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Egger M, Schneider M, Davey SGSpurious precision? Meta-analysis of observational studies. BMJ 316: 140-144
Abstract
In previous articles we have focused on the potentials, principles, and pitfalls of meta-analysis of randomised controlled trials.1 2 3 4 5 Meta-analysis of observational data is, however, also becoming common. In a Medline search we identified 566 articles (excluding those published as letters) published in 1995 and indexed with the medical subject heading (MeSH) term “meta-analysis.” We randomly selected 100 of these articles and examined them further. Sixty articles reported on actual meta-analyses, and 40 were methodological papers, editorials, and traditional reviews (1). Among the meta-analyses, about half were based on observational studies, mainly cohort and case-control studies of medical interventions or aetiological associations.
View this table:
Characteristics of 100 articles randomly selected from articles published in 1995 and indexed in Medline with keyword “meta-analysis”
The randomised controlled trial is the principal research design in the evaluation of medical interventions. However, aetiological hypotheses—for example, those relating common exposures to the occurrence of disease—cannot generally be tested in randomised experiments. Does breathing other people's tobacco smoke cause lung cancer, drinking coffee cause coronary heart disease, and eating a diet rich in saturated fat cause breast cancer? Studies of such “menaces of daily life”6 use observational designs or examine the presumed biological mechanisms in the laboratory. In these situations the risks involved are generally small, but once a large proportion of the population is exposed, the potential public health implications of these associations—if they are causal—can be striking.
Analyses of observational data also have a role in medical effectiveness research.7 The evidence available from clinical trials will rarely answer all the important questions. Most trials are conducted to establish efficacy and safety of a single agent in a specific clinical situation. Owing to the limited size of such trials, less common adverse effects of drugs may only be detected in case-control …
... Observational studies provide estimates of association and are influenced by biases and confounding effects, while these aspects are already addressed in RCTs thanks to the inherent advantages of this study type. 8 Hence, combining a variety of study designs may minimize the strength of evidence, as may be the case in the current report by Liu et al. 6 As anesthesiologists, it is crucial to understand whether our anesthesia techniques and management plan can significantly impact the patients' postoperative course. Nonetheless, the type of anesthetic-influencing outcomes such as mortality is only a piece of a larger puzzle, especially in this frail population when postoperative complications and mortality are multifactorial. ...
... Les études observationnelles fournissent des estimations de l'association et sont influencées par les biais et les effets de confusion, alors que ces aspects sont déjà abordés dans les ERC grâce aux avantages inhérents à ce type d'étude. 8 Par conséquent, la combinaison d'une variété de méthodologies d'étude pourrait minimiser la force des données probantes, comme cela pourrait être le cas dans le compte rendu actuel de Liu et coll. 6 En tant qu'anesthésiologistes, il est crucial de comprendre si nos techniques d'anesthésie et notre plan de prise en charge peuvent avoir un impact significatif sur l'évolution postopératoire des personnes que nous traitons. ...
... The limitation of observational studies is their qualitative nature, as the results could be influenced by bias and confounding variables. Nevertheless, their use in meta-analyses is allowed on condition that the sources of heterogeneity are carefully evaluated and study quality is assessed [18]. Eligible studies included patients aged 13+ years, irrespective of sex, with histologically confirmed differentiated thyroid carcinoma (papillary, follicular, Hürthle-cell carcinoma) and treated with total/ near-total thyroidectomy followed by remnant ablation with adjuvant RAI therapy of any dose. ...
... Well-designed and large-sized RCTs rank top in study quality because of the high internal validity, while observational studies, in contrast, are more qualitative and exposed to higher risk of bias. Nevertheless, their use in meta-analyses is allowed on condition that the sources of heterogeneity are carefully evaluated and study quality is assessed [18]. One of the aims of systematic reviews is to investigate the generalizability of the results reported by primary studies to the general population. ...
Adjuvant radioactive iodine (RAI) is administered to thyroid cancer patients following thyroidectomy for
remnant tissue ablation and metastatic disease management. Patients are prepared with thyroid hormone
withdrawal (THW) or recombinant human thyroid stimulating hormone (rhTSH). Long-term salivary gland
dysfunction (LT-SGD) is a common, dosage-dependent, RAI adverse effect. Although rhTSH preparation seems to
reduce LT-SGD, this effect could be due to lower RAI activity generally used in rhTSH-prepared patients.
Therefore, this meta-analysis investigated the effect of preparation type on LT-SGD development. Literature
search (PubMed, Medline, EmBase, Cochrane, Web of Science, LILACS, Google Scholar) was performed four
times (January-November 2022) and studies reporting LT-SGD incidence ≥1 year after RAI in patients prepared
with rhTSH/THW were identified. The LT-SGD risk ratio (RR) was estimated with various models considered for
sensitivity analysis (fixed-effect, random-effects, study-quality adjusted, publication-bias adjusted, individualpatient-
data meta-analysis adjusted for RAI). Subgroup analysis according to RAI activity (<3.7/≥3.7 GBq)
also was performed. Literature search resulted in five studies (321 rhTSH, 632 THW patients). The pooled RRs
according to various models were 0.65 (95% confidence interval –95CI, 0.49–0.86; fixed-effect); 0.62 (95CI,
0.38–1.02; random-effects); 0.72 (95CI, 0.54–0.96; quality adjusted); 0.76 (95CI, 0.58–0.99; publication-bias
adjusted); 0.0.80 (95CI, 0.55–1.14; individual-patient-data meta-analysis). The pooled RRs stratified for RAI
activity were 0.26 (95CI, 0.05–1.30) for <3.7 GBq; 0.75 (95CI, 0.57–0.98) for ≥3.7 GBq. The number of patients
needed to be prepared with rhTSH to prevent one case of LT-SGD ranged between seven and thirty-seven. There
is moderate-quality scientific evidence that rhTSH preparation may consistently protect salivary gland function
... To the authors' knowledge, our data targeted an evidence gap [47,48] and reported the only level I evidence comparing modern (locked) FNF and ORIF. Prior review of randomized and nonrandomized comparative evidence found no difference in mean OMAS for intramedullary fixation (72) and plate fixation (71). Notably, the authors pooled both observational and experimental data and locked and unlocked fibular nailing data [49]. ...
... There are several strengths to this report. First, the current report was the first conducted within a systematic framework to minimize bias and explicitly address the evidence methodologic quality [71][72][73]. Subsequently, our findings complete an evidence gap identified in previous reviews without the negative ramifications imposed by nonrandomized data and limited statistical power of single RCT [48,49]. Meta analyses benefits from increased statistical power to ensure definitive answers, particularly important considering that RCTs in orthopaedic surgery are underpowered [74][75][76][77]. ...
Background
What level I evidence exists to support the use of FNF for surgical management of ankle fractures in high risk patients? The purpose of this study was to compare clinical outcomes following fibular intramedullary nail fixation (FNF) and open reduction and internal fixation (ORIF) of ankle fractures.
Methods
A systematic review of the current literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Certainty of evidence reported according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Our primary hypothesis was that patients undergoing FNF procedures to manage an ankle fracture would have significantly higher patient reported outcome scores (PROs) than patients undergoing ORIF. Primary study outcome measures were validated PROs. Secondary outcome measures included complication rate, secondary surgery rate, and bony union.
Results
The primary outcome analysis revealed no evidence of a significant effect difference on Olerud and Molander Ankle Score (OMAS) PRO and no evidence of statistical heterogeneity. Secondary outcome analysis revealed a significant 0.30 (0.12–0.74 95CI) relative risk reduction for complications in FNF (P = 0.008). No evidence of an effect difference for bony union. The GRADE certainty of the evidence was rated as low for bone union. No evidence of reporting bias was appreciated. Sensitivity analyses did not significantly alter effect estimates.
Conclusion
This systematic review and meta-analysis restricted to evidence derived from RCTs revealed that the quality of evidence is reasonably strong and likely sufficient to conclude: (1) there is likely no clinically important difference between FNF and ORIF up to 12 months post-operatively, as defined by OMS (moderate certainty); (2) surgeons may reasonably expect reduced complications in 14 out of every 100 patients treated with FNF (moderate certainty); (3) there is likely no difference in bony union (low certainty). Future studies should investigate more patient-centered outcomes and if short-term findings are durable over time if these findings apply to lower risk populations.
Level of Evidence
Systematic review and meta-analysis of level I evidence
... Sources of heterogeneity can include differences in study design or in demographic characteristics. We performed meta-regression and subgroup analyses [44] to explore the sources of heterogeneity expected in meta-analyses of observational studies [45]. We conducted a sensitivity analysis to determine the influence of each individual study on the overall 4 of 14 result by omitting studies one by one. ...
... Sources of heterogeneity can include differences in study design or in demographic characteristics. We performed meta-regression and subgroup analyses [44] to explore the sources of heterogeneity expected in meta-analyses of observational studies [45]. We conducted a sensitivity analysis to determine the influence of each individual study on the overall result by omitting studies one by one. ...
Background:
Since the onset of the COVID-19 pandemic, the psychological state of university students has been a cause for concern. In particular, odontology students have experienced symptoms of anxiety due to the closure of universities and the suspension of clinical training.
Methods:
Medline via PubMed was searched for studies on the prevalence of anxiety in dental undergraduates, published from 1 December 2019 to 1 August 2021.
Results:
A total of fifteen studies were included in this review. Our results show a prevalence of anxiety of 35% reported by dental students, which was independent of gender, response rate or methodological quality. The only significant finding was a lower prevalence of anxiety in studies located in Europe compared to those located in other continents.
Conclusions:
The results suggest dental students are experiencing significant levels of anxiety during this COVID-19 pandemic and that there seem to be differences between students from different regions of the world. Therefore, it is important to help dental students psychologically as the pandemic situation continues.
... To assess publication bias, funnel plots Egger's test were employed. Each dot on the funnel plot represents a distinct study, and an uneven distribution provides evidence of publication bias [39]. The effect sizes of the studies were plotted against their standard errors, and the funnel plots were evaluated, which indicated publication bias for the prevalence of MEs as the plot appeared to be asymmetric. ...
Background
Nurses may make medication errors during the implementation of therapeutic interventions, which initially threaten the patient’s health and safety and prolong their hospital stay. These errors have always been a challenge for healthcare systems. Given that factors such as the timing, type, and causes of medication errors can serve as suitable predictors for their occurrence, we have decided to conduct a review study aiming to investigate the prevalence of medication errors and the associated factors among Iranian nurses.
Methods
In this systematic review and meta-analysis, studies were searched on PubMed, Web of Science, Scopus, Google Scholar, IranMedex, Magiran, and SID databases using a combination of keywords and Boolean functions. The study that reported the prevalence of medication errors among nurses in Iran without time limitation up to May 2023 was included in this study.
Results
A total of 36 studies were included in the analysis. The analysis indicates that 54% (95% CI: 43, 65; I2 = 99.3%) of Iranian nurses experienced medication errors. The most common types of medication errors by nurses were wrong timing 27.3% (95% CI: 19, 36; I2 = 95.8%), and wrong dosage 26.4% (95% CI: 20, 33; I2 = 91%). Additionally, the main causes of medication errors among nurses were workload 43%, fatigue 42.7%, and nursing shortage 38.8%. In this study, just 39% (95% CI: 27, 50; I2 = 97.1%) of nurses with medication errors did report their errors. Moreover, the prevalence of medication errors was more in the night shift at 41.1%. The results of the meta-regression showed that publication year and the female-to-male ratio are good predictors of medical errors, but they are not statistically significant(p > 0.05).
