The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity.

Quantifying heterogeneity in a meta‐analysis

BACKGROUND: Somatoform disorders are characterised by chronic, medically unexplained physical symptoms (MUPS). Although different medications are part of treatment routines for people with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications. We aimed to synthesise to improve optimal treatment decisions.OBJECTIVES: To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults.SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 17 January 2014). This register includes relevant randomised controlled trials (RCTs) from The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). To identify ongoing trials, we searched ClinicalTrials.gov, Current Controlled Trials metaRegister, the World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry. For grey literature, we searched ProQuest Dissertation {\&} Theses Database, OpenGrey, and BIOSIS Previews. We handsearched conference proceedings and reference lists of potentially relevant papers and systematic reviews and contacted experts in the field.SELECTION CRITERIA: We selected RCTs or cluster RCTs of pharmacological interventions versus placebo, treatment as usual, another medication, or a combination of different medications for somatoform disorders in adults. We included people fulfilling standardised diagnostic criteria for somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, or somatoform pain disorder.DATA COLLECTION AND ANALYSIS: One review author and one research assistant independently extracted data and assessed risk of bias. Primary outcomes included the severity of MUPS on a continuous measure, and acceptability of treatment.MAIN RESULTS: We included 26 RCTs (33 reports), with 2159 participants, in the review. They examined the efficacy of different types of antidepressants, the combination of an antidepressant and an antipsychotic, antipsychotics alone, or natural products (NPs). The duration of the studies ranged between two and 12 weeks.One meta-analysis of placebo-controlled studies showed no clear evidence of a significant difference between tricyclic antidepressants (TCAs) and placebo for the outcome severity of MUPS (SMD -0.13; 95{\%} CI -0.39 to 0.13; 2 studies, 239 participants; I(2) = 2{\%}; low-quality evidence). For new-generation antidepressants (NGAs), there was very low-quality evidence showing they were effective in reducing the severity of MUPS (SMD -0.91; 95{\%} CI -1.36 to -0.46; 3 studies, 243 participants; I(2) = 63{\%}). For NPs there was low-quality evidence that they were effective in reducing the severity of MUPS (SMD -0.74; 95{\%} CI -0.97 to -0.51; 2 studies, 322 participants; I(2) = 0{\%}).One meta-analysis showed no clear evidence of a difference between TCAs and NGAs for severity of MUPS (SMD -0.16; 95{\%} CI -0.55 to 0.23; 3 studies, 177 participants; I(2) = 42{\%}; low-quality evidence). There was also no difference between NGAs and other NGAs for severity of MUPS (SMD -0.16; 95{\%} CI -0.45 to 0.14; 4 studies, 182 participants; I(2) = 0{\%}).Finally, one meta-analysis comparing selective serotonin reuptake inhibitors (SSRIs) with a combination of SSRIs and antipsychotics showed low-quality evidence in favour of combined treatment for severity of MUPS (SMD 0.77; 95{\%} CI 0.32 to 1.22; 2 studies, 107 participants; I(2) = 23{\%}).Differences regarding the acceptability of the treatment (rate of all-cause drop-outs) were neither found between NGAs and placebo (RR 1.01, 95{\%} CI 0.64 to 1.61; 2 studies, 163 participants; I(2) = 0{\%}; low-quality evidence) or NPs and placebo (RR 0.85, 95{\%} CI 0.40 to 1.78; 3 studies, 506 participants; I(2) = 0{\%}; low-quality evidence); nor between TCAs and other medication (RR 1.48, 95{\%} CI 0.59 to 3.72; 8 studies, 556 participants; I(2) =14{\%}; low-quality evidence); nor between antidepressants and the combination of an antidepressant and an antipsychotic (RR 0.80, 95{\%} CI 0.25 to 2.52; 2 studies, 118 participants; I(2) = 0{\%}; low-quality evidence). Percental attrition rates due to adverse effects were high in all antidepressant treatments (0{\%} to 32{\%}), but low for NPs (0{\%} to 1.7{\%}).The risk of bias was high in many domains across studies. Seventeen trials (65.4{\%}) gave no information about random sequence generation and only two (7.7{\%}) provided information about allocation concealment. Eighteen studies (69.2{\%}) revealed a high or unclear risk in blinding participants and study personnel; 23 studies had high risk of bias relating to blinding assessors. For the comparison NGA versus placebo, there was relatively high imprecision and heterogeneity due to one outlier study. Although we identified 26 studies, each comparison only contained a few studies and small numbers of participants so the results were imprecise.AUTHORS' CONCLUSIONS: The current review found very low-quality evidence for NGAs and low-quality evidence for NPs being effective in treating somatoform symptoms in adults when compared with placebo. There was some evidence that different classes of antidepressants did not differ in efficacy; however, this was limited and of low to very low quality. These results had serious shortcomings such as the high risk of bias, strong heterogeneity in the data, and small sample sizes. Furthermore, the significant effects of antidepressant treatment have to be balanced against the relatively high rates of adverse effects. Adverse effects produced by medication can have amplifying effects on symptom perceptions, particularly in people focusing on somatic symptoms without medical causes. We can only draw conclusions about short-term efficacy of the pharmacological interventions because no trial included follow-up assessments. For each of the comparisons where there were available data on acceptability rates (NGAs versus placebo, NPs versus placebo, TCAs versus other medication, and antidepressants versus a combination of an antidepressant and an antipsychotic), no clear differences between the intervention and comparator were found.Future high-quality research should be carried out to determine the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly, and to follow-up participants over longer periods (the longest follow up was just 12 weeks). Another idea for future research would be to include other outcomes such as functional impairment or dysfunctional behaviours and cognitions as well as the classical outcomes such as symptom severity, depression, or anxiety.

