three generic (KIDSCREEN-52, PedsQL 4.0, and EuroQol) HRQoL questionnaires were administered at baseline (T0), after treatment (T1), and 1 year later (T2). Generalized Linear Mixed Models and partial correlations were used to analyze changes in HRQoL and associations with changes in SDS-BMI. RESULTS: Statistically significant improvements in generic and weight-related HRQoL overall and domain scores were observed at T1and at T2 in comparison with T0, despite partial weight regain from T1 to T2. Larger weight loss at T2 was correlated with larger improvements in physical HRQoL domains. CONCLUSION: Children and adolescents with severe obesity experienced long-term improvements in generic and weight-related HRQoL after participating in intensive lifestyle treatment, despite partial weight regain.

Economic Evaluation of Intensive Inpatient Treatments for Severely Obese Children and Adolescents.

BACKGROUND: Considering the large economic consequences of severe childhood obesity for the society, we aimed to conduct an economic evaluation comparing two intensive 1-year lifestyle treatments with varying inpatient periods for severely obese children and adolescents with regard to standard deviation score BMI (SDS-BMI) and quality-adjusted life years (QALYs). METHODS: An economic evaluation from a societal perspective accompanying a randomized controlled trial with a 24-month follow-up. 80 participants (8-19 years) with severe obesity were included. Participants received an intensive 1-year lifestyle treatment with an inpatient period of 2 months (short-stay group) or 6 months (long-stay group). Data were collected at baseline, 6, 12 ,and 24 months and included SDS-BMI and QALYs. RESULTS: SDS-BMI decreased in the first 6 months of treatment, stabilized in the second 6 months, and increased during the 2nd year in both groups. After 24 months, SDS-BMI was similar in both groups, but remained lower than baseline values (mean difference -0.24, 95% CI -0.42; -0.06). There was no difference in QALYs between the groups after 24 months. For SDS-BMI, the probability of the short-stay treatment being cost-effective in comparison with the long-stay treatment was 1 at a willingness-to-pay of 0 EUR/unit of effect, which slowly decreased to 0.54 for larger willingness-to-pay values. CONCLUSIONS: Based on the results of this study, the short-stay treatment is considered to be more cost-effective from the societal perspective in comparison with the long-stay treatment. Future research should provide insight in whether the short-stay treatment is cost-effective in comparison with usual care.

One-year effects of two intensive inpatient treatments for severely obese children and adolescents.

BACKGROUND: Intensive inpatient lifestyle treatment may be a suitable alternative for severely obese children and adolescents who do not benefit from ambulatory obesity treatment. The aim was to evaluate the effectiveness of two intensive one-year lifestyle treatments with varying inpatient periods for severely obese children and adolescents with regard to SDS-BMI and cardiometabolic risk factors. METHODS: The study was designed as a randomized controlled trial with two active treatment groups. Eighty participants (8-19 years) with severe obesity received treatment at a specialized childhood obesity center in the Netherlands. Severe obesity was defined as a SDS-BMI ≥ 3.0 or a SDS-BMI ≥ 2.3 in combination with obesity-related comorbidity. Participants received an intensive one-year lifestyle treatment with an inpatient period of either two months and biweekly return visits during the next four months (short-stay group) or six months (long-stay group), both followed by six monthly return visits. Outcomes were assessed at baseline, six and 12 months and included SDS-BMI as primary outcome and cardiometabolic risk factors such as SDS-waist circumference, systolic- and diastolic blood pressure, and blood measurements as secondary outcomes. To evaluate differences in the course of the primary- and secondary outcomes over time between the two treatment groups, Generalized Estimating Equations (GEE) were performed. RESULTS: No differences in the course of SDS-BMI or secondary outcomes over time were found between the two treatment groups after one year of treatment. SDS-BMI decreased statistically significantly after one year of treatment compared with baseline in both groups (0.33 (0.48) in the short-stay and 0.52 (0.49) in the long-stay group). Similar results were found for SDS-waist circumference, diastolic blood pressure and HDL-cholesterol. CONCLUSIONS: Since there were no significant differences in effects between the short- and long-stay treatment and considering the burden of the long-stay treatment for children and families, we recommend implementation of the short-stay treatment. TRIAL REGISTRATION: Netherlands Trial Register NTR1678 , registered 20-Feb-2009.