Conclusions
To reduce medication errors, nurses need to work in a calm environment that allows for proper nursing interventions and prevents overcrowding in departments. Additionally, considering the low reporting of medication errors to managers, support should be provided to nurses who report medication errors, in order to promote a culture of reporting these errors among Iranian nurses and ensure patient safety is not compromised.
... To assess publication bias, we employed funnel plots, and Begg and Egger's tests. Each dot on the funnel plot represents a distinct study, and an uneven distribution provides evidence of publication bias [24,25]. We plotted the study effect sizes against their standard errors and evaluated the ensuing funnel plots, which indicated publication bias for the prevalence of NSIs due to asymmetry (Figure 5). ...
Background Healthcare workers (HCWs) are at risk of acquiring blood-borne
infections such as hepatitis B, hepatitis C, and human immunodeficiency virus
through needlestick injuries (NSIs). We aimed to investigate the prevalence of
needlestick injuries and other related indicators among HCWs in Iran through
a systematic review and meta-analysis.
Methods We searched various databases until the end of May 2023 for studies
reporting the prevalence of NSIs among healthcare workers in Iran. We used a
random model with 95% confidence intervals (CIs) to analyse the data and the
Joanna Briggs Institute (JBI) tool to evaluate the quality of included studies. We
conducted and reported the study according to the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Results We included 87 studies in the analysis and found that 47% (95%
CI=42-52, I2=98.9%) of Iranian HCWs experienced NSI. NSIs were most fre-
quently related to syringe needles (58%; 95% CI=52-65, I2=96.8%) and most
often caused by recapping (30%; 95% CI=22-38, I2=98.5%). In this study,
56% (95% CI=45-67, I2=98.6%) of HCWs with NSIs did not report their in-
jury. Moreover, the prevalence of NSIs the highest in the morning shift (0.44;
95% CI=0.36-0.53, I2=97.2%), emergency unit (0.20; 95% CI=0.16-0.24,
I2=93.7%), and intensive care unit (0.20; 95% CI=0.16-0.24, I2=94.3%).
Conclusions To reduce the high prevalence of NSIs, HCWs, especially those
in emergency departments, should use safety equipment. Healthcare managers
should provide a calm and stress-free environment for HCWs, educate them
on safety principles and standards, and support experienced HCWs with NSIs.
... Systematic reviews are the gold standard method of synthesizing and summarizing all relevant primary publications in an unbiased manner, and with high evidence; facilitating decision-making and developing guidelines for patient care [33,34]. Recent advances in systematic review methods have made it possible to combine quantitative and qualitative methods, approaches, and concepts [35][36][37][38][39][40]. Through this powerful study design, we aimed here to clarify the anticancer effects of YM155 in clinical trials and thereby facilitate clinical decision-making for the treatment of cancer patients. ...
Most cancer cells overexpress the anti-apoptotic protein survivin and display redox dysregulation originating from genotypic and phenotypic alterations. These disturbances contribute to the uncontrolled proliferation, invasion , and chemoresistance of cancer cells, yet they also represent a specific vulnerability that could be exploited therapeutically in selected tumors. YM155 (sepantronium bromide) is a naphthoquinone-containing imidazole-based compound that selectively inhibits survivin expression at the transcriptional and post-transcriptional levels. Here, we performed a systematic review and meta-analysis of clinical studies in which YM155 was administered as monotherapy or combination therapy for patients with cancer. We assessed fully or partially reported clinical outcomes and pharmacological parameters, and further performed subgroup analysis based on tumor type and treatment regimen. Our comprehensive analysis, which included patients of many ethnicities, demonstrated that YM155 was effective as a monotherapy or combination therapy. Clinical benefits, including regression and/or stabilization of tumor progression and prolonged survival, were observed within a reasonable time after treatment initiation, and YM155 displayed good synergistic effects with combination drugs. YM155 appears to be effective against a wide range of tumor types and has an acceptable safety profile, with the main toxicities being decreased blood cell counts; fatigue/weakness; renal, hepatic, and/or cardiac issues; and electrolyte disturbance. KEYWORDS YM155 (sepantronium bromide); systematic review; safety; anticancer effect; meta-synthesis; Naphthoquinone This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
... Sources of heterogeneity include differences in study design or demographic characteristics. The researchers performed meta-regression and subgroup analyses [54] to explore the sources of heterogeneity expected in the metaanalyses of observational studies [55]. We also conducted a sensitivity analysis to determine the influence of each individual study on the overall result by omitting studies one by one. ...
Background: Since the World Health Organization (WHO) declared the COVID-19 pandemic in March 2020, many measures have been taken to prevent the spread of the virus. Consequently, many minors have been confined to their homes and have had to subsequently adapt to countless protocol changes. These factors appear to have contributed to post-traumatic stress disorder (PTSD) in many children. Materials and Methods: The authors searched Medline through PubMed and other databases for studies published from 1 December 2019 to 31 December 2021 on the prevalence of PTSD in schoolchildren. The authors used a random-effects model to calculate the pooled prevalence of PTSD. Results: A total of six studies were included in this review. Our results show a pooled prevalence of PTSD of 14% in children and adolescents. Subgroup analyses identify a significantly higher prevalence of PTSD for studies conducted in China and a higher prevalence in boys. The prevalence of PTSD appeared independent of child age or the methodological rigor of the study. Conclusions: Our results suggest that a large number of children may be suffering from PTSD (post-traumatic stress disorder). Public health measures are thus needed to improve children’s mental health during and after the pandemic, so that the suffering is mitigated to prevent long-lasting effects.
... Again, our premise stands in the way of achieving this, since we assume that time pressure will not permit the running of large trials due to a combination of: lack of volunteers, lack of drug doses, lack of time to prepare clinical trials, and low chances of patients coming in contact with the pathogen. Furthermore, a large sample size only provides us with a reason to believe that the measured effect size is not due to random noise (precision) but no guarantee that the measured effect size is accurate: precision is no guarantee for accuracy [61]. ...
Public heath emergencies such as the outbreak of novel infectious diseases represent a major challenge for drug regulatory bodies, practitioners, and scientific communities. In such critical situations drug regulators and public health practitioners base their decisions on evidence generated and synthesised by scientists. The urgency and novelty of the situation create high levels of uncertainty concerning the safety and effectiveness of drugs. One key tool to mitigate such emergencies is pandemic preparedness. There seems to be, however, a lack of scholarly work on methodology for assessments of new or existing drugs during a pandemic. Issues related to risk attitudes, evidence production and evidence synthesis for drug approval require closer attention. This manuscript, therefore, engages in a conceptual analysis of relevant issues of drug assessment during a pandemic. To this end, we rely in our analysis on recent discussions in the philosophy of science and the philosophy of medicine. Important unanswered foundational questions are identified and possible ways to answer them are considered. Similar problems often have similar solutions, hence studying similar situations can provide important clues. We consider drug assessments of orphan drugs and drug assessments during endemics as similar to drug assessment during a pandemic. Furthermore, other scientific fields which cannot carry out controlled experiments may guide the methodology to draw defeasible causal inferences from imperfect data. Future contributions on methodologies for addressing the issues raised here will indeed have great potential to improve pandemic preparedness.
... Meta-analysis results of observational studies, if conducted following the principles of systematic reviews and guidelines, including reproducible and objective data extraction, are important pieces of evidence, both for comparison with results of different settings and for hypothesis generation [23]. Some years ago, Stroup et al. [24] published reporting guidelines for meta-analysis of observational studies. ...
Background: Random-effects meta-analysis models account for between-study heterogeneity by estimating and incorporating the heterogeneity variance parameter tau2. Numerous estimators for tau2 have been proposed, but no widely accepted guidance exists on when to best use which meta-analysis method. Especially in the context of observational studies, systematic evaluations and comparisons of the various meta-analysis methods are lacking. Since between-study heterogeneity is of crucial importance, particularly in meta-analysis of observational studies, where control groups typically do not exist, considerable attention should be paid to its estimation. This study aims to investigate the advantages of different meta-analysis methods for typical situations through comprehensive simulations in a neutral comparison study and with an empirical application.
Methods: We compared seven methods for random-effects meta-analysis. The methods were selected with a focus on methodological diversity and availability and were evaluated both empirically and in a simulation study. We simulated typical meta-analysis scenarios for continuous and binary outcomes in a single-group meta-analysis setting.
Results: Specific study characteristics, such as the number of studies included in a meta-analysis, the amount of heterogeneity in the data and binary outcome data with rare events, strongly affected the performance of the heterogeneity variance estimator. Moreover, we discovered that most heterogeneity variance estimators produce zero heterogeneity estimates under all simulated conditions, even though heterogeneity was present. The estimated overall effect was found to be relatively robust regarding different methods in the empirical application and in our simulation study.
Conclusions: Although different meta-analysis methods produce substantially different heterogeneity variance estimates, too little attention is paid to selecting a suitable meta-analysis method in research applications. Based on our literature review, we conclude that the awareness about different heterogeneity variance estimators and their properties needs to be strengthened in practice. Our simulation study showed that all evaluated heterogeneity estimators were imprecise and often failed to estimate the true amount of heterogeneity. The estimation is particularly imprecise in situations where the meta-analysis contained few studies or when the binary outcomes included rare events. As it is rarely appropriate to rely on a single heterogeneity variance estimator, therefore we suggest careful consideration and evaluation of a wider range of plausible estimators in a sensitivity analysis before drawing a final conclusion about the meta-analysis results.
... A meta-analysis of results from observational studies indicated a benefit for vitamin A whereas a meta-analysis of RCTs suggested an increase in the risk of mortality. 40 However, a comparison analysis suggested that well-designed observational studies do not overestimate treatment effects in comparison with RCTs. 41 Hence, there are contrasting suggestions regarding the reliability of observational studies and their results should be validated in RCTs. ...
In regulatory evaluations, high-quality randomized controlled trials (RCTs) are considered the gold standard for assessing the efficacy of medical interventions. However, during the COVID-19 pandemic, the urgent need for treatment options led to regulatory approvals being made based on evidence from non-randomized, observational studies. In this study we contrast results from observational studies and RCTs of six drugs to treat COVID-19 infection. Across a range of studies evaluating hydroxychloroquine, remdesivir, ivermectin, aspirin, molnupiravir and tenofovir for COVID-19, there was statistically significant evidence of benefit from non-randomized observational studies, which was then not seen in RCTs. We propose that all observational studies need to be labelled as 'non-randomized' in the title. This should indicate that they are not as reliable for evaluating the efficacy of a drug and should not be used independently for regulatory approval decisions.
... Second, all included studies were observational studies, and the results of meta-analysis (62). However, sensitivity analyses indicated that our overall results were robust. ...
Objective
Rheumatoid arthritis (RA) is an autoimmune disorder. Multiple studies have investigated the risk of thyroid dysfunction in patients with RA but have reached conflicting conclusions. This systematic review aimed to determine whether patients with RA are at higher risk of thyroid dysfunction.
Methods
We comprehensively reviewed online literature databases, including PubMed, Scopus, Embase, and the Cochrane Library, from their respective inception dates to March 25, 2022. Studies that provided data on at least one case of thyroid dysfunction in RA patients and their controls were included. Based on these data, we calculated pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for thyroid dysfunction in RA and non-RA patients.
Results
Twenty-nine studies met the inclusion criteria, involving a total of 35,708 patients with RA. The meta-analysis showed that, compared with non-RA patients, RA patients had an increased risk of developing thyroid dysfunction, particularly hypothyroidism (OR 2.25, 95% CI 1.78–2.84). Subgroup analysis suggested that study type and sample source of control group were the source of heterogeneity.
