Loss‐of‐function mutations in the melanocortin‐3 receptor gene confer risk for human obesity: A systematic review and meta‐analysis

The association between rare coding loss‐of‐function (LOF) mutations in the melanocortin receptor 3 (MC3R) gene and human obesity is controversial. To fill this gap of knowledge, we performed a systematic review and meta‐analysis of genetic association studies in all ages and ethnicities. Two reviewers independently performed risk of bias assessment and extracted data. We searched Medline, Embase, Web of Science Core Collection, BIOSIS Preview, CINAHL, ProQuest Dissertations & Theses, and reference lists of relevant studies. All case‐control, cross‐sectional, prospective, and retrospective studies that evaluated prevalence of rare (less than 1% frequency) coding partial/complete LOF mutations in MC3R among individuals with obesity and normal weight were included. Our systematic search identified 1925 references relevant to the present review. Six studies were deemed eligible. Meta‐analysis of 2969 individuals with obesity and 2572 with normal weight showed a positive association between rare heterozygous coding partial/complete LOF mutations in MC3R and obesity in children and adults of European, North African, and Asian ancestries (odds ratio = 3.07; 95% CI, 1.48‐7.00; P = 4.2 × 10^?3). Our data demonstrates that rare partial/complete LOF mutations in the coding region of MC3R confer three‐time increased risk of obesity in humans, and implies that rare genetic variants with intermediate effects contribute to the missing heritability of obesity.     

Intelligence in relation to obesity: a systematic review and meta‐analysis

We performed a systematic review describing obesity/intelligent quotient (IQ) association, particularly childhood IQ in relation to adulthood obesity. After screening 883 citations from five electronic databases, we included 26 studies, most of medium quality. The weighted mean difference (WMD) of the full IQ (FIQ)/obesity association in the pre‐school children was ?15.1 (P > 0.05). Compared with controls, the WMD of FIQ and performance IQ of obese children were ?2.8 and ?10.0, respectively (P < 0.05), and the WMD of verbal IQ was ?7.01 (P > 0.05). With increasing obesity, the FIQ in pre‐school children declined, with a significant difference for severely obese children and FIQ. In pubertal children, a slightly different effect of FIQ and obesity emerged. Two studies reported an inverse FIQ/obesity association in adults, but it was non‐significant after adjusting for educational attainment. Four papers found that childhood FIQ was inversely associated with adult body mass index, but after adjusting for education, became null. Overall there was an inverse FIQ/obesity association, except in pre‐school children. However, after adjusting for educational attainment, FIQ/obesity association was not significantly different. A lower FIQ in childhood was associated with obesity in later adulthood perhaps with educational level mediating the persistence of obesity in later life.     

Predicting adult obesity from childhood obesity: a systematic review and meta‐analysis

A systematic review and meta‐analysis was performed to investigate the ability of simple measures of childhood obesity such as body mass index (BMI) to predict future obesity in adolescence and adulthood. Large cohort studies, which measured obesity both in childhood and in later adolescence or adulthood, using any recognized measure of obesity were sought. Study quality was assessed. Studies were pooled using diagnostic meta‐analysis methods. Fifteen prospective cohort studies were included in the meta‐analysis. BMI was the only measure of obesity reported in any study, with 200,777 participants followed up. Obese children and adolescents were around five times more likely to be obese in adulthood than those who were not obese. Around 55% of obese children go on to be obese in adolescence, around 80% of obese adolescents will still be obese in adulthood and around 70% will be obese over age 30. Therefore, action to reduce and prevent obesity in these adolescents is needed. However, 70% of obese adults were not obese in childhood or adolescence, so targeting obesity reduction solely at obese or overweight children needs to be considered carefully as this may not substantially reduce the overall burden of adult obesity.     

