Regression to the mean, heteroscedasticity, and prognostic imbalance in randomized controlled trials

Background: Several studies have suggested that exercise capacity and quality of life are reduced in patients with pulmonary hypertension (PH), and exercise-based rehabilitation can improve exercise capacity and quality of life in patients with PH. The aim of this study is to assess the efficacy and safety of exercise-based rehabilitation in patients with PH through a meta-analysis of randomized controlled trials. Methods: We searched PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials up to November 2018. All randomized controlled trials (RCTs) comparing exercise capacity and quality of life between patients undergoing exercise-based rehabilitation and those undergoing non-exercise training were included. Data were extracted separately and independently by two investigators, and discrepancies were arbitrated by the third investigator. We used the random-effects model to analyze the results, the GRADE to assess the risk of bias in the included studies, and I Â² statistic to estimate the degree of heterogeneity. Results: Nine RCTs are included, however, only seven RCTs were able to extract data. Including inpatients and outpatients, the total number of participants was 234, most of whom were diagnosed as pulmonary artery hypertension (PAH). The study duration ranged from 3 to15 weeks. The mean six-minute walk distance after exercise training was 51.94 metres higher than control (27.65 to 76.23 metres, n=234, 7 RCTs, low quality evidence), the mean peakÂ oxygen uptakeÂ Â was 2.96 ml/kg/minute higher (2.49 to 3.43 ml/kg/minute, n=179, 4 RCTs, low-quality evidence) than in the control groupÂ . Concluded: Our finding suggest that an exercise-based training program positively influences exercise capacity in patients with PH.

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The Antihypertensive Effects and Safety of LCZ696 in Patients with Hypertension: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Journal of Clinical Medicine ◽

10.3390/jcm10132824 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2824

Author(s):

Su-Kiat Chua ◽

Wei-Ting Lai ◽

Lung-Ching Chen ◽

Huei-Fong Hung

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Randomized Controlled Trials ◽

Diastolic Blood Pressure ◽

Publication Bias ◽

Meta Analysis ◽

Systemic Review ◽

Controlled Trials ◽

Randomized Controlled ◽

The Mean

Background: The management of hypertension remains suboptimal throughout the world. Methods: We performed a random-effects model meta-analysis of randomized controlled trials to determine the effectiveness and safety of sacubitril/valsartan (LCZ696) for the treatment of high arterial pressure. Relevant published articles from PubMed, Cochrane base, and Medline were examined, and the last search date was December 2020. Only published randomized controlled trials and double-blind studies were selected for further analysis. The mean reductions in systolic blood pressure (msSBP) and diastolic blood pressure (msDBP) in the sitting position, as well as the mean reductions in ambulatory systolic blood pressure (maSBP) and ambulatory diastolic blood pressure (maDBP), were assumed as efficacy endpoints. Adverse events (AEs) were considered as safety outcomes. Results: Ten studies with a total of 5931patients were included for analysis. Compared with placebo, LCZ696 had a significant reduction in msSBP (weight mean difference (WMD) = −6.52 mmHg, 95% confidence interval (CI): −8.57 to −4.47; p < 0.001), msDBP (WMD = −3.32 mmHg, 95% CI: −4.57 to −2.07; p < 0.001), maSBP (WMD = −7.08 mmHg, 95% CI: −10.48 to −3.68; p < 0.001), maDBP (WMD = −3.28 mmHg, 95% CI: −4.55 to −2.02, p < 0.001). In subgroup analysis, only 200 mg and 400 mg LCZ696 showed a significant BP reduction. There was no difference in the AE rate between the LCZ696 and placebo groups (WMD = 1.02, 95% CI: 0.83 to 1.27, p = 0.54). Egger’s test revealed a potential publication bias for msSBP (p = 0.025), but no publication bias for other outcomes. Conclusion: LCZ696 may reduce blood pressure more efficaciously than traditional therapy in hypertensive patients without increasing adverse effects.