Conclusions
Patients with RA are at increased risk of developing thyroid dysfunction, especially hypothyroidism. Routine biochemical examination of thyroid function in RA patients should be strengthened. Larger prospective studies are needed to explore the causal relationship between RA and thyroid dysfunction, and to investigate the impact of thyroid dysfunction on RA disease activity, drug efficacy, and medication safety.
Systematic review registration
https://www.crd.york.ac.uk/prospero/ , identifier CRD42022331142.
... First, blinding the therapeutic intervention would not be possible. Second, there is no satisfactory control group to compare to patients treated with salvage TIPS.Third, it is likely that patients who could be enrolled in a randomized trial would differ from the average patients seen in daily practice.Hence, the results of observational studies appear to be more relevant to clinical practice.52 Currently, self-expanding metal stents are the only alternative as an emergency treatment for refractoryF I G U R E 4 Occurrence of hepatic encephalopathy: Pooled estimate rate for hepatic encephalopathy after transjugular intrahepatic portosystemic shunt (TIPS) insertion in patients with cirrhosis and refractory variceal bleeding. ...
Background:
Transjugular intrahepatic portosystemic shunt (TIPS) may be used as a salvage treatment in patients with cirrhosis and refractory variceal bleeding.
Aim:
To synthesize the available evidence on the efficacy of TIPS in patients with cirrhosis and refractory variceal bleeding.
Methods:
Meta-analysis of trials evaluating TIPS in patients with cirrhosis and refractory variceal bleeding, including subgroup analysis to assess the impact of recent changes in the management of variceal bleeding (i.e., the use of Polytetrafluoroethylene-covered TIPS and the availability of pre-emptive TIPS as a first-line treatment for acute variceal bleeding).
Results:
Twenty-three studies with 1430 patients were included. The pooled estimate rates were 0.33 (95% CI = 0.29-0.37) for death at 1 month-6 weeks, 0.46 (95% CI = 0.40-0.52) for death at 1 year, and 0.09 (95% CI = 0.06-0.11) for death due to rebleeding in the follow-up. The pooled estimate rates for death at 1 month or 6 weeks were similar in subgroup analyses including studies that did not use covered TIPS or that did not include patients after the pre-emptive TIPS area compared to the ones that did (pooled estimate rate 0.33 [95% CI = 0.28-0.38] and 0.32 [95% CI = 0.25-0.39], respectively). The pooled estimate rates were 0.16 (95% CI = 0.13-0.18) for rebleeding, 0.25 (95% CI = 0.17-0.36) for occurrence of hepatic encephalopathy, and 0.08 (95% CI = 0.05-0.13) for access to liver transplantation after TIPS insertion.
Conclusions:
One third of patients with cirrhosis and refractory variceal bleeding treated with salvage TIPS died within the first 6 weeks. Recent improvements in the management of variceal bleeding did not improve the survival of patients presenting with refractory variceal bleeding.
... Meta-analysis may offer a way to highlight findings within such heterogeneity, including exposing areas for future research. It also provides a tool for helping to understand the extent of variability [79][80][81]. In the field of spinal procedures, a growing opinion suggests that inclusion of observational studies in meta-analyses might lead to more robust conclusions without compromising the quality of the results [82,83]. ...
Purpose
To assess clinical and safety outcomes associated with different rod materials and diameters in adult spinal deformity (ASD) surgery.
Methods
A systematic literature review and meta-analysis evaluated ASD surgery using pedicle screw fixation systems with rods of different materials and sizes. Postoperative outcomes (i.e., Cobb, sagittal vertical axis, and pelvic tilt angle) and complications (i.e., pseudarthrosis and rod breakage) were assessed. Random effects models (REMs) pooled data for outcomes reported in ≥ 2 studies.
Results
Among 50 studies evaluating ASD surgery using pedicle screw fixation systems, 17 described rod material/diameter. Postoperative outcomes did not statistically differ between cobalt–chromium (CoCr) vs. titanium (Ti) rods ( n = 2 studies; mean [95% confidence interval (CI)] sagittal vertical axis angle: CoCr 37.00° [18.58°–55.42°] and Ti 32.58° [24.62°–40.54°]; mean [95% CI] pelvic tilt angle: CoCr 26.20° [22.87°–29.53°] and Ti 20.15° [18.0°–22.31°]). The pooled proportion (95% CI) of pseudarthrosis was 15% (7–22%) for CoCr and 12% (− 8–32%) for stainless steel (SS) ( n = 2 studies each; Chi ² = 0.07, p = 0.79). The pooled proportion (95% CI) of broken rods was 12% (1–22%) for Ti ( n = 3 studies) and 10% (2–19) for CoCr ( n = 1 study). Among 6.0–6.35 mm rods, the pooled (95% CI) postoperative Cobb angle ( n = 2) was 12.01° (9.75°–14.28°), sagittal vertical axis angle ( n = 4) was 35.32° (30.02°–40.62°), and pelvic tilt angle was 21.11° (18.35°–23.86°).
Conclusions
For ASD patients undergoing posterior fixation and fusion, there are no statistically significant differences in postoperative outcomes or complications among rods of varying materials and diameters. Benchmark postsurgical outcomes and complication rates by rod material and diameter are provided.
Level of Evidence
III
... Sources of heterogeneity can include differences in study design or in demographic characteristics. We performed meta-regression and subgroup analyses [39] to explore the sources of heterogeneity expected in meta-analyses of observational studies [40]. We conducted a sensitivity analysis to determine the influence of each individual study on the overall result by omitting studies one by one. ...
Background: Most universities around the world have been heavily affected by the COVID-19 pandemic, as declared by the World Health Organization (WHO) in March 2020. Many students were isolated at home and underwent a forced transition from face-to-face learning to e-learning, at least in the first few months. The subsequent months and years were typically characterised by a slow return to normal learning under COVID-19 protocols and restrictions. A potential consequence of the lockdowns, social restrictions and changes to learning is the development of PTSD (post-traumatic stress disorder) in university students, affecting their health and well-being (SDG3) and quality of education (SDG4). Materials and Methods: Medline was searched through PubMed for studies on the prevalence of PTSD in university students from 1 December 2019 to 31 December 2021. The pooled prevalence of PTSD was calculated with random-effects models. Results: A total of six studies were included, across which the prevalence of PTSD among university students was 23%. Meta-regression showed that the prevalence of PTSD was significantly higher with older age, but independent of the percentage of women in a study or its methodological quality. Conclusions: Our results suggest that students suffer from PTSD at a moderate rate. Measures are needed to address the mental health issues of university students that have arisen during COVID-19 all around the world.
... Systematic reviews are the gold standard method of synthesizing and summarizing all relevant primary publications in an unbiased manner, and with high evidence; facilitating decision-making and developing guidelines for patient care [33,34]. Recent advances in systematic review methods have made it possible to combine quantitative and qualitative methods, approaches, and concepts [35][36][37][38][39][40]. Through this powerful study design, we aimed here to clarify the anticancer effects of YM155 in clinical trials and thereby facilitate clinical decision-making for the treatment of cancer patients. ...
... First, apart from the meta-analysis by Bye et al., all the other reviews included mainly non-randomized studies. Moreover, the many concerns about the conduct and reporting of systematic reviews of nonrandomized studies are well known (18,24). Furthermore, our review clearly shows the strong heterogeneity in SP definition. ...
Background
Sarcopenia (SP) is defined as the quantitative and functional impairment of skeletal muscles. SP is commonly related to older age and is frequent in patients with cancer. To provide an overview of SP in patients treated with radiotherapy (RT) and to evaluate the current evidence, we analyzed the available systematic reviews and meta-analyses.
Methods
Reviews were identified using PubMed, Scopus, and Cochrane library databases, without date restriction. Only systematic reviews and meta-analyses on the prognostic impact of SP and on any treatments aimed at reducing SP effect, in patients undergoing RT, were included in this review. The analyses not separately reporting the results in patients treated with RT were excluded. The quality assessment was performed using AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews).
Results
From the 84 papers identified, five reviews met the inclusion criteria with four reports mainly including non-randomized trials. Three reviews on the effect of SP showed a significantly negative impact on overall survival in patients undergoing RT and/or chemoradiation for H&N cancers (HR: 1.63-2.07). Two reviews on interventional studies showed the possibility of 1) improving physical functions through nutritional and physical interventions and 2) avoiding muscle wasting by means of sufficient protein intake. The quality assessment of the included review showed that two and three analyses are classifiable as having low and moderate overall confidence rating, respectively.
Conclusions
The analyzed reviews uniformly confirmed the negative impact of SP in patients with H&N tumors undergoing RT and the possibility of improving muscle mass and function through nutritional and physical interventions. These results justify further research on this topic based on a more uniform SP definition and on a complete evaluation of the potentially confounding parameters.
... since observational and small studies show more heterogeneity than other designs, and heterogeneity interferes with the detection of publication bias (Delgado-Rodríguez, 2006;Egger et al., 1998). Future worldwide studies with longitudinal designs, representative samples, and disaggregated data reported according to uniform WAI criteria for different categories of work ability are needed to facilitate a comparison of prevalence rates within and between studies. ...
Purpose:
To estimate the worldwide pooled prevalence of inadequate work ability among hospital nursing personnel using the Work Ability Index (WAI).
Design:
Systematic review and meta-analysis.
Methods:
A systematic search was conducted on Medline/PubMed, Scopus, Web of Science, Scielo, PsychInfo, CINAHL, Nursing and Allied Health, LILACS, and Google Scholar from inception to July 2021 to identify observational studies on work ability among hospital nursing personnel using the WAI. Two researchers independently completed the study selection, quality assessments, and data extraction on the prevalence of inadequate work ability that was pooled using the random effects model. Finally, subgroup analyses were performed to explore sources of heterogeneity.
Findings:
A total of 42 studies were included, consisting of 24,728 subjects worldwide from 14 countries. Of these, 35 studies were included in the meta-analytical analyses. The worldwide pooled prevalence of inadequate work ability among hospital nursing personnel was 24.7% (95% CI = 20.2%-29.4%). High levels of heterogeneity were detected in all studies. Prevalence was higher in studies where samples were composed of nurses and nursing assistive personnel (26.8%; 95% CI = 22.4%-31.5%) than in those of nurses alone (22.2%; 95% CI = 13.1%-32.9%) and in studies where the sample was over 40 (28.1%; 95% CI = 19.5%-37.5%) than in those with a sample under that age (22.4%; 95% CI = 15.8%-29.7%).
Conclusions:
Almost one in four members of hospital nursing staff in the world has inadequate work ability and therefore are at risk of several negative outcomes during their working life. These prevalence data correspond to the pre-pandemic period, so new studies should also be especially useful in quantifying the impact of the COVID-19 pandemic on work ability in the hospital nursing workforce.
Clinical relevance:
The above findings justify the launch of initiatives that include annual assessment for the early identification of inadequate work ability, offering the possibility of anticipated corrective measures. Nursing workforce older than 40 years and those belonging to the professional category of nursing assistive personnel should be priority target groups for screening and intervention to improve work ability.
... Sources of heterogeneity can include differences in study design or in demographic characteristics. We performed meta-regression and subgroup analyses [42] to explore the sources of heterogeneity expected in metaanalyses of observational studies [43]. We conducted a sensitivity analysis to determine the influence of each individual study on the overall result by omitting studies one by one. ...