Birth weight and subsequent risk of obesity: a systematic review and meta‐analysis

This report describes the association between birth weight (BW) and obesity. Screening of 478 citations from five electronic databases resulted in the inclusion of 33 studies, most of medium quality. The meta‐analysis included 20 of these published studies. The 13 remaining articles did not provide sufficient dichotomous data and were systematically reviewed, revealing results consistent with the meta‐analysis. Our results revealed that high BW (>4000 g) was associated with increased risk of obesity (odds ratio [OR], 2.07; 95% confidence interval [CI], 1.91–2.24) compared with subjects with BW ≤ 4000 g. Low BW (<2500 g) was associated with decreased risk of obesity (OR, 0.61; 95% CI, 0.46–0.80) compared with subjects with BW ≥ 2500 g. However, when two studies exhibited selection bias were removed, the results indicated no significant association between low BW and obesity (OR, 0.77; 95% CI, 0.58–1.04). Sensitivity analyses showed that differences in the study design, sample size and quality grade of the study had an effect on the low BW/obesity association, which low BW was not associated with the risk of obesity in cohort studies, studies with large sample sizes and studies with high quality grades. Pooled results were similar when normal birth weight (2500–4000 g) was used as the reference category. Subgroup analyses based on different growth and developmental stages (pre‐school children, school children and adolescents) also revealed that high BW was associated with increased risk of obesity from childhood to early adulthood. No significant evidence of publication bias was present. These results suggest that high BW is associated with increased risk of obesity and may serve as a mediator between prenatal influences and later disease risk.     

Childhood obesity as a predictor of morbidity in adulthood: a systematic review and meta‐analysis

Obese children are at higher risk of being obese as adults, and adult obesity is associated with an increased risk of morbidity. This systematic review and meta‐analysis investigates the ability of childhood body mass index (BMI) to predict obesity‐related morbidities in adulthood. Thirty‐seven studies were included. High childhood BMI was associated with an increased incidence of adult diabetes (OR 1.70; 95% CI 1.30–2.22), coronary heart disease (CHD) (OR 1.20; 95% CI 1.10–1.31) and a range of cancers, but not stroke or breast cancer. The accuracy of childhood BMI when predicting any adult morbidity was low. Only 31% of future diabetes and 22% of future hypertension and CHD occurred in children aged 12 or over classified as being overweight or obese. Only 20% of all adult cancers occurred in children classified as being overweight or obese. Childhood obesity is associated with moderately increased risks of adult obesity‐related morbidity, but the increase in risk is not large enough for childhood BMI to be a good predictor of the incidence of adult morbidities. This is because the majority of adult obesity‐related morbidity occurs in adults who were of healthy weight in childhood. Therefore, targeting obesity reduction solely at obese or overweight children may not substantially reduce the overall burden of obesity‐related disease in adulthood.     

Emotional processing in obesity: a systematic review and exploratory meta‐analysis

The role of emotional functioning in the development and maintenance of obesity has been investigated, but the literature is poorly integrated. A systematic review and meta‐analysis was performed to explore emotional processing impairments in obesity. PubMed, Web of Knowledge and PsycINFO databases were searched in March 2016, yielding 31 studies comparing emotional processing competencies in individuals with obesity, with or without binge eating disorder (BED), and control groups. Meta‐analyses demonstrated that individuals with obesity had higher scores of alexithymia (d = 0.53), difficulty in identifying feelings (d = 0.34) and externally oriented thinking style (d = 0.31), when compared with control groups. On other competencies, patients with obesity, especially those with comorbid BED, reported lower levels of emotional awareness and difficulty in using emotion regulation strategies, namely, reduced cognitive reappraisal and acceptance, and greater suppression of expression. No evidence of impaired ability to recognize emotions in others or verbally express emotions was found. A general emotion‐processing deficit in obesity was not supported. Instead, an emotional avoidance style may occur modulating later responses of emotion regulation. Additional research is needed to extend the comprehension of these conclusions and the role of BED in emotional functioning in obesity.     

Risk of dipeptidyl peptidase‐4 (DPP‐4) inhibitors on site‐specific cancer: A systematic review and meta‐analysis