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A qualitative assessment of randomized controlled trials in otolaryngology

The Journal of Laryngology & Otology ◽

10.1017/s0022215100140770 ◽

1998 ◽

Vol 112 (5) ◽

pp. 460-463 ◽

Cited By ~ 30

Author(s):

K. W. Ah-See ◽

N. C. Molony

Keyword(s):

Randomized Controlled Trials ◽

Consort Statement ◽

Qualitative Assessment ◽

Controlled Trials ◽

Randomized Controlled ◽

Future Assessment ◽

The Consort Statement ◽

The Mean ◽

Better Than

AbstractIn 1996 the CONSORT statement made recommendations on the strict reporting of randomized controlled trials (RCT). This will facilitate the future assessment of such trials and will highlight those trials that have been performed suboptimally and whose results may be biased.We have devised a scoring system, based on CONSORT, to assess RCT quality and by reading each original paper in full we have now assessed the quality of trials published from 1966 to 1995.The mean score for trials identified was 7.3 out of a maximum 12 points. No one journal was significantly better than the others. Trials in rhinology are reported better than head and neck oncology trials (mean scores 7.6 and 6.5 respectively). The past 30 years has not seen an improvement in the quality of the trials.The reporting of RCTs in the ENT literature is poor. CONSORT guidelines now exist and trialists are encouraged to adopt them when conducting future clinical trials.

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Reporting of Randomized Controlled Trials in Cleft Lip and Palate: A 10-Year Review

The Cleft Palate-Craniofacial Journal ◽

10.1597/14-267 ◽

2017 ◽

Vol 54 (2) ◽

pp. 142-152 ◽

Cited By ~ 4

Author(s):

Joseph Hardwicke ◽

Mohammad Nassimizadeh ◽

Bruce Richard

Keyword(s):

Randomized Controlled Trials ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Journal Article ◽

Controlled Trials ◽

Jadad Score ◽

Quality Of Reporting ◽

Randomized Controlled ◽

The Mean

Objectives Reviews of the quality of reporting of randomized controlled trials (RCTs) have recently been conducted in different surgical specialties. In this review of RCTs relating to cleft lip, cleft palate, and cleft lip and palate (CL/P), we investigate the quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist. Design A systematic review of CL/P RCTs published from 2004 to 2013, with the included articles scored against the CONSORT checklist. Patients, Participants The literature search identified 174 articles. Studies were selected for participants with CL/P who were involved in an RCT with prospective data collection and reported in a full journal article. A total of 6352 participants were included from 65 CUP RCTs during the study period. Main Outcome Measures The methodological quality of RCTs was assessed using the CONSORT checklist and Jadad scale. Results The mean CONSORT score was 15.8, and the mean Jadad score was 3.3. There was a significant positive correlation between the CONSORT and Jadad score ( P < .0001, ρ = .47). The only significant correlation showed that with an increasing number of authors, both the CONSORT and the Jadad score increased. Conclusion This analysis has shown that that there are deficiencies in the transparent reporting of factors such as randomization implementation, blinding, and participant flow. Interventions, outcomes, and the interpretation of results are well presented. We would recommend that RCTs are conceived and undertaken using the CONSORT checklist and reported in a clear and reproducible manner.

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The Effect of Zinc Supplementation on Serum Leptin Levels: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Hormone and Metabolic Research ◽

10.1055/a-0955-6662 ◽

2019 ◽

Vol 51 (08) ◽

pp. 503-510

Author(s):

Masoud Khorshidi ◽

Meysam Zarezadeh ◽

Alireza Sadeghi ◽

Alireza Teymouri ◽

Mohammad Reza Emami ◽

...

Keyword(s):

Clinical Trials ◽

Randomized Controlled Trials ◽

Zinc Supplementation ◽

Meta Analysis ◽

Control Group ◽

Controlled Trials ◽

Serum Leptin ◽

Randomized Controlled ◽

Human Adults ◽

The Mean

AbstractRecently, obesity has become a common worldwide concern. Leptin, as an adipocytokine, plays a major role in the etiology of obesity. Prior studies have demonstrated that zinc potentially affects serum leptin levels. However, clinical trials carried out in this regard are not consistent. Therefore, current meta-analysis was conducted to ascertain the actual effect of zinc supplementation on serum leptin levels in adults. Databases of PubMed, SCOPUS, and Google Scholar were methodically searched to identify relevant articles up to April 2018. Clinical trials that examined the effect of zinc supplementation on serum leptin concentrations as outcome variables in human adults were included. The mean difference (SD) of leptin changes in the intervention and placebo groups were used to calculate the overall effect size. Totally, 663 articles were identified, of which 6 studies were eligible randomized controlled trials (RCTs) with 7 treatment arms. The analysis suggested that zinc supplementation exerts no significant effect on overall serum leptin (WMD: 0.74 ng/ml; 95% CI: −1.39 to 2.87, p=0.49). Nevertheless, sex and duration of intervention seemed to impact the extent of zinc’s influence. In trials with female subjects, zinc consumption led to a significant decrease in serum leptin level (WMD: −1.93 ng/ml; 95% CI: −3.72 to −0.14, p=0.03) as well as trials that lasted for more than 6 weeks (WMD: −1.71 ng/ml; 95% CI: −3.07 to −0.35, p=0.01), in comparison to the control group. Zinc supplementation did not significantly improve leptin concentrations, but it may result in a decreased circulating leptin level in studies with a duration of more than 6 weeks especially among females.