Background and Objectives: The COVID-19 pandemic has a negative impact on the mental health of the population in general, and in college students in particular. Dental students have seen their teaching altered and their clinical practice reduced. This study was aimed at conducting a systematic review and meta-analysis of studies reporting levels of depression among dental students during the COVID-19 and estimating the pooled prevalence of depression. Materials and Methods: Medline via PubMed and other databases were searched for studies on the prevalence of depression in dental undergraduates, published from 1 December 2019 to 1 September 2021. The pooled proportions of depression were calculated with random effects models. Results: We identified 13 studies from 9 countries. The pooled prevalence of depression in dental students was 37% (95% CI: 26–49%) with no variation due to gender, response rate or methodological quality. We only found a significantly higher prevalence of depression in studies from Asia compared to Europe and America. Conclusions: Our results suggest that dental students are suffering from higher levels of depression compared with the general population or other college students during the COVID-19 pandemic, with differences across regions. Measures to improve mental health and wellbeing of dental students during the pandemic are needed.
... Sources of heterogeneity can include differences in study design or in demographic characteristics. We performed subgroup analyses to explore the sources of heterogeneity expected in meta-analyses of observational studies [51]. Meta-regression was not performed, due to lack of statistical power with less than 10 studies included in a meta-analysis [52]. ...
Background:
Since the beginning of the COVID-19 pandemic, teachers have been accumulating adverse psychological symptoms due to the closure of educational centers and the need to adapt to different teaching modalities.
Methods:
Medline and PubMed were searched for studies on the prevalence of depression, anxiety, stress, and burn-out in teachers, published from 1 December 2019 to 15 June 2021.
Results:
In total, eight studies were included in this study. The results show that teachers report levels of anxiety (17%), depression (19%), and stress (30%). In Asia, there has been more anxiety compared to other continents. Overall, anxiety has been higher among teachers in schools compared to universities. However, stress levels have been higher among teachers in universities compared to schools. Statistically, there were no significant differences regarding gender and age in any of the symptoms.
Conclusions:
The results suggest that teachers at different educational levels are experiencing adverse psychological symptomatology during the COVID-19 pandemic, and that anxiety levels vary between different countries. However, more international studies are needed to fully understand the impact of the pandemic on teachers' mental health.
... A limitation is that we did not assess publication bias. However, formal assessment of publication bias using funnel plots would have been inappropriate as both meta-analyses conducted contained less than 10 studies each and involved observational studies [100,101]. ...
Lower screening uptake could impact cancer survival in rural areas. This systematic review sought studies comparing rural/urban uptake of colorectal, cervical and breast cancer screening in high income countries. Relevant studies (n = 50) were identified systematically by searching Medline, EMBASE and CINAHL. Narrative synthesis found that screening uptake for all three cancers was generally lower in rural areas. In meta-analysis, colorectal cancer screening uptake (OR 0.66, 95 % CI = 0.50−0.87, I² = 85 %) was significantly lower for rural dwellers than their urban counterparts. The meta-analysis found no relationship between uptake of breast cancer screening and rural versus urban residency (OR 0.93, 95 % CI = 0.80–1.09, I² = 86 %). However, it is important to note the limitation of the significant statistical heterogeneity found which demonstrates the lack of consistency between the few studies eligible for inclusion in the meta-analyses. Cancer screening uptake is apparently lower for rural dwellers which may contribute to poorer survival. National screening programmes should consider geography in planning.
... Different study designs or demographic characteristics may explain the heterogeneity. Thus, we calculated meta-regression and carried out subgroup analyses [21] to find potential sources of heterogeneity [22]. A sensitivity analysis was also made by omitting studies one by one. ...
Background:
There is evidence of a high psychological toll from the COVID-19 pandemic in healthcare workers. This paper was aimed at conducting a systematic review and meta-analysis of studies reporting levels of depression among healthcare workers during the COVID-19 and estimating the pooled prevalence of depression.
Methods:
We searched for cross-sectional studies listed on PubMed from 1 December 2019 to 15 September 2020 that reported prevalence of depression in healthcare workers, nurses, medical doctors, and COVID-19 frontline professionals. The pooled proportions of depression were calculated with random effects models.
Results:
We identified 57 studies from seventeen countries. The pooled prevalence of depression in healthcare workers was 24% (95% CI: 20-28%), 25% for nurses (95% CI: 18-33%), 24% for medical doctors (95% CI: 16-31%), and 43% for frontline professionals (95% CI: 28-59%).
Conclusions:
The proportion of depression in nurses and medical doctors during the COVID-19 pandemic was similar to that found in the general population as previously reported in other meta-analyses conducted with smaller numbers of studies. Importantly, almost half of the frontline healthcare workers showed increased levels of depression. There is need for a comprehensive, international response to prevent and treat common mental health problems in healthcare workers.
Objective
To determine the health benefits and harms of various ingredients in Christmas desserts from The Great British Bake Off.
Design
Umbrella review of umbrella reviews of meta-analyses of observational studies.
Data sources
The Great British Bake Off website, Embase, Medline, and Scopus.
Inclusion criteria
Umbrella reviews of meta-analyses of observational studies evaluating the associations between Christmas dessert ingredients and the risk of death or disease.
Main outcome measures
Proportion of protective and harmful summary associations between ingredient groups from The Great British Bake Off Christmas dessert recipes and the risk of death or disease.
Results
48 recipes for Christmas desserts (ie, cakes, biscuits, pastries, and puddings and desserts) were provided on The Great British Bake Off website with 178 unique ingredients that were collapsed into 17 overarching ingredient groups. A literature search identified 7008 titles and abstracts, of which 46 eligible umbrella reviews reported 363 unique summary associations between the ingredient groups and risk of death or disease. Of these summary associations, 149 (41%) were significant, including 110 (74%) that estimated that the ingredient groups reduced the risk of death or disease and 39 (26%) that increased the risk. The most common ingredient groups associated with a reduced risk of death or disease were fruit (44/110, 40%), coffee (17/110, 16%), and nuts (14/110, 13%), whereas alcohol (20/39, 51%) and sugar (5/39, 13%) were the most common ingredient groups associated with increased risk of death or disease.
Conclusions
Recipes for Christmas desserts from The Great British Bake Off often use ingredient groups that are associated with reductions, rather than increases, in the risk of death or disease. This Christmas, if concerns about the limitations of observational nutrition research are set aside, you can have your cake and eat it too.
Abstract
Back ground
A disaster is defined by the World Health Organization as a sudden ecological phenomenon of sufficient magnitude to necessitate outside help. Health institutions play an important part in the healthcare system during a disaster by providing critical medical care to their communities. It is critical that health professionals are prepared for catastrophes in order to protect themselves and the community.
Method
Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we systematically reviewed and meta-analyzed articles from PubMed, Google Scholar and other electronics database that investigated levels of health professional knowledge toward disaster preparedness. To assess the pooled national health professional knowledge level, a weighted inverse variance random-effects model was used.
Result
For the analysis, a total of 7 studies with a total of 1579 participants were used. In Ethiopia, the pooled good knowledge levels of health professional toward disaster preparedness was 48.58% (95% CI: 43.43, 53.73), implying that 48.58% of health professionals had good knowledge towards disaster preparedness. Based on the included studies positive predictive factors associated with health professional good knowledge of disaster preparedness include being a nursing professional, past experience in big disaster management, disaster training, and disaster simulation practice.
Conclusion
In conclusion, only 48.58% of health professionals had good understanding of disaster preparedness, while the remaining 51.42% lacked disaster preparedness knowledge. The government, educational institutions, and non-governmental organizations should place a special emphasis on preparing health professionals for disaster management by providing training, sharing experience, and incorporating disaster management training into health professional curricula in their higher education programs.
Limited guidance exists regarding the assessment and management of psychogenic non‐epileptic seizures (PNES) in children. Our aim was to develop consensus‐based recommendations to fill this gap. The members of the International League Against Epilepsy (ILAE) Task Force on Pediatric Psychiatric Issues conducted a scoping review adhering to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for Scoping Reviews (PRISMA‐SR) standards. This was supplemented with a Delphi process sent to pediatric PNES experts. Consensus was defined as ≥80% agreement. The systematic search identified 77 studies, the majority (55%) of which were retrospective (only one randomized clinical trial). The primary means of PNES identification was video electroencephalography (vEEG) in 84% of studies. Better outcome was associated with access to counseling/psychological intervention. Children with PNES have more frequent psychiatric disorders than controls. The Delphi resulted in 22 recommendations: Assessment—There was consensus on the importance of (1) taking a comprehensive developmental history; (2) obtaining a description of the events; (3) asking about potential stressors; (4) the need to use vEEG if available parent, self, and school reports and video recordings can contribute to a “probable” diagnosis; and (5) that invasive provocation techniques or deceit should not be employed. Management—There was consensus about the (1) need for a professional with expertise in epilepsy to remain involved for a period after PNES diagnosis; (2) provision of appropriate educational materials to the child and caregivers; and (3) that the decision on treatment modality for PNES in children should consider the child's age, cognitive ability, and family factors. Comorbidities—There was consensus that all children with PNES should be screened for mental health and neurodevelopmental difficulties. Recommendations to facilitate the assessment and management of PNES in children were developed. Future directions to fill knowledge gaps were proposed.
Software cost and effort estimation is one of the most significant tasks in the area of software engineering. Research conducted in this field has been evolving with new techniques that necessitate periodic comparative analyses. Software project success largely depends on accurate software cost estimation as it gives an idea of the challenges and risks involved in the development. The great diversity of ML and Non-ML techniques has generated a comparison and progressed into the integration of these techniques. Based on varying advantages it has become imperative to work out preferred estimation techniques to improve the project development process. This study aims to present a systematic literature review (SLR) to investigate the trends of the articles published in the recent one and a half decades and to propose a way forward. This systematic literature review has proposed a three-stage approach to plan (Tollgate approach), conduct (Likert type scale), and report the results from five renowned digital libraries. For the selected 52 articles, artificial neural network model (ANN) and constructive cost model (COCOMO) based approaches have been the favored techniques. The mean magnitude of relative error (MMRE) has been the preferred accuracy metric, software engineering, and project management are the most relevant fields, and the promise repository has been identified as the widely accessed database. This review is likely to be of value for the development, cost, and effort estimations.
Introduction
To evaluate the current evidence estimating the association between antidepressant use during pregnancy and stillbirth.
Search Strategy
MEDLINE, EMBASE, and PsychINFO for studies investigating antidepressant use during pregnancy and risk of stillbirth, from inception until 21 January 2022.
Selection Criteria
Studies including pregnant women exposed to antidepressants during pregnancy investigating stillbirth were eligible, compared with either unexposed, indicated pregnant women or unexposed women in the general obstetric population.
Data Collection and Analysis
Data extraction and quality assessment were performed by two authors independently. Meta‐analysis was used to generate pooled‐effect estimates, and the ROBINS‐I tool was used to assess risk of bias for individual studies.
Main Results
Seventeen studies were eligible. Although estimates from meta‐analysis models suggest a small increased risk of stillbirth, summary effect estimate 1.19 (95% confidence interval [CI] 1.06, 1.34) between those individuals taking antidepressants during pregnancy and all other pregnant women, confounding control is likely inadequate. The risk of bias assessment showed most studies were low quality, with no studies scoring low risk; in a meta‐analysis of studies with moderate risk of bias ( n = 2), no association was noted, summary effect estimate 1.17 (95% CI 0.97, 1.41). Only six studies adjusted for confounding by indication, the findings of which were summarised narratively.
Conclusions
Although the overall meta‐analysis found a small association between antidepressant use during pregnancy and stillbirth, this result was likely due to the overall low quality of studies included and by confounding in the underlying studies. Future studies must adequately address potential confounding by indication.
Objective:
To estimate the global prevalence of low resilience among the general population and health professionals during the COVID-19 pandemic.