Nonalcoholic fatty liver disease and cardiovascular risk in children with obesity.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) has been recognized as an independent risk factor for cardiovascular disease in adults. It has not been established whether NAFLD is related to early atherosclerotic changes in children. METHODS: In a cross-sectional study, 78 non diabetic, non smoking children with severe obesity were evaluated for NAFLD. Proton magnetic resonance spectroscopy was used to detect liver steatosis and serum ALT was used as a surrogate marker for steatohepatitis. Carotid intima-media thickness (CIMT) and arterial wall stiffness were measured using ultrasound. RESULTS: Steatosis was present in 41 (53%) of subjects. Of these children, 26 out of 41 (63%) had elevated ALT levels. No differences in CIMT and arterial wall stiffness were observed between those without and with steatosis and those with steatosis plus elevated ALT levels [CIMT = 0.47 (±0.06), 0.48 (±0.06) and 0.48 (±0.07) mm, respectively; stiffness = 2.78 (±0.50), 3.00 (±0.81), and 2.90 (±0.78), respectively]. Steatosis and ALT were not correlated to CIMT (r = -0.02 and -0.14, respectively) or arterial wall stiffness (r = 0.13 and -0.11, respectively). CONCLUSIONS: In this study, no relationship between NAFLD and early atherosclerotic changes in children was observed. An atherogenic effect of steatohepatitis (NASH) on pediatric age and long-term atherogenic consequences of simple steatosis cannot be excluded based on this study.

Cardiometabolic risk factors and quality of life in severely obese children and adolescents in The Netherlands.

BACKGROUND: The prevalence of severe obesity in children and adolescents is increasing. However, little is known about cardiometabolic risk factors and quality of life of children with severe obesity.Therefore, the aim of this study was to assess the demographic characteristics and the prevalence of cardiometabolic risk factors and quality of life in severely obese children and adolescents undergoing intensive inpatient treatment for obesity. METHODS: Data were collected between August 2009 and April 2011 on 16 children (8-13y) and 64 adolescents (13-19y) with severe obesity (SDS-BMI >= 3.0 or SDS-BMI >= 2.3 and comorbidity) participating in an RCT evaluating two intensive inpatient treatment programs for obesity. Demographic, anthropometric, clinical characteristics and two components of the EuroQol for the assessment of quality of life are described. RESULTS: Eighty percent of participants in this study had at least one cardiometabolic risk factor in addition to severe obesity. Low HDL-cholesterol and hypertension were most prevalent (65.0% respectively 31.2%). The highest significant correlations were found between SDS-BMI and SDS-waist circumference, fasting plasma insulin and HOMA-IR (correlation coefficients respectively 0.80, 0.49, and 0.48). With regard to quality of life, the mean utility score of the participants was 0.79 on a scale of 0.0 to 1.0 on the EuroQol questionnaire and their mean individual valuation was 69.1 on a scale of 0 to100. CONCLUSION: Cardiometabolic risk factors are already highly prevalent in this group of severely obese children and adolescents. The score of 69.1 found for quality of life in this study suggests that participants experience important limitations in their quality of life. However, quality of life is not associated with the prevalence of cardiometabolic risk factors. TRIAL REGISTRATION: Netherlands Trial Register (NTR1678, registered 20-Feb-2009).

The controversy over pediatric bariatric surgery: an explorative study on attitudes and normative beliefs of specialists, parents, and adolescents with obesity.

Despite the reported limited success of conventional treatments and growing evidence of the effectiveness of adult bariatric surgery, weight loss operations for (morbidly) obese children and adolescents are still considered to be controversial by health care professionals and lay people alike. This paper describes an explorative, qualitative study involving obesity specialists, morbidly obese adolescents, and parents and identifies attitudes and normative beliefs regarding pediatric bariatric surgery. Views on the etiology of obesity-whether it should be considered primarily a medical condition or more a psychosocial problem-seem to affect the specialists' normative opinions concerning the acceptability of bariatric procedures as a treatment option, the parents' feelings regarding both being able to influence their child's health and their child being able to control their own condition, and the adolescents' sense of competence and motivation for treatment. Moreover, parents and adolescents who saw obesity as something that they could influence themselves were more in favor of non-surgical treatment and vice versa. Conflicting attitudes and normative views-e.g., with regard to concepts of disease, personal influence on health, motivation, and the possibility of a careful informed consent procedure-play an important role in the acceptability of bariatric surgery for childhood obesity.