The long‐term impact of dipeptidyl peptidase‐4 (DPP‐4) inhibition is unknown, and there are concerns about the influence of DPP‐4 inhibition on carcinogenesis of the pancreas and thyroid. As DPP‐4 is a rather unselective enzyme present in many tissues, we focused on all specific cancer types. PubMed and EMBASE were searched between January 2005 and April 2017 to identify studies comparing DPP‐4 inhibitors with either placebo or active drugs on cancer risk. Studies were included if they reported on at least one specific cancer outcome and had a follow‐up of at least 1 year after start of drug use. Methodological quality of the studies was assessed by the Cochrane Collaboration's tool and the Newcastle‐Ottawa Scale. Twenty‐five studies met the inclusion criteria (12 randomized controlled trials and 13 observational studies). Sample sizes of the DPP‐4 inhibitor groups ranged from 29 to 8212 patients for randomized controlled trials and from 2422 to 71 137 patients for observational studies. Mean age ranged from 51 to 76 years, and mean follow‐up was 1.5 years. None of the pooled (sensitivity) analyses, except the observational studies studying breast cancer (hazard ratio [95% CI]: 0.76 [0.60‐0.96]), showed evidence for an association between DPP‐4 inhibitors and site‐specific cancer. Also for pancreatic and thyroid cancer, no statistically significant risk was found. Based on the current literature, it is not possible to conclude whether DPP‐4 inhibitors were associated with an increased risk of site‐specific cancer. Future studies should address the methodological limitations and follow patients for a longer period to determine the long‐term cancer risk of DPP‐4 inhibitors.     

Efficacy and safety of darbepoetin alpha in patients with myelodysplastic syndromes: a systematic review and meta‐analysis

We conducted a systematic review and meta‐analysis to estimate the efficacy of darbepoetin alpha (DA) for treatment of myelodysplastic syndrome (MDS)‐related anaemia. Eligible studies were prospective, interventional, and reported World Health Organization, French‐American‐British, or International Prognostic Scoring System (IPSS) criteria. Outcomes included erythroid response rate (primary); haemoglobin response; change in haemoglobin, transfusion status, and quality‐of‐life (QoL); and safety. Ten studies (N = 647) were analysed. Erythroid response rate range was 38–72%; median response duration range was 12–51+ months. Patients with erythropoietin (EPO) <100 iu/l had 35% [95% confidence interval (CI): 22–48%; P < 0·001) better response than patients with EPO >100 iu/l. Erythropoesis‐stimulating agent (ESA)‐naïve patients had 17% (95% CI: 3–32%; P = 0·022) greater response rate than those previously treated with ESA. Nonetheless, previously treated patients had response rates of 25–75%. Higher baseline haemoglobin levels, higher dose, transfusion‐independence and low‐risk IPSS status were reported by several studies to be associated with better response. QoL, transfusion rates and haemoglobin levels improved with treatment. Hypertension, thromboembolism and progression to acute myeloid leukaemia were reported in 2%, 1% and 1% of patients, respectively. This meta‐analysis suggests that DA treatment can be useful for improving erythroid response in MDS patients with anaemia, even among patients previously treated with ESA.     

Cognitive training on eating behaviour and weight loss: A meta‐analysis and systematic review

Cognitive deficits play a role in the development and maintenance of overeating and obesity, and cognitive training in obesity refers to a family of interventions aimed at reducing overeating and obesity by improving these cognitive deficits. In this review, we synthesize the current literature on these issues by conducting a meta‐analysis of studies investigating the effects of cognitive trainings on eating behaviour and presenting a systematic review of studies investigating the effects of cognitive trainings on weight loss. We examined 66 independent experiments that examined the effects of cognitive training aimed at reducing cognitive bias or improving executive control on eating behaviour and weight loss. Overall, inhibition training, attention bias modification training, and episodic future thinking training significantly influenced eating behaviour; however, approach/avoidance training did not significantly influence eating behaviour. Moderator analyses indicated that the effect of inhibition training on eating behaviour was moderated by training task and food novelty, the effect of approach/avoidance training was moderated by food type, and the effect of episodic future thinking training was moderated by type of episodic future thinking. Literature reviewed on cognitive training and weight loss provided preliminary support for the effects of food‐specific inhibition training on weight loss from pre‐intervention to post intervention. However, because most of the included studies focused on short‐term outcomes in normal‐weight samples, longer duration studies in clinical populations (eg, individuals with obesity) are needed to examine the generalizability of these results.     

Introduction to systematic reviews and meta‐analysis

Systematic reviews provide a method for collating and synthesizing research, and are used to inform healthcare decision making by clinicians, consumers and policy makers. A core component of many systematic reviews is a meta‐analysis , which is a statistical synthesis of results across studies. In this review article, we introduce meta‐analysis, focusing on the different meta‐analysis models, their interpretation, how a model should be selected and discuss potential threats to the validity of meta‐analyses. We illustrate the application of meta‐analysis using data from a review examining the effects of early use of inhaled corticosteroids in the emergency department treatment of acute asthma.