Methods:
Embase, Ovid-MEDLINE, PubMed, Scopus, Web of Science, CINAHL, WHO COVID-19 databases, and grey literature were searched for studies from January 1, 2020, to August 22, 2022. Hoy's assessment tool was used to assess for risk of bias. Meta-analysis and moderator analysis was performed using the Generalized Linear Mixed Model with a corresponding 95 % confidence interval (95 % CI) adopting the random-effect model in R software. Between-study heterogeneity was measured using I2 and τ2 statistics.
Results:
Overall, 44 studies involving 51,119 participants were identified. The pooled prevalence of low resilience was 27.0 % (95 % CI: 21.0 %-33.0 %) with prevalence among the general population being 35.0 % (95 % CI: 28.0 %-42.0 %) followed by 23.0 % (95 % CI: 16.0 %-30.9 %) for health professionals. The 3-month trend analysis of the prevalence of low resilience beginning January 2020 to June 2021 revealed upward then downward patterns among overall populations. The prevalence of low resilience was higher in females, studied during the delta variant dominant period, frontline health professionals, and undergraduate degree education.
Limitations:
Study outcomes showed high heterogeneity; however, sub-group and meta-regression analyses were conducted to identify potential moderating factors.
Conclusions:
Globally, 1 out of 4 people among the general population and health professionals experienced low resilience due to COVID-19 adversity. The prevalence of low resilience was twice as much among the general population compared to health professionals. These findings provide information for policymakers and clinicians in the development and implementation of resilience-enhancing programs.
Background:
To examine the association between optical coherence tomography angiography (OCTA) retinal measurements and Parkinson's disease (PD).
Methods:
We searched MEDLINE and EMBASE from inception up to November 5th, 2021 for studies examining the differences between OCTA retinal measurements in PD patients and healthy controls. We used the Hartung-Knapp-Sidik-Jonkman random-effects method to combine study-specific standardized mean differences (SMD) in pooled effect estimates and a meta-analytic extension of the E-value metric to quantify the confounding bias capable of nullifying the pooled estimates.
Results:
Nine eligible studies for our systematic review were identified through our search strategy. The pooled SMD between the retinal vessel density of PD patients and healthy participants in the whole superficial vascular plexus (SVP), foveal SVP, parafoveal SVP and foveal avascular zone (FAZ) was -0.68 (95% CI: -1.18 to -0.17, p value = 0.02, n = 7 studies), -0.14 (95% CI: -0.88 to 0.59, p value = 0.62, n = 5 studies), -0.59 (95% CI: -1.41 to 0.23, p value = 0.12, n = 5 studies) and -0.20 (95% CI: -0.79 to 0.38, p value = 0.39, n = 5 studies), respectively. An unmeasured confounder would need to be associated with a 3.01-fold, 1.54-fold, 2.81-fold and 1.70-fold increase in the risk of PD and OCTA retinal measurements, in order for the pooled SMD estimate of vessel density in whole SVP, parafoveal SVP and FAZ, respectively, to be nullified.
Conclusions:
Our results provide evidence on an inverse association between whole SVP vessel density and PD.
Background
Low-density lipoprotein cholesterol (LDL-C) is an established marker for cardiovascular disease (CVD) and a therapeutic target. Oxidized LDL (oxLDL) is known to be associated with excessive inflammation and abnormal lipoprotein metabolism. Chronic inflammatory diseases confer an elevated risk of premature atherosclerosis and adverse cardiovascular events. Whether oxLDL may serve as a potential biomarker for CVD stratification in populations with chronic inflammatory conditions remains understudied.
Objective
To perform a systematic review and meta-analysis evaluating the relationship between oxLDL and CVD (defined by incident CVD events, carotid intima-media thickness, presence of coronary plaque) in patients with chronic inflammatory diseases.
Methods
A systematic literature search was performed using studies published between 2000 and 2022 from PubMed, Cochrane Library, Embase (Elsevier), CINHAL (EBSCOhost), Scopus (Elsevier), and Web of Science: Core Collection (Clarivate Analytics) databases on the relationship between oxLDL and cardiovascular risk on inflamed population. The pooled effect size was combined using the random effect model and publication bias was assessed if P < 0.05 for the Egger or Begg test along with the funnel plot test.
Results
A total of three observational studies with 1,060 participants were ultimately included in the final meta-analysis. The results demonstrated that oxLDL is significantly increased in participants with CVD in the setting of chronic inflammatory conditions. This meta-analysis suggests that oxLDL may be a useful biomarker in risk stratifying cardiovascular disease in chronically inflamed patients.
IntroductionLimited evidence has been reported for surgical site infections (SSIs) in patients undergoing surgery who are carriers of extended-spectrum cephalosporin-resistant Enterobacterales (ESCR-E). A systematic review and meta-analysis were conducted to evaluate the risk of postoperative infections in adult inpatients colonised with ESCR-E before surgery.Methods
The Medline, Embase and Cochrane databases were searched between January 2011 and April 2022, following PRISMA indications. Random effects meta-analysis was used to quantify the association between ESCR-E colonisation and infection.ResultsAmong the 467 articles reviewed, 9 observational studies encompassing 7219 adult patients undergoing surgery were included. The ESCR-E colonisation rate was 13.7% (95% CI 7.7–19.7). The most commonly reported surgeries included abdominal surgery (44%) and liver transplantation (LT; 33%). The SSI rate was 23.2% (95% CI 13.2–33.1). Pooled incidence risk was 0.36 (95% CI 0.22–0.50) vs 0.13 (95% CI 0.02–0.24) for any postoperative infection and 0.28 (95% CI 0.18–0.38) vs 0.17 (95% CI 0.07–0.26) for SSIs in ESCR-E carriers vs noncarriers, respectively. In ESCR-E carriers, the ESCR-E infection ratio was 7 times higher than noncarriers. Postoperative infection risk was higher in carriers versus noncarriers following LT. Sources of detected heterogeneity between studies included ESCR-E colonisation and the geographic region of origin.Conclusions
Patients colonised with ESCR-E before surgery had increased incidence rates of post-surgical infections and SSIs compared to noncarriers. Our results suggest considering the implementation of pre-surgical screening for detecting ESCR-E colonisation status according to the type of surgery and the local epidemiology.
Risk factors for osteoarthritis (OA) often exert effects over protracted time-courses. Mendelian randomization (MR) studies therefore have an advantage over conventional observational studies when studying the causal effect of long-term lifestyle-related risk factors on OA. However, given the heterogeneous design of existing MR studies on OA, the reported causal estimates of these effects remain inconsistent, thus obscuring the true extent of the biological effects of OA lifestyle-risk factors. We conducted a PRISMA systematic review and specifically included MR studies that investigated the causal effect between lifestyle-related risk factors and OA, where causal estimates for various lifestyle factors were pooled for meta-analysis. Quality of studies was assessed according to STROBE-MR guidelines. A total of 1576 studies were evaluated and 23 were included. Overall, the studies included were of high quality and had a low risk of bias. Our meta-analysis demonstrates the positive causal effect of BMI (ORIVW-random effects 1.49 [1.23–1.80]) and negative causal effects of serum calcium (ORIVW-random effects 0.69 [0.57–0.83]) and LDL levels (ORIVW-random effects 0.93 [0.90–0.96]) on OA. Despite the heterogeneous designs and estimates of causal effects provided by various MR studies, our meta-analysis suggests that lifestyle-related risk factors in the form of BMI, serum calcium, and LDL have true biological effects on the development of OA.
Background
The Measurement Tool to Assess systematic Reviews (AMSTAR) 2 is a critical appraisal tool for systematic reviews (SRs) and meta-analyses (MAs) of interventions. We aimed to perform the first AMSTAR 2-based quality assessment of heart failure-related studies.
Methods
Eleven high-impact journals were searched from 2009 to 2019. The included studies were assessed on the basis of 16 domains. Seven domains were deemed critical for high-quality studies. On the basis of the performance in these 16 domains with different weights, overall ratings were generated, and the quality was determined to be “high,” “moderate,” “low,” or “critically low.”
Results
Eighty-one heart failure-related SRs with MAs were included. Overall, 79 studies were of “critically low quality” and two were of “low quality.” These findings were attributed to insufficiency in the following critical domains: a priori protocols (compliance rate, 5%), complete list of exclusions with justification (5%), risk of bias assessment (69%), meta-analysis methodology (78%), and investigation of publication bias (60%).
Conclusions
The low ratings for these potential high-quality heart failure-related SRs and MAs challenge the discrimination capacity of AMSTAR 2. In addition to identifying certain areas of insufficiency, these findings indicate the need to justify or modify AMSTAR 2’s rating rules.
Background
There are several studies on nonunion, but there are no systematic overviews of the current evidence of risk factors for nonunion. The aim of this study was to systematically review risk factors for nonunion following surgically managed, traumatic, diaphyseal fractures.
Methods
Medline, Embase, Scopus, and Cochrane were searched using a search string developed with aid from a scientific librarian. The studies were screened independently by two authors using Covidence. We solely included studies with at least ten nonunions. Eligible study data were extracted, and the studies were critically appraised. We performed random-effects meta-analyses for those risk factors included in five or more studies. PROSPERO registration number: CRD42021235213.
Results
Of 11,738 records screened, 30 were eligible, and these included 38,465 patients. Twenty-five studies were eligible for meta-analyses. Nonunion was associated with smoking (odds ratio (OR): 1.7, 95% CI: 1.2–2.4), open fractures (OR: 2.6, 95% CI: 1.8–3.9), diabetes (OR: 1.6, 95% CI: 1.3–2.0), infection (OR: 7.0, 95% CI: 3.2–15.0), obesity (OR: 1.5, 95% CI: 1.1–1.9), increasing Gustilo classification (OR: 2.2, 95% CI: 1.4–3.7), and AO classification (OR: 2.4, 95% CI: 1.5–3.7). The studies were generally assessed to be of poor quality, mainly because of the possible risk of bias due to confounding, unclear outcome measurements, and missing data.
Conclusion
Establishing compelling evidence is challenging because the current studies are observational and at risk of bias. We conclude that several risk factors are associated with nonunion following surgically managed, traumatic, diaphyseal fractures and should be included as confounders in future studies.
Background:
Rivaroxaban and apixaban are the most widely used nonvitamin K oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE). This meta-analysis evaluates the effectiveness and safety of both NOACs versus standard of care (SoC) in real-world practice.
Methods:
Real-world evidence (RWE) studies were identified through a systematic literature review conducted between January 2012 and July 2020, using Embase, MEDLINE, and the websites of cardiological, hematological, and oncological associations. Eligible RWE studies recruited adult patients with deep vein thrombosis and/or pulmonary embolism and presented a comparison between rivaroxaban and apixaban versus SoC, consisting either of vitamin K antagonists, heparins, or combinations thereof. Hazard ratios (HRs) for the comparison between NOACs and SoC were extracted from the relevant studies or estimated based on the reported binary data. The between-treatment contrasts were reported as HRs with associated 95% confidence intervals.
Results:
A total of 65 RWE studies were identified and considered relevant for the meta-analysis. Compared with SoC, both rivaroxaban and apixaban were associated with reduced risks of recurrent VTE and a lower rate of major bleeding events. Patients treated with rivaroxaban were at a lower risk of all-cause death compared with those receiving SoC (HR = 0.56 [0.39-0.80]), while evidence for apixaban from the identified studies was insufficient to demonstrate a statistically significant change in mortality (HR = 0.66 [0.30-1.47]).
