Jin-Ling Tang

Misleading funnel plot for detection of bias in meta-analysis.

Publication and other forms of selection biases pose a threat to the validity of meta-analysis. Funnel plots are usually used to detect such biases; asymmetrical plots are interpreted to suggest that biases are present. Using 198 published meta-analyses, we demonstrate that the shape of a funnel plot is largely determined by the arbitrary choice of the method to construct the plot. When a different definition of precision and/or effect measure were used, the conclusion about the shape of the plot was altered in 37 (86%) of the 43 meta-analyses with an asymmetrical plot suggesting selection bias. In the absence of a consensus on how the plot should be constructed, asymmetrical funnel plots should be interpreted cautiously. These findings also suggest that the discrepancies between large trials and corresponding meta-analyses and heterogeneity in meta-analyses may also be determined by how they are evaluated.

Comparative Effectiveness and Safety of Oral Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction: A Systematic Review and Network Meta-analysis

CONTEXT Phosphodiesterase type 5 inhibitors (PDE5-Is) are currently the first-line therapy for erectile dysfunction (ED), but available studies investigating the comparative effects of different PDE5-Is are limited. OBJECTIVE To compare the efficacy and safety of different classes of oral PDE5-Is for ED. EVIDENCE ACQUISITION A systematic search was performed in PubMed, Cochrane Library, and Embase to identify randomized controlled trials that compared different PDE5-Is or PDE5-Is with a placebo for ED. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation system. EVIDENCE SYNTHESIS A total of 118 trials (31 195 individuals) were included. There was no major difference in the results between the traditional meta-analysis and the network meta-analysis. Network meta-analysis demonstrated that PDE5-Is were superior to placebo to improve erectile function. Compared with tadalafil (relative risk [RR]: 0.61; 95% confidence interval [CI], 0.33-0.90) and vardenafil (RR: 0.63; 95% CI, 0.35-0.92), avanafil was less effective on Global Assessment Questionnaire question 1. Tadalafil was more effective than vardenafil (mean difference [MD]: 1.49; 95% CI, 0.50-2.50) and udenafil (MD: -1.84; 95% CI, -3.31 to -0.33) as measured by the erectile function domain of the International Index of Erectile Function. For all efficacy outcomes, the absolute effects and the rank tests indicated that tadalafil and vardenafil were the most effective agents. After adjusting for dosage, the conclusion remained the same. Safety analysis showed there was no major difference among different agents. CONCLUSIONS In recommended doses, oral PDE5-Is are more effective than placebo for ED, and tadalafil seems to be the most effective agent, followed by vardenafil. PDE5-Is are generally safe and well tolerated, and there is no major difference on the safety profile.

The efficacy of thymosin in the treatment of chronic hepatitis B virus infection: a meta-analysis

Trials of thymosin treatment in chronic hepatitis B virus infection have been small and the results have been inconsistent.

Meta-analysis on night shift work and risk of metabolic syndrome

This study aims to quantitatively summarize the association between night shift work and the risk of metabolic syndrome (MetS), with special reference to the dose–response relationship with years of night shift work. We systematically searched all observational studies published in English on PubMed and Embase from 1971 to 2013. We extracted effect measures (relative risk, RR; or odd ratio, OR) with 95% confidence interval (CI) from individual studies to generate pooled results using meta‐analysis approach. Pooled RR was calculated using random‐ or fixed‐effect model. Downs and Black scale was applied to assess the methodological quality of included studies. A total of 13 studies were included. The pooled RR for the association between ‘ever exposed to night shift work’ and MetS risk was 1.57 (95% CI = 1.24–1.98, pheterogeneity = 0.001), while a higher risk was indicated in workers with longer exposure to night shifts (RR = 1.77, 95% CI = 1.32–2.36, pheterogeneity = 0.936). Further stratification analysis demonstrated a higher pooled effect of 1.84 (95% CI = 1.45–2.34) for studies using the NCEP‐ATPIII criteria, among female workers (RR = 1.61, 95% CI = 1.10–2.34) and the countries other than Asia (RR = 1.65, 95% CI = 1.39–1.95). Sensitivity analysis confirmed the robustness of the results. No evidence of publication bias was detected. The present meta‐analysis suggested that night shift work is significantly associated with the risk of MetS, and a positive dose–response relationship with duration of exposure was indicated.

KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer

The authors conducted a systematic review and meta‐analysis to examine whether patients who had metastatic colorectal cancer (mCRC) with the v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G13D mutation (an amino acid substitution at position 13 in KRAS from a glycine to an aspartic acid) and received cetuximab treatment had better clinical outcomes than patients who had mCRC tumors with KRAS codon 12 mutations.