Accuracy of prediction scores and novel biomarkers for predicting nonalcoholic fatty liver disease in obese children.

BACKGROUND: Accurate prediction scores for liver steatosis are demanded to enable clinicians to noninvasively screen for nonalcoholic fatty liver disease (NAFLD). Several prediction scores have been developed, however external validation is lacking. OBJECTIVE: The aim was to determine the diagnostic accuracy of four existing prediction scores in severely obese children, to develop a new prediction score using novel biomarkers and to compare these results to the performance of ultrasonography. DESIGN AND RESULTS: Liver steatosis was measured using proton magnetic resonance spectroscopy in 119 severely obese children (mean age 14.3 ± 2.1 years, BMI z-score 3.35 ± 0.35). Prevalence of steatosis was 47%. The four existing predictions scores ("NAFLD liver fat score," "fatty liver index," "hepatic steatosis index," and the pediatric prediction score) had only moderate diagnostic accuracy in this cohort (positive predictive value (PPV): 70, 61, 61, 69% and negative predictive value (NPV) 77, 69, 68, 75%, respectively). A new prediction score was built using anthropometry, routine biochemistry and novel biomarkers (leptin, adiponectin, TNF-alpha, IL-6, CK-18, FGF-21, and adiponutrin polymorphisms). The final model included ALT, HOMA, sex, and leptin. This equation (PPV 79% and NPV 80%) did not perform substantially better than the four other equations and did not outperform ultrasonography for excluding NAFLD (NPV 82%). CONCLUSION: The conclusion is in severely obese children and adolescents existing prediction scores and the tested novel biomarkers have insufficient diagnostic accuracy for diagnosing or excluding NAFLD.

The role of self-regulating abilities in long-term weight loss in severely obese children and adolescents undergoing intensive combined lifestyle interventions (HELIOS); rationale, design and methods.

BACKGROUND: Adequate treatment of severe childhood obesity is important given its serious social, psychological and physical consequences. Self-regulation may be a crucial determinant of treatment success. Yet, little is known about the role that self-regulation and other psychosocial factors play in the long-term outcome of obesity treatment in severely obese children and adolescents.In this paper, we describe the design of a study that aims to determine whether the ability to self-regulate predicts long-term weight loss in severely obese children and adolescents. An additional objective is to identify other psychosocial factors that may modify this relation. METHODS/DESIGN: The study is designed as a prospective observational study of 120 severely obese children and adolescents (8-19 years) and their parents/caregivers undergoing an intensive combined lifestyle intervention during one year. The intervention uses behavior change techniques to improve the general ability to self-regulate.Measurements will be taken at three points in time: at baseline (start of treatment), at the end of treatment (1 year after baseline) and at follow-up (2 years after baseline). The primary outcome measurement is the gender and age-specific change in SDS-BMI.The children's general self-regulation abilities are evaluated by two behavioral computer tasks assessing two distinct aspects of self-regulation that are particularly relevant to controlling food intake: inhibitory control (Stop Signal Task) and sensitivity to reward (Balloon Analogue Risk Task). In addition to the computer tasks, a self-report measure of eating-specific self-regulation ability is used. Psychosocial factors related to competence, motivation, relatedness and outcome expectations are examined as moderating factors using several questionnaires for the patients and their parents/caregivers. DISCUSSION: This study will provide knowledge about the relation between self-regulation and long-term weight loss after intensive lifestyle interventions over a two-year period in severely obese children and adolescents, a growing but often overlooked patient group. We aim to investigate to what extent (changes in) the general ability to self-regulate predicts weight loss and weight loss maintenance. This study will also contribute to the knowledge on how this association is modified by other psychosocial factors. The results may contribute to the development of more successful interventions. TRIAL REGISTRATION: Netherlands Trial Register (NTR1678, registered 20-Feb-2009).

High cardiovascular risk in severely obese young children and adolescents.