Pharmacological interventions for somatoform disorders in adults.

Background
Latent autoimmune diabetes in adults (LADA) is a slowly developing type 1 diabetes.

Objectives
To compare interventions used for LADA.

Search methods
Studies were obtained from searches of electronic databases, supplemented by handsearches, conference proceedings and consultation with experts. Date of last search was December 2010.

Selection criteria
Randomised controlled trials (RCT) and controlled clinical trials (CCT) evaluating interventions for LADA or type 2 diabetes with antibodies were included.

Data collection and analysis
Two authors independently extracted data and assessed risk of bias. Studies were summarised using meta-analysis or descriptive methods.

Main results
Searches identified 13,306 citations. Fifteen publications (ten studies) were included, involving 1019 participants who were followed between three months to 10 years (1060 randomised). All studies had a high risk of bias. Sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone at three months (one study, n = 15) and at 12 months (one study, n = 14) of treatment and follow-up. SU (with or without metformin) gave poorer metabolic control compared to insulin alone (mean difference in glycosylated haemoglobin A1c (HbA1c) from baseline to end of study, for insulin compared to oral therapy: -1.3% (95% confidence interval (CI) -2.4 to -0.1; P = 0.03, 160 participants, four studies, follow-up/duration of therapy: 12, 30, 36 and 60 months; however, heterogeneity was considerable). In addition, there was evidence that SU caused earlier insulin dependence (proportion requiring insulin at two years was 30% in the SU group compared to 5% in conventional care group (P < 0.001); patients classified as insulin dependent was 64% (SU group) and 12.5% (insulin group, P = 0.007). No intervention influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5)). In a five year follow-up of GAD65 (glutamic acid decarboxylase formulated with aluminium hydroxide), improvements in fasting and stimulated C-peptide levels (20 μg group) were maintained after five years. Short term (three months) follow-up in one study (n = 74) using Chinese remedies did not demonstrate a significant difference in improving fasting C-peptide levels compared to insulin alone (0.07 µg/L (95% CI -0.05 to 0.19). One study using vitamin D with insulin showed steady fasting C-peptide levels in the vitamin D group but declining fasting C-peptide levels (368 to 179 pmol/L, P = 0.006) in the insulin alone group at 12 months follow-up. Comparing studies was difficult as there was a great deal of heterogeneity in the studies and in their selection criteria. There was no information regarding health-related quality of life, complications of diabetes, cost or health service utilisation, mortality and limited evidence on adverse events (studies on oral agents or insulin reported no adverse events in terms of severe hypoglycaemic episodes).