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Effect of Vitamin D or Activated Vitamin D on Circulating 1,25-Dihydroxyvitamin D Concentrations: A Systematic Review and Metaanalysis of Randomized Controlled Trials

Clinical Chemistry ◽

10.1373/clinchem.2015.244913 ◽

2015 ◽

Vol 61 (12) ◽

pp. 1484-1494 ◽

Cited By ~ 20

Author(s):

Armin Zittermann ◽

Jana B Ernst ◽

Ingvild Birschmann ◽

Marcus Dittrich

Keyword(s):

Vitamin D ◽

Randomized Controlled Trials ◽

Control Group ◽

Controlled Trials ◽

Significant Heterogeneity ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Randomized Controlled ◽

The Mean ◽

Vitamin D Supplements

Abstract BACKGROUND Evidence is accumulating that circulating 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations are inversely related to overall mortality. METHODS We searched PubMed, Embase and ISI Web of Science for randomized controlled trials with a control group receiving a placebo instead of vitamin D/activated vitamin D and performed a metaanalysis to evaluate the effect of oral vitamin D/activated vitamin D on circulating 1,25(OH)2D concentrations using a random effects model. RESULTS We included 52 vitamin D intervention groups (4796 individuals) and 14 intervention groups with activated vitamin D (668 individuals). Vitamin D supplements increased circulating 1,25(OH)2D by 12.2 pmol/L (95% CI, 7.8–16.5 pmol/L) and 18.8 pmol/L (95% CI, 9.2–28.4 pmol/L) if only studies with a low risk of bias in study design and reporting were considered (n = 18). There was significant heterogeneity among studies (Cohran's Q P < 0.001, I2 = 91%). The incremental effect was larger in studies using vitamin D alone compared with coadministration of calcium supplements (18.6 pmol/L; 95% CI, 12.7–24.4 pmol/L vs 4.9 pmol/L; 95% CI, −0.4 to 10.2 pmol/L; P = 0.001), and if quantification was performed with RIA vs other methods (17.1 pmol/L; 95% CI, 11.1–23.1 pmol/L vs 6.9 pmol/L; 95% CI, 1.0–12.8 pmol/L; P = 0.02). Activated vitamin D increased the mean circulating 1,25(OH)2D by 20.5 pmol/L (95% CI, 8.3–32.7 pmol/L; P = 0.04). Again, there was evidence for significant heterogeneity among studies (Cochran Q = 85.4; P < 0.001; I2 = 87%), but subgroup analysis did not identify parameters significantly influencing the increment in 1,25(OH)2D concentrations. CONCLUSIONS Both vitamin D and activated vitamin D significantly increase circulating 1,25(OH)2D concentrations, but in vitamin D users this increase is suppressed by calcium coadministration.

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Efficacy of glucocorticoids for the treatment of macrolide refractory mycoplasma pneumonia in children: meta-analysis of randomized controlled trials

BMC Pulmonary Medicine ◽

10.1186/s12890-019-0990-8 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 3

Author(s):

Hwan Soo Kim ◽

In Suk Sol ◽

Donghe Li ◽

Miyoung Choi ◽

Yun Jung Choi ◽

...