Promising biomarkers for predicting the outcomes of patients with KRAS wild-type metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: A systematic review with meta-analysis

KRAS mutations have been established as a major predictive biomarker for resistance to the treatment of metastatic colorectal cancer (mCRC) with anti‐epidermal growth factor receptor monoclonal antibodies (anti‐EGFR MoAbs). However, many patients with KRAS wild‐type tumors still do not respond to the treatment. We conducted a systematic review with meta‐analysis to assess whether BRAF mutations, PIK3CA mutations and PTEN loss can predict the outcomes of patients with KRAS wild‐type mCRC treated with anti‐EGFR MoAbs. Studies that explored the association of one or more of the three biomarkers with progression‐free survival (PFS), overall survival (OS) and/or objective response rate (ORR) were identified through August 2012. Summary hazard ratios (HRs) and rate differences (RDs) and corresponding 95% confidence intervals (CIs) were calculated by using the random‐effects model. BRAF mutations, PIK3CA exon 20 mutations and PTEN loss were all associated with shorter PFS (HR = 2.59, 95% CI 1.67–4.03; HR = 2.52, 95% CI 1.33–4.78 and HR = 1.75, 95% CI 1.19–2.56, respectively), shorter OS (HR = 2.74, 95% CI 1.79–4.19; HR = 3.29, 95% CI 1.60–6.75 and HR = 1.85, 95% CI 1.30–2.64, respectively) and lower ORR (RD = −36%, 95% CI −44 to −28%; RD = −38%, 95% CI −51 to −24% and RD = −41%, 95% CI −68 to −14%, respectively). PIK3CA exon 9 mutations were associated with none of the outcomes. Studies with relevant data consistently demonstrated a stronger predictive power of combined multiple biomarkers as compared to one alteration alone. These results suggest that BRAF mutations, PIK3CA exon 20 mutations and PTEN loss are predictive of better outcomes in KRAS wild‐type mCRC treated with anti‐EGFR MoAbs. However, the quality of included studies varied, and some of the meta‐analyses were limited by significant between‐study heterogeneity. In the future, well‐designed large randomized controlled trials conducted in KRAS wild‐type mCRC patients with subgroup analysis according to BRAF, PIK3CA exon 20 and PTEN status are essential to fully assess the clinical relevance of these biomarkers.

Patients’ Experiences in Different Models of Community Health Centers in Southern China

PURPOSE Current health care reforms in China have an overall goal of strengthening primary care through the establishment and expansion of primary care networks based on community health centers (CHCs). Implementation in urban areas has led to the emergence of different models of ownership and management. The objective of this study was to evaluate the primary care experiences of patients in the Pearl River Delta as measured by the Primary Care Assessment Tool (PCAT) and the relationships with ownership and management in the 3 different models we describe. METHODS This cross-sectional study was conducted on-site at CHCs in 3 cities within the Pearl River Delta, China, using a multistage cluster sampling method. A validated Mandarin Chinese version of the PCAT–Adult Edition (short version) was adopted to collect information from adult patients regarding their experiences with primary care sources. PCAT scores for individual primary care attributes and total primary care assessment scores were assessed with respect to sociodemographic characteristics, health characteristics, and health care service utilization across 3 primary care models. RESULTS One thousand four hundred forty (1,440) primary care patients responded to the survey, for an overall response rate of 86.1%. Respondents gave government-owned and -managed CHCs the highest overall PCAT scores when compared with CHCs either managed by hospitals (95.18 vs 90.81; P = .005) or owned by private and social entities (95.18 vs 90.69; P =.007) as a result of better first-contact care (better first-contact utilization) and coordination of care (better service coordination and information system). Factors that were positively and significantly associated with higher overall assessment scores included the presence of a chronic condition (P <.001), having medical insurance (P = .006), and a self-reported good health status (P <.001). CONCLUSIONS This study suggests that government-owned and -managed CHCs may be able to provide better first-contact care in terms of utilization and coordination of care, and may be better at solving the problem of underutilization of the CHCs as the first-contact point of care, one key problem facing the reforms in China.

Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases

Current data on the concordance of KRAS, BRAF, PIK3CA mutation status or PTEN expression status between primary tumors and metastases in colorectal cancer (CRC) are conflicting. We conducted a systematic review and meta-analysis to examine concordance and discordance of the status of these four biomarkers between primary tumors and corresponding metastases in CRC patients. The biomarker status in primary tumors was used as the reference standard. Concordance data for KRAS, BRAF, PIK3CA and PTEN were provided by 43, 16, 9 and 7 studies, respectively. The pooled concordance rate was 92.0% (95% CI: 89.7%–93.9%) for KRAS, 96.8% (95% CI: 94.8%–98.0%) for BRAF, 93.9% (95% CI: 89.7%–96.5%) for PIK3CA and 71.7% (95% CI: 57.6%–82.5%) for PTEN. The pooled false positive and false negative rates for KRAS were 9.0% (95% CI: 6.5%–12.4%) and 11.3% (95% CI: 8.0%–15.8%), respectively. KRAS, BRAF and PIK3CA mutations are highly concordant between primary tumors and corresponding metastases in CRC, but PTEN loss is not. Nine percent of patients with wild-type KRAS in primary tumors who received anti-EGFR treatment had mutant KRAS in metastases, while 11.3% patients with mutant KRAS primary tumors had wild-type KRAS in the metastases. These 11.3% patients currently do not receive potentially beneficial anti-EGFR treatment.