Authors' conclusions
Two studies show SU leading to earlier insulin dependence and a meta-analysis of four studies with considerable heterogeneity showed poorer metabolic control if SU is prescribed for patients with LADA compared to insulin. One study showed that vitamin D with insulin may protect pancreatic beta cells in LADA. Novel treatments such as GAD65 in certain doses (20 μg) have been suggested to maintain fasting and stimulated C-peptide levels. However, there is no significant evidence for or against other lines of treatment of LADA.

/pdf/interventions-for-latent-autoimmune-diabetes-lada-in-adults-575yg4pwr3.pdf

Interventions for latent autoimmune diabetes (LADA) in adults.

Improving the design and implementation of evidence-based practice depends on successful behaviour change interventions. This requires an appropriate method for characterising interventions and linking them to an analysis of the targeted behaviour. There exists a plethora of frameworks of behaviour change interventions, but it is not clear how well they serve this purpose. This paper evaluates these frameworks, and develops and evaluates a new framework aimed at overcoming their limitations. A systematic search of electronic databases and consultation with behaviour change experts were used to identify frameworks of behaviour change interventions. These were evaluated according to three criteria: comprehensiveness, coherence, and a clear link to an overarching model of behaviour. A new framework was developed to meet these criteria. The reliability with which it could be applied was examined in two domains of behaviour change: tobacco control and obesity. Nineteen frameworks were identified covering nine intervention functions and seven policy categories that could enable those interventions. None of the frameworks reviewed covered the full range of intervention functions or policies, and only a minority met the criteria of coherence or linkage to a model of behaviour. At the centre of a proposed new framework is a 'behaviour system' involving three essential conditions: capability, opportunity, and motivation (what we term the 'COM-B system'). This forms the hub of a 'behaviour change wheel' (BCW) around which are positioned the nine intervention functions aimed at addressing deficits in one or more of these conditions; around this are placed seven categories of policy that could enable those interventions to occur. The BCW was used reliably to characterise interventions within the English Department of Health's 2010 tobacco control strategy and the National Institute of Health and Clinical Excellence's guidance on reducing obesity. Interventions and policies to change behaviour can be usefully characterised by means of a BCW comprising: a 'behaviour system' at the hub, encircled by intervention functions and then by policy categories. Research is needed to establish how far the BCW can lead to more efficient design of effective interventions.

/pdf/the-behaviour-change-wheel-a-new-method-for-characterising-4vp816z23u.pdf

The behaviour change wheel: a new method for characterising and designing behaviour change interventions.

Objective. —To determine if inadequate approaches to randomized controlled trial design and execution are associated with evidence of bias in estimating treatment effects. Design. —An observational study in which we assessed the methodological quality of 250 controlled trials from 33 meta-analyses and then analyzed, using multiple logistic regression models, the associations between those assessments and estimated treatment effects. Data Sources. —Meta-analyses from the Cochrane Pregnancy and Childbirth Database. Main Outcome Measures. —The associations between estimates of treatment effects and inadequate allocation concealment, exclusions after randomization, and lack of double-blinding. Results. —Compared with trials in which authors reported adequately concealed treatment allocation, trials in which concealment was either inadequate or unclear (did not report or incompletely reported a concealment approach) yielded larger estimates of treatment effects ( P P =.01), with odds ratios being exaggerated by 17%. Conclusions. —This study provides empirical evidence that inadequate methodological approaches in controlled trials, particularly those representing poor allocation concealment, are associated with bias. Readers of trial reports should be wary of these pitfalls, and investigators must improve their design, execution, and reporting of trials. ( JAMA . 1995;273:408-412)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=386770&pdfFileName=jama_273_5_030.pdf

Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials.

This study investigates the prevalence of current somatization in the population by taking different levels of symptom severity into account. Somatization is described along a continuum from mild and negligible bodily misperceptions to severe and disabling somatoform symptoms. A representative sample of 2.552 persons in Germany was examined with a screening instrument for medically unexplained physical complaints that had occurred during the past 7 days. All 53 symptoms from the ICD-10/DSM-IV sections of somatoform disorders were included. 81.6% reported at least one symptom causing at least mild impairment and 22.1% at least one symptom causing severe impairment. The entire sample had an average of 6.6 symptoms associated with at least mild distress. Somatization of any degree was associated with female gender, age above 45, lower educational level, lower household income and rural area. The most common symptoms with prevalence rates > 20% were various types of pain (back, head, joints, extremities), food intolerance, sexual indifference, painful menstruations and erectile/ejaculatory dysfunction. This population survey demonstrates that medically unclear complaints are an everyday phenomenon. About three out of four cases are below clinical relevance with only low level of impairment. Epidemiological correlates are similar between clinical and non-clinical forms of somatization.