Conclusion:
This analysis indicates that in real-world practice, rivaroxaban and apixaban are associated with a lower risk of recurrent VTE and major bleeding events compared with SoC. Survival benefit in patients treated with rivaroxaban was also observed.
Aim:
To evaluate the efficacy and safety of corticosteroids for treating hospitalized COVID-19 patients.
Materials & methods:
Efficacy outcomes included time to negative SARS-CoV-2 tests, length of stay, duration and incidence of intensive unit care stay, incidence of mortality and duration and incidence of mechanical ventilation. Safety outcomes included the incidence of adverse events and severe adverse events, incidence of hyperglycemia and incidence of nosocomial infections.
Results:
Ninety-five randomized controlled trials (RCTs) and observational studies (n = 42,205) were included. Corticosteroids were associated with increased length of stay (based on RCT only), increased time to negative tests, decreased length of mechanical ventilation and increased odds of hyperglycemia.
Conclusion:
Corticosteroids should be considered in patients requiring mechanical ventilation, and glycemic monitoring may be needed when administering corticosteroids.
Systematic reviews of randomized controlled trials (RCTs) are considered the gold standard evidence for health care interventions. Nevertheless, nonrandomized studies of interventions (NRSIs) are often necessary to answer research questions about long‐term or rare (adverse) outcomes or to evaluate interventions for which RCTs are unavailable. Review methods for NRSIs are broadly similar to those for reviews of RCTs. Assessing risk of bias is a particularly important step for NSRIs, because NRSIs have an inherently greater risk of bias than RCTs. NRSIs may be available in a variety of different designs, each with their own strengths and weaknesses. The decision on whether to combine estimates from NRSIs statistically should be guided by the similarity of populations, interventions, and outcomes in included studies, and informed by the risk of bias assessment. If such a synthesis is conducted, careful consideration and exploration of differences in study characteristics and statistical heterogeneity are essential.
The past 30 years of genetic analysis have helped to confirm theories, conceived at the beginning of the twentieth century, that complex diseases are heritable and likely to be influenced by many genetic factors, each exhibiting small effects. Detecting these genetic factors could be valuable for developing new drugs or predicting adverse outcomes before onset, but detection is generally only possible when the sample sizes are very large. We describe the failures in genetic analyses that have brought us to this understanding, and led to the development of the genome‐wide association study (GWAS) framework. Meta‐analysis has played a central role in GWAS and has helped to yield tens of thousands of genetic associations for a wide range of complex traits and diseases. We discuss how meta‐analysis is implemented in the GWAS context, noting the technical challenges that arise and the various contexts in which it can be applied.
Systematic reviews and meta‐analyses of observational, epidemiological studies are common. In this chapter, we focus on epidemiological studies of etiology and prevalence. We discuss the rationale for systematic reviews of such studies, highlighting fundamental differences between observational studies and randomized controlled trials (RCTs). We address the steps from shaping the research question, to defining the Population, Exposures, Comparators, and Outcomes (PECO) or Population and Condition (PC) in reviews of etiology or prevalence, to exploring heterogeneity and interpreting results. In contrast to high‐quality RCTs, confounding and bias often distort the findings of epidemiological studies. Bigger is not necessarily better: smaller studies may devote more attention to characterizing populations, exposures, or conditions than larger studies. Indeed, there is a danger that meta‐analyses of observational data produce precise but spurious results. A set of criteria should be developed, guided by general principles, to assess the risk of bias in different observational study designs. In the analysis and interpretation of observational studies, more is often gained by examining possible sources of heterogeneity between these studies' results than by calculating overall estimates of relative risks or prevalences.
In this study, we aimed to investigate differences in lifestyle factors and prevalence of metabolic syndrome (MetS) in the Indonesian population between 2013 and 2018. In addition, we investigated whether adherence to the 2015-released national healthy lifestyle guideline (‘GERMAS’) is associated with MetS in different sex, age, urban/rural, and BMI categories. We performed cross-sectional analyses in individuals aged >15 of the 2013 (n = 34,274) and 2018 (n = 33,786) Indonesian National Health Surveys. A stratified, multi-stage, systematic random sampling design and the probability proportional to size method were used to select households in the 34 provinces across the country. MetS was defined according to the Joint Interim Statement Criteria, and adherence to ‘GERMAS’ guideline was defined as fulfilling the national healthy lifestyle recommendations of ≥150 min/week physical activity (PA), ≥5 portions/day fruit and vegetable (FV), no smoking (NS), and no alcohol consumption (NA). We examined the associations of each lifestyle factor with MetS using logistic regression categorised by sex, age groups, urban/rural, and BMI, and adjusted for sociodemographic factors. We observed that men who adhered to the guideline had lower odds ratio of MetS [OR(95%CI) associated with PA: 0.85(0.75–0.97); NA: 0.75(0.56–1.00)] than non-adherent men. Middle-aged adults who adhered to the guideline had lower OR of MetS [PA: 0.85(0.72–1.01); FV: 0.78(0.62–0.99); NA: 0.66(0.46–0.93)] than non-adherent adults
Purpose:
To quantify the risk of perioperative and postoperative complications of derotational femoral and/or tibial osteotomies in patellofemoral disorders (anterior knee pain and patellar instability) in adolescents and active young patients.
Methods:
MEDLINE, EMBASE, Cochrane and Scopus databases were used to identify studies published from database inception and June 30, 2021. Meta-analysis was performed to pool the rates of complications related to femur and tibia osteotomies. Values of proportion of complications were expressed as proportions and 95% confidence intervals (CI) and then transformed using a Freeman Tukey double arcsine transformation. Meta-regression was used to explore factors that potentially may influence on heterogeneity such as year of publication, quality of the included studies and site of the osteotomy.
Results:
The 22 studies identified included a total of 648 derotational osteotomies in 494 patients. Studies consisted of 20 case series (non-comparative) and 2 comparative observational non-randomized cohorts. Tibial osteotomies showed higher risk of complications than femoral osteotomies (random pooled prevalence 9%; 95% CI 4-15% versus 1%; 95% CI 0-5%, respectively, p < 0.01). The meta-regression analysis of the articles showed that the only parameters responsible of the variance in number of complications were the osteotomy site.
Conclusions:
Derotational femoral and/or tibial osteotomy is a safe surgical procedure in the treatment of patellofemoral disorders (anterior knee pain and patellar instability) in adolescents and active young people.
Level of evidence:
IV.
Objective: The aim of this meta-analysis was to compare the impact of the quality of root canal treatment versus the quality of coronal restoration on periapical health.
Materials and Method: A literature review was conducted using the search terms “endodontics”, “periapical index”, “periapical status”, “quality of root canal treatment”, “root treatment”, “root canal treatment”, “coronal restoration”, “quality of root canal treatment”, “cone beam computed tomography”, and “restoration”. The studies evaluating the effect of the quality of root canal filling and the quality of coronal restoration on periapical tissues were selected. Data were collected by two researchers according to the inclusion and exclusion criteria. The ratio of teeth with apical periodontitis was recorded for each category: adequate root canal treatment (AC), inadequate root canal treatment (IC), adequate restoration (AR), and inadequate restoration (IR). The data were analyzed using meta-analysis for odds ratios. The significance level was set at α=0.05.
Results: There were statistically significant differences between AC-IR and AC-AR [p=0.02 and OR=1.88, 95% confidence interval (CI): 1.13-3.13], between IC-AR and AC-AR [p=0.006 and OR=3.23 (1.41-7.39)], between IC-IR and AC-AR [p
Aims: To evaluate the efficacy and safety of hydroxychloroquine/chloroquine, with or without azithromycin, in treating hospitalized COVID-19 patients. Materials and Methods: Data from randomized and observational studies were included in a random-effects meta-analysis. Primary outcomes included time to negative conversion of SARS-CoV-2 tests, length of stay, mortality, incidence of mechanical ventilation, time to normalization of body temperature, incidence of adverse events, and incidence of QT prolongations. Results: Fifty-one studies (n=61,221) were included. Hydroxychloroquine/chloroquine showed no efficacy in all primary efficacy outcomes, but was associated with increased odds of QT prolongations. Conclusions: Due to a lack of efficacy and increased odds of cardiac adverse events, hydroxychloroquine/chloroquine should not be used for treating hospitalized COVID-19 patients.
Introduction
Dysphagia is a common and critical consequence of acquired brain injury (ABI) and can cause severe complications. Dysphagia rehabilitation is transforming from mainly compensatory strategies to the retraining of swallowing function using principles from neuroscience. However, there are no studies that map interventions available to retrain swallowing function in patients with moderate-to-severe ABI.
Objective
To systematically map the accessible research literature to answer the research question: Which non-surgical, non-pharmacological interventions are used in the treatment of dysphagia in patients with moderate and severe ABI in the acute and subacute phase?
Design
Scoping review based on the methodology of Arksey and O’Malley and methodological advancement by Levac et al.
Data sources
MEDLINE, Embase, Cochrane Library, CINAHL, PsycINFO, Web of Science, OTseeker, speechBITE and PEDro were searched up until 14 March 2021.
Eligibility criteria
All studies reporting rehabilitative interventions within 6 months of injury for patients with moderate-to-severe ABI and dysphagia were included.
Data extraction and synthesis
Data was extracted by two independent reviewers and studies were categorised based on treatment modality.
Results
A total of 21 396 records were retrieved, and a final of 26 studies were included. Interventions were categorised into cortical or non-cortical stimulation of the swallowing network. Cortical stimulation interventions were repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation. Non-cortical were complex swallowing interventions, neuromuscular electrical stimulation, pharyngeal electrical stimulation (PES), sensory stimulation, strengthening exercises and respiratory muscle training.
Conclusion
This scoping review provides an overview of rehabilitative dysphagia interventions for patients with moderate and severe ABI, predominantly due to stroke, in the acute and subacute phase. Positive tendencies towards beneficial effects were found for rTMS, complex swallowing interventions, PES and cervical strengthening. Future studies could benefit from clear reporting of patient diagnosis and disease severity, the use of more standardised treatment protocols or algorithms and fewer but standardised outcome measures to enable comparison of effects across studies and interventions.
Background
The role of the critical shoulder angle (CSA) as a risk factor for rotator cuff tear (RCT) remains controversial. Studies on the association between the CSA and RCT show considerable differences in design, and this could be responsible for the variation in study results.
Purpose
To (1) describe the reliability of CSA measurement and (2) evaluate the results of the studies reporting the association between the CSA and RCT using meta-analytical techniques to explore potential sources of variation of study results.
Study Design
Systematic review and meta-analysis; Level of evidence, 4.
Methods
MEDLINE, EMBASE, and CINAHL electronic databases were searched through June 30, 2019. Case-control and cross-sectional studies reporting the association of the CSA and RCT were selected. The weighted mean difference in the CSA was estimated using a random-effects model. Prediction interval was computed to better express uncertainties in the effect estimate. Metaregression and subgroup analyses were performed to explore potential sources of heterogeneity.
Results
A total of 14 studies, including 1154 cases and 1271 controls, were identified. Of these studies, 79% (11/14) assessed the reliability of the CSA measurement, demonstrating an excellent intraobserver (range, 0.91-0.99) and interobserver (range, 0.87-0.99) reliability. Compared with controls, cases with RCT showed larger measurements of the CSA (3.3° [95% CI, 2.3°- 4.4°]). However, there was a high heterogeneity ( I ² = 93%), and the 95% prediction interval (-0.4° to 7.1°) included no difference in the CSA. Results of the metaregression analysis showed a significant association of several methodological aspects with the heterogeneity. The difference in the CSA tended to be larger when only full-thickness tears were included, when no specific defined criterion for assessing radiographic viewing perspective was used, in studies with smaller sample sizes, and in studies at higher risk of bias.