Gemcitabine plus erlotinib for advanced pancreatic cancer: a systematic review with meta-analysis.

Background This study aims to comprehensively summarize the currently available evidences on the efficacy and safety of gemcitabine plus erlotinib for treating advanced pancreatic cancer. Methodology/Principal Findings PubMed, EMBASE, The Cochrane Library and abstracts of recent major conferences were systematically searched to identify relevant publications. Studies that were conducted in advanced pancreatic cancer patients treated with gemcitabine plus erlotinib (with or without comparison with gemcitabine alone) and reporting objective response rate, disease control rate, progression-free survival, time-to-progression, overall survival, 1-year survival rate and/or adverse events were included. Data on objective response rate, disease control rate, 1-year survival rate and adverse events rate, respectively, were combined mainly by using Meta-Analyst software with a random-effects model. Data on progression-free survival, time-to-progression and overall survival were summarized descriptively. Sixteen studies containing 1,308 advanced pancreatic cancer patients treated with gemcitabine plus erlotinib were included. The reported median progression-free survival (or time-to-progression), median overall survival, 1-year survival rates, objective response rates and disease control rates were 2–9.6 months, 5–12.5 months, 20%–51%, 0%–28.6% and 25.0%–83.3%, respectively. The weighted 1-year survival rate, objective response rate and disease control rate based on studies reporting robust results were 27.9%, 9.1% and 57.0%, respectively. According to the studies with relevant data, the incidences of total and severe adverse events were 96.3% and 62.9%, respectively. The most frequently reported adverse events were leucopenia, rash, diarrhea, vomitting, neutropenia, thrombocytopenia, anaemia, stomatitis, drug-induced liver injury, fatigue and fever. Compared with gemcitabine alone, the progression-free survival and overall survival with gemcitabine plus erlotinib were significantly longer, but there were also more deaths and interstitial lung disease-like syndrome related to this treatment. Conclusions/Significance Gemcitabine plus erlotinib represent a new option for the treatment of advanced pancreatic cancer, with mild but clinically meaningful additive efficacy compared with gemcitabine alone. Its safety profile is generally acceptable, although careful management is needed for some specific adverse events.

Low cigarette consumption and risk of coronary heart disease and stroke: meta-analysis of 141 cohort studies in 55 study reports

Abstract Objective To use the relation between cigarette consumption and cardiovascular disease to quantify the risk of coronary heart disease and stroke for light smoking (one to five cigarettes/day). Design Systematic review and meta-analysis. Data sources Medline 1946 to May 2015, with manual searches of references. Eligibility criteria for selecting studies Prospective cohort studies with at least 50 events, reporting hazard ratios or relative risks (both hereafter referred to as relative risk) compared with never smokers or age specific incidence in relation to risk of coronary heart disease or stroke. Data extraction/synthesis MOOSE guidelines were followed. For each study, the relative risk was estimated for smoking one, five, or 20 cigarettes per day by using regression modelling between risk and cigarette consumption. Relative risks were adjusted for at least age and often additional confounders. The main measure was the excess relative risk for smoking one cigarette per day (RR1_per_day−1) expressed as a proportion of that for smoking 20 cigarettes per day (RR20_per_day−1), expected to be about 5% assuming a linear relation between risk and consumption (as seen with lung cancer). The relative risks for one, five, and 20 cigarettes per day were also pooled across all studies in a random effects meta-analysis. Separate analyses were done for each combination of sex and disorder. Results The meta-analysis included 55 publications containing 141 cohort studies. Among men, the pooled relative risk for coronary heart disease was 1.48 for smoking one cigarette per day and 2.04 for 20 cigarettes per day, using all studies, but 1.74 and 2.27 among studies in which the relative risk had been adjusted for multiple confounders. Among women, the pooled relative risks were 1.57 and 2.84 for one and 20 cigarettes per day (or 2.19 and 3.95 using relative risks adjusted for multiple factors). Men who smoked one cigarette per day had 46% of the excess relative risk for smoking 20 cigarettes per day (53% using relative risks adjusted for multiple factors), and women had 31% of the excess risk (38% using relative risks adjusted for multiple factors). For stroke, the pooled relative risks for men were 1.25 and 1.64 for smoking one or 20 cigarettes per day (1.30 and 1.56 using relative risks adjusted for multiple factors). In women, the pooled relative risks were 1.31 and 2.16 for smoking one or 20 cigarettes per day (1.46 and 2.42 using relative risks adjusted for multiple factors). The excess risk for stroke associated with one cigarette per day (in relation to 20 cigarettes per day) was 41% for men and 34% for women (or 64% and 36% using relative risks adjusted for multiple factors). Relative risks were generally higher among women than men. Conclusions Smoking only about one cigarette per day carries a risk of developing coronary heart disease and stroke much greater than expected: around half that for people who smoke 20 per day. No safe level of smoking exists for cardiovascular disease. Smokers should aim to quit instead of cutting down to significantly reduce their risk of these two common major disorders.