OBJECTIVE: To assess the prevalence of cardiovascular risk factors in severely obese children and adolescents. METHODS: A nationwide prospective surveillance study was carried out from July 2005 to July 2007 where paediatricians were asked to report all new cases of severe obesity in 2-18-year-old children to the Dutch Paediatric Surveillance Unit. Severe obesity is defined by gender and age-dependent cut-off points for body mass index based on Dutch National Growth Studies corresponding to the adult cut-off point of 35 kg/m(2). Paediatricians were asked to complete a questionnaire for every severely obese child regarding socio-demographic characteristics and cardiovascular risk factors (blood pressure, fasting blood glucose and lipids). RESULTS: In 2005, 2006 and 2007, 94%, 87% and 87%, respectively, of paediatricians in the Netherlands responded to the monthly request from the Dutch Paediatric Surveillance Unit and 500 children with newly diagnosed severe obesity were reported. 72.6% (n=363) of paediatricians responded to a subsequent questionnaire. Cardiovascular risk factor data were available in 255/307 (83%) children who were correctly classified as severely obese. 67% had at least one cardiovascular risk factor (56% hypertension, 14% high blood glucose, 0.7% type 2 diabetes and up to 54% low HDL-cholesterol). Remarkably, 62% of severely obese children aged ≤12 years already had one or more cardiovascular risk factors. CONCLUSION: A high number (2/3) of severely obese children have cardiovascular risk factors. Internationally accepted criteria for defining severe obesity and guidelines for early detection and treatment of severe obesity and comorbidity are urgently needed.

US cannot be used to predict the presence or severity of hepatic steatosis in severely obese adolescents.

PURPOSE: To evaluate the diagnostic accuracy of ultrasonography (US) for the assessment of hepatic steatosis in severely obese adolescents, with proton magnetic resonance (MR) spectroscopy as the reference standard, and to provide insight on the influence of prevalence on predictive values by calculating positive and negative posttest probabilities. MATERIALS AND METHODS: This prospective study was institutional review board approved. All participants, and/or their legal representatives, gave written informed consent. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the overall presence of steatosis and for the presence of substantial (moderate to severe) steatosis. Positive and negative posttest probabilities were calculated and plotted against prevalence. RESULTS: A total of 104 children (47 male, 57 female) were prospectively included. Mean age was 14.5 years (range, 8.3-18.9 years) and mean age-adjusted standard deviation body mass index (BMI) score (BMI z score) was 3.3 (range, 2.6-4.1). The overall prevalence of hepatic steatosis was 46.2% (48 of 104). Sensitivity of US was 85.4% (41 of 48), specificity was 55.4% (31 of 56), PPV was 62.1% (41 of 66), and NPV was 81.6% (31 of 38). The prevalence of substantial steatosis was 15.4% (16 of 104), with US sensitivity of 75.0% (12 of 16) and specificity of 87.5% (77 of 88). PPV was 52.2% (12 of 23) and NPV was 95.1% (77 of 81). Plotting of posttest probabilities against prevalence for both disease degrees demonstrated how disease prevalence influences US accuracy. CONCLUSION: Positive US results in severely obese adolescents cannot be used to accurately predict the presence and severity of hepatic steatosis, and additional imaging is required. Negative US results exclude the presence of substantial steatosis with acceptable accuracy. Steatosis prevalence differs among specific populations, strongly influencing posttest probabilities.

Cost-effectiveness of intensive inpatient treatments for severely obese children and adolescents in the Netherlands; a randomized controlled trial (HELIOS).

BACKGROUND: Intensive combined lifestyle interventions are the recommended treatment for severely obese children and adolescents, but there is a lack of studies and their cost-effectiveness. The objective of this study is to compare the cost-effectiveness of two intensive one-year inpatient treatments and usual care for severely obese children and adolescents. METHODS/DESIGN: Participants are 40 children aged 8-13 and 40 adolescents aged 13-18 with severe obesity (SDS-BMI ≥ 3.0 or SDS-BMI ≥ 2.3 with obesity related co-morbidity). They will be randomized into two groups that will receive a comprehensive treatment program of 12 months that focuses on nutrition, physical activity and behavior change of the participant and their parents. The two programs are the same in total duration (12 months), but differ in inpatient treatment duration. Group A will participate in a 6 month intensive inpatient treatment program during weekdays, followed by six monthly return visits of 2 days. Group B will participate in a 2 month intensive inpatient treatment program during weekdays, followed by biweekly return visits of 2 days during the next four months, followed by six monthly return visits of 2 days. Several different health care professionals are involved, such as pediatricians, dieticians, psychologists, social workers, nurses and physiotherapists. Results will also be compared to a control group that receives usual care. The primary outcome is SDS-BMI. Secondary outcomes include quality of life using the EQ-5D and cardiovascular risk factors. Data will be collected at baseline and after 6, 12 and 24 months. An economic evaluation will be conducted alongside this study. Healthcare consumption will be based on actual resource use, using prospective data collection during 2 years through cost diaries. Quality Adjusted Life Years (QALYs) will be calculated using the EQ-5D. DISCUSSION: This study will provide useful information on the effectiveness and cost-effectiveness of inpatient treatment in severely obese children and adolescents. Valuable information on long term effects, after 2 years, is also included. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1678.