Somatization in the population: from mild bodily misperceptions to disabling symptoms

https://self-compassion.org/wp-content/uploads/publications/MajorDepression.pdf

Self-compassion as an emotion regulation strategy in major depressive disorder.

Objective: The primary aim of this study was to assess the overall effectiveness of and dropout from individual and group outpatient cognitive behavioral therapy (CBT) for adults with a primary diagnosis of unipolar depressive disorder in routine clinical practice Method: We conducted a random effects meta-analysis of 34 nonrandomized effectiveness studies on outpatient individual and group CBT for adult unipolar depressive disorder Standardized mean gain effect sizes are reported for end-of-treatment and 6-month follow-up effects for depression severity, dysfunctional cognitions, general anxiety, psychological distress, and functional impairment The mean dropout rate from CBT is reported We benchmarked our results against high-quality randomized controlled trials (RCTs) Results: Outpatient CBT was effective in reducing depressive severity in completer (d 113) and intention-to-treat (ITT) samples (d 106) Moderate to large posttreatment effect sizes (d 067–088) were found for secondary outcomes The weighted mean dropout rate was 2463% Posttreatment gains for depression were maintained at 6 months after completion of therapy Effect sizes for depression were inferior to those of benchmark RCTs Conclusions: Although clinical practice patients show lesser improvements in depressive symptoms than RCT patients, individual and group outpatient CBT can be effectively transported to routine clinical practice The considerable treatment dropout rate, especially in individual CBT, must be improved The small number of available studies and low quality of some reports stress the need for high-quality effectiveness studies

/pdf/effectiveness-of-and-dropout-from-outpatient-cognitive-16k67ynm7l.pdf

Effectiveness of and dropout from outpatient cognitive behavioral therapy for adult unipolar depression: a meta-analysis of nonrandomized effectiveness studies.

Objective To evaluate the 2 major components of tinnitus severity, loudness and annoyance, and their degree of dependence on characteristics of tinnitus manifestation, history, and etiology. Design Cross-sectional survey performed during the first months of 2004. Setting Nonclinical population. Participants A total of 4995 members of the German Tinnitus League. Main Outcome Measures Comprehensive screening questionnaire, including the Klockhoff and Lindblom loudness grading system and the miniversion of the Tinnitus Questionnaire. Results A moderate correlation of 0.45 was found between tinnitus loudness and annoyance. Both factors were generally higher in men, those older than 50 years, those with binaural and centrally perceived tinnitus, those with increased noise sensitivity, and those who had continuous tinnitus without interruptions. Tinnitus that lasted 12 months or less had a stronger influence on annoyance (odds ratio [OR], 1.96) than on loudness (OR, 0.45), whereas the contrary was found for tinnitus of more than 5 years' duration (ORs, 0.72 and 2.11, respectively). Loudness and annoyance were increased in subjects with coexisting hearing loss, vertigo, and hyperacusis. The impact of hyperacusis on annoyance was clearly stronger than on loudness (ORs, 21.91 vs 9.47). Conclusions Several clinical factors of tinnitus influence perceived loudness and annoyance. Both are distinguishable components of tinnitus severity.

https://jamanetwork.com/journals/jamaotolaryngology/articlepdf/484595/ooa60101_1323_1330.pdf

Wolfgang Hiller

Papers

Pharmacological interventions for somatoform disorders in adults.

Somatization in the population: from mild bodily misperceptions to disabling symptoms

Self-compassion as an emotion regulation strategy in major depressive disorder.

Effectiveness of and dropout from outpatient cognitive behavioral therapy for adult unipolar depression: a meta-analysis of nonrandomized effectiveness studies.

Factors Influencing Tinnitus Loudness and Annoyance