Conclusion
While the CSA can be reliably measured, the difference in the CSA between cases and controls varied from very large to modest or almost no difference. Several determinants of heterogeneity were determined. Owing to this heterogeneity, it is difficult to gain an insight into the strength and exact nature of the association between the CSA and RCT with the current evidence.
Objectives
We aimed to review how ‘Risk of Bias In Non-randomised Studies–of Interventions’ (ROBINS-I), a Cochrane risk-of-bias assessment tool, has been used in recent systematic reviews.
Study Design and Setting
Database and citation searches were conducted in March 2020 to identify recently published reviews using ROBINS-I. Reported ROBINS-I assessments and data on how ROBINS-I was used were extracted from each review. Methodological quality of reviews was assessed using AMSTAR 2 (‘A MeaSurement Tool to Assess systematic Reviews’).
Results
Of 181 hits, 124 reviews were included. Risk of bias was serious/critical in 54% of assessments on average, most commonly due to confounding. Quality of reviews was mostly low, and modifications and incorrect use of ROBINS-I were common, with 20% reviews modifying the rating scale, 20% understating overall risk of bias, and 19% including critical-risk-of-bias studies in evidence synthesis. Poorly conducted reviews were more likely to report low/moderate risk of bias (predicted probability 57% [95% CI: 47-67] in critically low-quality reviews, 31% 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 in high/moderate-quality reviews).
Conclusion
Low-quality reviews frequently apply ROBINS-I incorrectly, and may thus inappropriately include or give too much weight to uncertain evidence. Readers should be aware that such problems can lead to incorrect conclusions in reviews.
Over the past several years, there has been an increasing interest in- the role of free radical scavengers, particularly antioxidant vitamins in cardiovascular disease prevention. Free radicals are common by-products of many oxidative biochemical reactions in the body. They can damage or destroy biological molecules and have the po~ntial for causing serious tissue and organ damage. They have been implicated in aging and chronic disease processes, including atherosclerotic coronary heart disease. Substantial laboratory, animal, and human data suggest that oxidation of low-densitylipoprotein (LDL) cholesterol is an important step in
- the pathogenesis of atherosclerotic lesions
Introdution
Meta-analysis has received a mixed reception since the outset. Some people have rejected what they see as exercises in “mega-silliness,”1 while the purveyors of a highly distinguished series of meta-analyses of perinatal medical care2 have been dismissed as “an obstetrical Baader-Meinhof gang.”3 To some clinicians objecting to the findings of meta-analyses, “a tool has become a weapon.”4 At the other end of the spectrum, the application of a technique that basically consists of calculating a weighted average has been hailed as “Newtonian,”5 and it has been suggested that meta-analysis has left no place for the narrative review article.6 The truth is likely to lie somewhere between these extreme views.
Summary points
Bias can be introduced in many ways into the process of locating and selecting studies for inclusion in meta-analysisStudies with significant results are more likely to get published than studies without significant results, leading to publication biasAmong published studies, those with significant results are more likely to get published in English, more likely to be cited, and more likely to be published repeatedly, leading to English language bias, citation bias, and multiple publication biasIn less developed countries, studies with significant results may be more likely to get published in a journal indexed in a literature database, which can introduce database biasCriteria for including studies in a meta-analysis may be influenced by knowledge of the results of the set of potential studies, leading to inclusion biasThe likely presence or absence of bias should be routinely examined in sensitivity analyses and funnel plots
That meta-analysis holds potential problems can be illustrated by contrasting the conclusions of two meta-analyses comparing low molecular weight heparins and standard heparin in the prevention of thrombosis after surgery.7 8 One group concluded that “low molecular weight …
Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30
We conducted a combined analysis of the original data to evaluate the consistency of 12 case-control studies of diet and breast
cancer. Our analysis shows a consistent, statistically significant, positive association between breast cancer risk and saturated
fat intake in postmenopausal women (relative risk for highest vs. lowest quintile, 1.46; P <.0001). A consistent protective effect for a number of markers of fruit and vegetable intake was demonstrated; vitamin C
intake had the most consistent and statistically significant inverse association with breast cancer risk (relative risk for
highest vs. lowest quintile, 0.69; P <.0001). If these dietary associations represent causality, the attributable risk (i.e., the percentage of breast cancers
that might be prevented by dietary modification) in the North American population is estimated to be 24% for postmenopausal
women and 16% for premeno-pausal women. [J Natl Cancer Inst 82: 561–569, 1990]
To assess the hazards associated with long term use of tobacco.
Prospective study of mortality in relation to smoking habits assessed in 1951 and again from time to time thereafter, with causes sought of deaths over 40 years (to 1991). Continuation of a study that was last reported after 20 years' follow up (1951-71).
34,439 British male doctors who replied to a postal questionnaire in 1951, of whom 10,000 had died during the first 20 years and another 10,000 have died during the second 20 years.
Excess mortality associated with smoking was about twice as extreme during the second half of the study as it had been during the first half. The death rate ratios during 1971-91 (comparing continuing cigarette smokers with life-long non-smokers) were approximately threefold at ages 45-64 and twofold at ages 65-84. The excess mortality was chiefly from diseases that can be caused by smoking. Positive associations with smoking were confirmed for death from cancers of the mouth, oesophagus, pharynx, larynx, lung, pancreas, and bladder; from chronic obstructive pulmonary disease and other respiratory diseases; from vascular diseases; from peptic ulcer; and (perhaps because of confounding by personality and alcohol use) from cirrhosis, suicide, and poisoning. A negative association was confirmed with death from Parkinson's disease. Those who stopped smoking before middle age subsequently avoided almost all of the excess risk that they would otherwise have suffered, but even those who stopped smoking in middle age were subsequently at substantially less risk than those who continued to smoke.
Results from the first 20 years of this study, and of other studies at that time, substantially underestimated the hazards of long term use of tobacco. It now seems that about half of all regular cigarette smokers will eventually be killed by their habit.
To study the association of mortality from accidents, suicides, and other violent deaths with serum cholesterol concentration.
Baseline measurements in two randomly chosen independent cohorts were carried out in 1972 and 1977. Mortality was monitored over 10-15 years through the national death registry.
Eastern Finland.
The two cohorts comprised men (n = 10,898) and women (n = 11,534) born between 1913 and 1947. There were 193 deaths due to accidents, suicides, and violence among men and 43 among women.
Mortality from accidents, suicides, and other violent deaths was used as the end point. Deaths from these causes were pooled together in the analyses.
Serum cholesterol concentration was not associated with mortality from accidents, suicides, and other violent deaths in the univariate analyses or in the proportional hazards regression analyses including smoking, systolic blood pressure, alcohol drinking, and education. In both genders smoking was more prevalent among those who died from accidents, suicides, and other violent causes than from other causes. Frequent use of alcohol increased mortality from these causes.
The risk of accidents, suicides, and other violent deaths was not related to serum cholesterol concentration, whereas such deaths were more prevalent in smokers and alcohol drinkers.
There is strong evidence that breast cancer risk is influenced by environmental factors, and animal experiments and human ecological data suggest that increased dietary fat intake increases the incidence of the disease. Epidemiological evidence on the relationship of dietary fat to breast cancer from cohort and case control studies has however been inconsistent. To examine the available evidence we have carried out a meta-analysis to summarise quantitatively the large published literature on dietary fat in the aetiology of breast cancer. After assembling all of the published case control and cohort studies, we extracted the relative risk in each study that compared the highest to the lowest level of intake. We then calculated a summary relative risk for all studies. The summary relative risk for the 23 studies that examined fat as a nutrient was 1.12 (95% CI 1.04-1.21). Cohort studies had a summary relative risk of 1.01 (95% CI 0.90-1.13) and case control studies a relative risk of 1.21 (95% CI 1.10-1.34). Summary estimates of risk for specific types of fat excluded unity for only saturated fat. For the 19 studies that examined food intake, the summary relative risks were 1.18 (95% CI 1.06-1.32) for meat, 1.17 (95% CI 1.04-1.31) for milk, and 1.17 (95% CI 1.02-1.36) for cheese. Summary relative risks for total fat intake were examined for several potential modifying factors. Regression analysis showed that European studies were more likely than studies done in other countries to show an increased relative risk associated with dietary fat and breast cancer, after taking into account potential modifying factors that included study design and quality.
Current evidence suggests a strong positive correlation between cigarette consumption and depression; this study examined the relationship between cigarettes and suicide. Over 100,000 predominantly White, middle-aged, female registered nurses were followed via biannual questionnaires from 1976 through 1988. Respondents smoking 1 through 24 cigarettes per day had twice the risk and those smoking 25 or more cigarettes four times the risk of committing suicide, compared with those who had never smoked. Although no information on causation was available, this paper links cigarettes to another major health problem.
To determine (1) the most effective method of administering vitamin K to infants to prevent hemorrhagic disease of the newborn (HDNB) and (2) the safest method, in light of preliminary evidence suggesting that intramuscular administration of vitamin K is associated with childhood cancer.
A MEDLINE search of articles published between Jan. 1, 1991, and Apr. 30, 1994, with the use of MeSH terms "hemorrhagic disease of the newborn", articles were limited to those involving human subjects, from birth to adolescence, and to articles from journals indexed through Index Medicus and written in English. References of all articles found through the initial search, the earliest of which was published in 1967, were also reviewed.
Six controlled trials met the selection criteria: a minimum 4-week follow-up period, a minimum of 60 subjects and a comparison of oral and intramuscular administration or of regimens of single and multiple doses taken orally. All retrospective case reviews were evaluated. Because of its thoroughness, the authors selected a meta-analysis of almost all cases involving patients more than 7 days old published from 1967 to 1992. Only five studies that concerned safety were found, and all of these were reviewed.
In controlled trials, the risk of HDNB caused by vitamin K deficiency among infants receiving different regimens of vitamin K; in case studies, method of vitamin K administration and incidence of hemorrhagic disease; and in studies concerning safety, odds ratios and relative risks of childhood cancer following intramuscular administration of vitamin K.
Vitamin K (1 mg, administered intramuscularly) is currently the most effective method of preventing HDNB. The previously reported relation between intramuscular administration of vitamin K and childhood cancer has not been substantiated. An oral regimen (three doses of 1 to 2 mg, the first given at the first feeding, the second at 2 to 4 weeks and the third at 8 weeks) may be an acceptable alternative but needs further testing in large clinical trials.
There is no compelling evidence to alter the current practice of administering vitamin K intramuscularly to newborns.
Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders.
We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo.
A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years.
After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses.
Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews.
Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision.
In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias.
A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution.
Meta-analysis should be as carefully planned as any other research project, with a detailed written protocol being prepared in advance.The a priori definition of eligibility criteria for studies to be included and a comprehensive search for such studies are central to high quality meta-analysis.The graphical display of results from individual studies on a common scale is an important intermediate step, which allows a visual examination of the degree of heterogeneity between studiesDifferent statistical methods exist for combining the data, but there is no single ''correct'' method.A thorough sensitivity analysis is essential to assess the robustness of combined estimates to different assumptions and inclusion criteria.
In the previous two articles1 2 we outlined the potentials and principles of meta-analysis and the practical steps in performing a meta-analysis. Now we will examine how to use meta-analysis to do more than simply combine the results from all the individual trials into a single effect estimate. Firstly, we discuss the advantages and disadvantages of performing subgroup analyses. Secondly, we consider the situation in which the differences in effects between individual trials are related in a graded way to an underlying phenomenon, such as the degree of mortality risk of the trial participants.