Lifestyle intervention for non-alcoholic fatty liver disease: prospective cohort study of its efficacy and factors related to improvement.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has a high prevalence in obese children. Lifestyle intervention is the primary treatment for NAFLD. However, limited data are available regarding the efficacy of lifestyle interventions. OBJECTIVES: To prospectively determine the efficacy of a lifestyle intervention programme on NAFLD in severely obese children and identify the clinical parameters related to improvement in NAFLD. METHODS: Children admitted to a lifestyle intervention programme were screened for NAFLD. Steatosis was defined as increased echogenicity of the liver on ultrasonography. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were used as surrogate markers for steatohepatitis. The lifestyle intervention programme consisted of physical exercise, dietary counselling and behavioural counselling for a period of 6 months. RESULTS: 144 children were included with a mean age of 14.1 (±2.3) years, BMI z-score of 3.35 (±0.40) kg/m(2). Lifestyle intervention significantly reduced the prevalence of steatosis (31.2-11.9%, p<0.001) and the prevalence of elevated serum ALT (25.7-11.1%, p<0.001) and serum AST (13.3-4.3%, p<0.002). In multivariate regression analysis, improvement in the degree of steatosis and decrease in ALT and AST were all significantly related to improvement in insulin resistance. Improvement in insulin resistance only explained a small part of the observed changes in transaminases. CONCLUSIONS: A lifestyle intervention of 6 months is moderately effective in improving NAFLD in severely obese children. Improvement in insulin resistance is the clinical parameter most strongly associated with improvement in NAFLD. Other factors related to the successful treatment of NAFLD need to be identified so that these can be a focus for new lifestyle and drug interventions.

Aerobic exercise in adolescents with obesity: preliminary evaluation of a modular training program and the modified shuttle test.

BACKGROUND: Increasing activity levels in adolescents with obesity requires the development of exercise programs that are both attractive to adolescents and easily reproducible. The aim of this study was to develop a modular aerobic training program for adolescents with severe obesity, with a focus on variety, individual targets and acquiring physical skills. We report here the effects on aerobic fitness from a pilot study. Furthermore, we examined the feasibility of the modified shuttle test (MST) as an outcome parameter for aerobic fitness in adolescents with severe obesity. METHODS: Fifteen adolescents from an inpatient body weight management program participated in the aerobic training study (age 14.7 +/- 2.1 yrs, body mass index 37.4 +/- 3.5). The subjects trained three days per week for 12 weeks, with each session lasting 30-60 minutes. The modular training program consisted of indoor, outdoor and swimming activities. Feasibility of the MST was studied by assessing construct validity, test-retest reliability and sensitivity to change. RESULTS: Comparing pretraining and end of training period showed large clinically relevant and significant improvements for all aerobic indices: e.g. VO2 peak 17.5%, effect size (ES) 2.4; Wmax 8%, ES 0.8. In addition, a significant improvement was found for the efficiency of the cardiovascular system as assessed by the oxygen pulse (15.8%, ES 1.6). Construct validity, test-retest reliability and sensitivity to change of the MST were very good. MST was significantly correlated with VO2 peak (r = 0.79) and Wmax (r = 0.84) but not with anthropometric measures. The MST walking distance improved significantly by 32.5%, ES 2.5. The attendance rate at the exercise sessions was excellent. CONCLUSION: This modular, varied aerobic training program has clinically relevant effects on aerobic performance in adolescents with severe obesity. The added value of our aerobic training program for body weight management programs for adolescents with severe obesity should be studied with a randomized trial. This study further demonstrated that the MST is a reliable, sensitive and easy to administer outcome measure for aerobic fitness in adolescent body weight management trials.