Keyword(s):

Treatment Group ◽

Hospital Stay ◽

Randomized Controlled Trials ◽

Conventional Treatment ◽

Meta Analysis ◽

Controlled Trials ◽

Glucocorticoid Treatment ◽

Conventional Treatment Group ◽

Randomized Controlled ◽

The Mean

Abstract Background Mycoplasma pneumoniae is one of the most common pathogens causing community acquired pneumonia in children. Although the rate of macrolide-refractory Mycoplasma pneumoniae (MRMP) has increased, systemic glucocorticoids as a treatment option has not been validated yet. The purpose of this study was to assess the efficacy of glucocorticoids add-on in the treatment of MRMP in children through systematic review and meta-analysis. Methods Data sources A systematic literature search was conducted using ten electronic bibliographic databases including English, Korean, Chinese and Japanese languages, up to March 8, 2018. Study selection The study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and selected randomized control trials which compared the efficacy of glucocorticoids add-on to macrolide in the treatment of MRMP in children. Data extraction Two independent reviewers extracted: primary outcomes as hospital days, fever duration, and change in C-reactive protein (CRP) and main analysis was performed through meta-analysis with random effects model. Results Twenty-four unique randomized controlled trials met the inclusion criteria. The mean length of hospital stay in glucocorticoids treatment group was significantly shorter than that in conventional macrolide-treatment group (Weighted mean difference (WMD) = − 4.03 days). The mean length of fever duration was significantly shorter in the glucocorticoid treatment group in comparison with the conventional treatment group (WMD = -3.32 days). Level of CRP after treatment was significantly lower in the glucocorticoid treatment group than that in the conventional treatment group (WMD = -16.03). Sensitivity analysis and subgroup analysis showed no significant improvement in heterogeneity. As limitations of the study, most of the studies included were from a single country and we were unable to control for heterogeneity across interventions, lack of standardized measures, and different time points of assessments across studies. Conclusions Glucocorticoid add-on treatment for MRMP can significantly shorten the duration of fever and hospital stay and decrease the level of CRP. These results should be confirmed by adequately powered studies in the future.

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Acute glycemic and insulinemic effects of low-energy sweeteners: a systematic review and meta-analysis of randomized controlled trials

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqaa167 ◽

2020 ◽

Vol 112 (4) ◽

pp. 1002-1014 ◽

Cited By ~ 1

Author(s):

Arno Greyling ◽

Katherine M Appleton ◽

Anne Raben ◽

David J Mela

Keyword(s):

Systematic Review ◽

Type 2 Diabetes ◽

Randomized Controlled Trials ◽

Fasting Glucose ◽

Meta Analysis ◽

Low Energy ◽

Controlled Trials ◽

Randomized Controlled ◽

The Mean

ABSTRACT Background It has been suggested that low-energy sweeteners (LES) may be associated with an increased risk of metabolic diseases, possibly due to stimulation of glucose-responsive mechanisms. Objective We conducted a systematic review and meta-analysis of human intervention studies examining the acute effect of LES intake on postprandial glucose (PPG) and postprandial insulin (PPI) responses, in order to comprehensively and objectively quantify these relations. Methods We systematically searched the Medline, OVID FSTA, and SCOPUS databases until January 2020. Randomized controlled trials comparing acute postprandial effects on PPG and/or PPI after exposure to LES, either alone, with a meal, or with other nutrient-containing preloads to the same intervention without LES were eligible for inclusion. PPG and PPI responses were calculated as mean incremental area under the curve divided by time. Meta-analyses were performed using random effects models with inverse variance weighing. Results Twenty-six papers (34 PPG trials and 29 PPI trials) were included. There were no reports of statistically significant differences in the effects of LES on PPG and PPI responses compared with control interventions. Pooled effects of LES intake on the mean change difference in PPG and PPI were −0.02 mmol/L (95% CI: −0.09, 0.05) and −2.39 pmol/L (95% CI: −11.83, 7.05), respectively. The results did not appreciably differ by the type or dose of LES consumed, cointervention type, or fasting glucose and insulin levels. Among patients with type 2 diabetes, the mean change difference indicated a smaller PPG response after exposure to LES compared with the control (−0.3 mmol/L; 95% CI: −0.53, −0.07). Conclusions Ingestion of LES, administered alone or in combination with a nutrient-containing preload, has no acute effects on the mean change in postprandial glycemic or insulinemic responses compared with a control intervention. Apart from a small beneficial effect on PPG (−0.3 mmol/L) in studies enrolling patients with type 2 diabetes, the effects did not differ by type or dose of LES, or fasting glucose or insulin levels. This review and meta-analysis was registered at PROSPERO as CRD42018099608.

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Methods for meta-analysis of pharmacodynamic dose–response data with application to multi-arm studies of alogliptin

Statistical Methods in Medical Research ◽

10.1177/0962280216637093 ◽

2016 ◽

Vol 27 (2) ◽

pp. 564-578 ◽

Cited By ~ 1

Author(s):

Oliver Langford ◽

Jeffrey K Aronson ◽

Gert van Valkenhoef ◽

Richard J Stevens

Keyword(s):

Randomized Controlled Trials ◽

Least Squares ◽

Dose Response ◽

Meta Analysis ◽

Weighted Least Squares ◽

Controlled Trials ◽

Response Model ◽

Response Data ◽

Randomized Controlled ◽

The Mean

Standard methods for meta-analysis of dose–response data in epidemiology assume a model with a single scalar parameter, such as log-linear relationships between exposure and outcome; such models are implicitly unbounded. In contrast, in pharmacology, multi-parameter models, such as the widely used Emax model, are used to describe relationships that are bounded above and below. We propose methods for estimating the parameters of a dose–response model by meta-analysis of summary data from the results of randomized controlled trials of a drug, in which each trial uses multiple doses of the drug of interest (possibly including dose 0 or placebo). We assume that, for each randomized arm of each trial, the mean and standard error of a continuous response measure and the corresponding allocated dose are available. We consider weighted least squares fitting of the model to the mean and dose pairs from all arms of all studies, and a two-stage procedure in which scalar inverse-variance meta-analysis is performed at each dose, and the dose–response model is fitted to the results by weighted least squares. We then compare these with two further methods inspired by network meta-analysis that fit the model to the contrasts between doses. We illustrate the methods by estimating the parameters of the Emax model to a collection of multi-arm, multiple-dose, randomized controlled trials of alogliptin, a drug for the management of diabetes mellitus, and further examine the properties of the four methods with sensitivity analyses and a simulation study. We find that all four methods produce broadly comparable point estimates for the parameters of most interest, but a single-stage method based on contrasts between doses produces the most appropriate confidence intervals. Although simpler methods may have pragmatic advantages, such as the use of standard software for scalar meta-analysis, more sophisticated methods are nevertheless preferable for their advantages in estimation.

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Are Psychotherapies Less Effective for Black Youth in Communities with Higher Levels of Racism?

10.31219/osf.io/szu7v ◽

2020 ◽

Author(s):

Maggi Price ◽

John R. Weisz ◽

Sarah McKetta ◽

Micah Lattanner ◽

Allecia Reid ◽

...

Keyword(s):

Randomized Controlled Trials ◽

Mental Health Problems ◽

Black Youth ◽

General Social Survey ◽

Composite Index ◽

State Level ◽

Controlled Trials ◽

Randomized Controlled ◽

Cultural Racism ◽

The Mean

Objective: The study examined whether cultural racism moderates the efficacy of psychotherapy interventions among youth.Method: We analyzed a subset of studies from a previous meta-analysis of five decades of youth psychotherapy randomized controlled trials. Studies were published in English between 1963 and 2017 and identified through a systematic search. The 194 studies (N=14,081; ages 2-19) across 34 states comprised 2,678 effect sizes (ESs) measuring mental health problems (e.g., depression) targeted by interventions. Cultural racism was operationalized using a composite index of 31 items measuring explicit racial attitudes (obtained from publicly available sources; e.g., General Social Survey), aggregated to the state level and linked to the meta-analytic database. Analyses were conducted with samples of majority (i.e., ≥50%) Black (n=36 studies) and majority-White (n=158 studies) youth.Results: Two-level random effects meta-regression analyses indicated that higher cultural racism was associated with lower ESs for studies with majority-Black youth (β=-0.21, CI: -0.37, -0.05, p=0.01) but was unrelated to ESs for studies with majority-White youth (β=0.003, CI: -0.03, 0.03, p=0.80), controlling for state-level poverty and White population density. In studies with majority-Black youth, mean ESs were significantly lower in states with the highest cultural racism (>1 SD above the mean; g=0.19) compared to states with the lowest racism (<1 SD below the mean; g=0.60). Conclusions: Psychotherapy randomized controlled trials with samples comprised of majority-Black youth were significantly less effective in states with higher (vs. lower) levels of cultural racism, suggesting that cultural racism may be one contextual moderator of treatment effect heterogeneity.

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