#### Summary points
Meta-analysis can be used to examine differences in treatment effects across trials; however, the fact that randomised trials are included in meta-analyses does not mean that comparisons between trials are also randomised comparisons
Meta-analytic subgroup analyses, like subgroup analyses within trials, are prone to bias and need to be interpreted with caution
A more reliable way of assessing differences in treatment effects is to relate outcome to some underlying patient characteristic on a continuous, or ordered, scale
The underlying level of risk is a key variable which is often related to a given treatment effect, with patients at higher risk receiving more benefit then low risk patients
Individual patient data, rather than published summary statistics, are often required for meaningful subgroup analyses
The main aim of a meta-analysis is to produce an estimate of the average effect seen in trials of a particular treatment. The direction and magnitude of this average effect is intended to guide decisions about clinical practice for a wide range of patients. Clinicians are thus being asked to treat their patients as though each one is well represented by the patients in the clinical trials included in the meta-analysis. This runs against doctors' concerns to use the specific characteristics of a …
Background. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. Methods. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. Results. Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol (change in incidence as compared with those who did not, -2 percent; 95 percent confidence interval, -14 to 12 percent). Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent; 95 percent confidence interval, 3 to 36 percent). We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha- tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher (95 percent confidence interval, 1 to 16 percent) among the participants who received beta carotene than among those who did not, primarily because there were more deaths from lung cancer and ischemic heart disease. Conclusions. We found no reduction in the incidence of lung cancer among male smokers after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene. In fact, this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.
Objective.
—To examine the relationship between beta carotene plasma concentration and beta carotene supplementation and risk of death from major disease causes.Design.
—Cohort study of plasma concentrations; randomized, controlled clinical trial of supplementation.Setting.
—Medical school-affiliated dermatology practices.Patients.
—A total of 1188 men and 532 women with mean age of 63.2 years, who had enrolled in a randomized clinical trial of beta carotene supplementation to prevent nonmelanoma skin cancer.Intervention.
—Oral beta carotene, 50 mg per day for a median of 4.3 years.Main Outcome Measures.
—All-cause mortality and mortality from cardiovascular disease and cancer.Results.
—During a median follow-up period of 8.2 years, there were 285 deaths. Persons whose initial plasma beta carotene concentrations were in the highest quartile (>0.52 μmol/L [27.7 μg/dL]) had a lower risk of death from all causes (adjusted relative rate [RR], 0.52; 95% confidence interval [CI] 0.44 to 0.87) and from cardiovascular diseases (adjusted RR, 0.57; 95% CI, 0.34 to 0.95) compared with persons with initial concentrations in the lowest quartile (<0.21 μmol/L [11.2 μg/dL]). Patients randomly assigned to beta carotene supplementation showed no reduction in relative mortality rates from all causes (adjusted RR, 1.03; 95% CI, 0.82 to 1.30) or from cardiovascular disease (adjusted RR, 1.16; 95% CI, 0.82 to 1.64). There was no evidence of lower mortality following supplementation among patients with initial beta carotene concentrations below the median for the study group.Conclusions.
—These analyses provide no support for a strong effect of supplemental beta carotene in reducing mortality from cardiovascular disease or other causes. Although the possibility exists that beta carotene supplementation produces benefits that are too small or too delayed to have been detected in this study, noncausal explanations should be sought for the association between plasma concentrations of beta carotene and diminished risk of death.(JAMA 1996;275:699-703)
A sample of 2,706 adults, considered representative of the United States, was interviewed by telephone about coffee consumption and about experiences and personal characteristics that have been considered antecedents or risk factors of vascular diseases and malignancies. Consumption of more than 5.6 cups per day placed a person in the top quartile of total daily coffee. People in the top quartile of caffeine‐containing coffee consumption averaged 429 mg of caffeine in coffee each day and were more likely than others to smoke cigarettes, and less likely to take vitamin supplements and to consume a “healthy” diet (i.e., containing large amounts of fiber, vitamins and cruciferous vegetables, and small amounts of fat). Thus, the heightened risk of disease sometimes associated with coffee consumption might reflect the characteristics and disease‐promoting activities of some drinkers and not necessarily their consumption of caffeine and coffee. The findings of this study are consistent with the hypothesis that drinkers of relatively large amounts of coffee are less likely than others to feel the need for health‐promoting behaviors.
BACKGROUND The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. METHODS Individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. FINDINGS The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95 percent CI] in current users 1.24 [1.15-1.33], 2p<0.00001; 1-4 years after stopping 1.16 [1.08-1.23], 2p=0.00001; 5-9 years after stopping 1.07 [1.02-1.13], 2p=0.009). Second, there is no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use (relative risk 1.01 [0.96-1.05], NS). The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives for ever-users compared with never-users, the relative risk for tumours that had spread beyond the breast compared with localised tumours was 0.88 (0.81-0.95; 2p=0.002). There was no pronounced variation in the results for recency of use between women with different background risks of breast cancer, including women from different countries and ethnic groups, women with different reproductive histories, and those with or without a family history of breast cancer. The studies included in this collaboration represent about 90 percent of the epidemiological information on the topic, and what is known about the other studies suggests that their omission has not materially affected the main conclusions. Other features of hormonal contraceptive use such as duration of use, age at first use, and the dose and type of hormone within the contraceptives had little additional effect on breast cancer risk, once recency of use had been taken into account. Women who began use before age 20 had higher relative risks of having breast cancer diagnosed while they were using combined oral contraceptives and in the 5 years after stopping than women who began use at older ages, but the higher relative risks apply at ages when breast cancer is rare and, for a given duration of use, earlier use does not result in more cancers being diagnosed than use beginning at older ages. Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use: for example, among 10 000 women from Europe or North America who used oral contraceptives from age 16 to 19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess number of cancers diagnosed up to 10 years after stopping use is 0.5 (95 percent CI 0.3-0.7), 1.5 (0.7-2.3), and 4.7 (2.7-6.7). Up to 20 years after cessation of use the difference between ever-users and never-users is not so much in the total number of cancers diagnosed, but in their clinical presentation, with the breast cancers diagnosed in ever-users being less advanced clinically than those diagnosed in never-users. The relation observed between breast cancer risk and hormone exposure is unusual, and it is not possible to infer from these data whether it is due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of reasons...
A cross-sectional study of stable monogamous couples, recruited from 16 clinical and surveillance centers in Italy between 1987 and 1992, was carried out to investigate the risk factors of woman-to-man sexual transmission of human immunodeficiency virus (HIV). The male partners of all HIV-infected women attending the centers were invited to participate in the study. Of the 275 male partners who were tested for HIV and interviewed with use of a structured questionnaire, 51 were excluded because they had other possible risk factor for HIV infection, no established risk factor was found in the index case, or they had stopped engaging in sexual intercourse. Fourteen of the 224 men (6.3%) were seropositive for HIV. At logistic regression, the highest risks of transmission were for men practicing peno-anal intercourse [odds ratio (OR), 4.6; 95% confidence interval (Cl), l.CV-22.2] and for men whose partner had acquired immune deficiency syndrome (AIDS) or a CD4+ lymphocyte count of <=400/mm3. No seropositive men were observed among those who were aware of the woman's HIV seropositivity since the beginning of the relationship or were partners of a zidovudine-treated woman. The results suggest that the risk factors described in man-to-woman and man-to-man HIV sexual transmission also operate in woman-to-man transmission.
(C) Lippincott-Raven Publishers.
This chapter focuses on the bias in analytic research. Case-control studies are attractive. They can be executed quickly and at low cost, even when the disorders of interest are rare. The execution of pilot case-control studies is becoming automated; strategies have been devised for the “computer scanning” of large files of hospital admission diagnoses and prior drug exposures, with detailed analyses carried out in the same data set on an ad hoc basis. As evidence of their growing popularity, when one original article was randomly selected from each issue of The New England Journal of Medicine, The Lancet, and the Journal of the American Medical Association for the years 1956, 1966, and 1976, the proportion that reported case-control analytic studies increased fourfold over these two decades; however, the proportion reporting cohort analytic studies fell by half; a general trend toward fewer study subjects but more study authors was also noted.
Incidence rates for 27 cancers in 23 countries and mortality rates for 14 cancers in 32 countries have been correlated with a wide range of dietary and other variables. Dietary variables were strongly correlated with several types of cancer, particularly meat consumption with cancer of the colon and fat consumption with cancers of the breast and corpus uteri. The data suggest a possible role for dietary factors in modifying the development of cancer at a number of other sites. The usefulness and limitations of the method are discussed.
Two widely used criteria for determining whether an association between a risk factor and a disease is causal are dose response and independence from other factors. Data from a large US risk factor study (MRFIT) throw up a relation between cigarette smoking and suicide that meets these criteria, yet appears to be biologically implausible. It is likely that many more such associations, for other exposures and other diseases, are equally spurious, but are protected by their lack of obvious implausibility.
To determine the extent to which the elderly have been excluded from trials of drug therapies used in the treatment of acute myocardial infarction, to identify factors associated with such exclusions, and to explore the relationship between the exclusion of elderly and the representation of women.
We conducted a systematic search of the English-language literature from January 1960 through September 1991 to identify all relevant studies of specific pharmacotherapies employed in the treatment of acute myocardial infarction. To accomplish this, we searched MEDLINE, major cardiology textbooks, meta-analyses, reviews, editorials, and the bibliographies of all identified articles.
Only trials in which patients were randomly allocated to receive a specific therapeutic regimen or a placebo or nonplacebo control regimen were included for review.
Studies were abstracted for year of publication, source of support, performance location, drug therapies to which patients were randomized, use of invasive diagnostic tests or therapeutic procedures, exclusion criteria, size and demographic characteristics of the randomized study population, and principal outcome measures.
A total of 214 trials met inclusion criteria, involving 150,920 study subjects. Over 60% of trials excluded persons over the age of 75 years. Studies published after 1980 were more likely to have age-based exclusions compared with studies published before 1980 (adjusted odds ratio, 4.92; 95% confidence interval, 2.33 to 10.54). Trials of thrombolytic therapy involving an invasive procedure were more likely to exclude elderly patients compared with other studies (adjusted odds ratio, 2.45; 95% confidence interval, 1.10 to 5.47). Studies with age-based exclusions had a smaller percentage of women compared with those without such exclusions (18% vs 23%; P = .0002), with the mean age of the study population significantly associated with the proportion of women participants (P = .0001, R2 = .29).
Age-based exclusions are frequently used in clinical trials of medications used in the treatment of acute myocardial infarction. Such exclusions limit the ability to generalize study findings to the patient population that experiences the most morbidity and mortality from acute myocardial infarction.
Clinical Pharmacology and Therapeutics (1991) 50, 641–646; doi:10.1038/clpt.1991.201
A relative risk estimate which relates an exposure to risk of disease will tend to be estimated too close to unity if that exposure is subject to random measurement error or intra-subject variability. "Independent" relative risk estimates, for the effect of one exposure after adjusting for confounding exposures, may be biased in either direction, depending on the amount of measurement imprecision in the exposure of interest and in the confounders. We describe two methods which estimate the bias in multivariate relative risk estimates due to the effect of measurement imprecision in one or more of the exposure variables in the model. Results from the two methods are compared in an example involving HDL cholesterol, triglycerides and coronary heart disease. In this example, the degree of bias in relative risk estimates is shown to be highly dependent on the amount of measurement imprecision ascribed to the exposures. It is concluded that when two exposures are substantially correlated, and one or both is subject to sizeable measurement imprecision, a study in which exposures are measured only once will be inadequate for investigating the independent effect of the exposures. Where feasible, epidemiologists should seek study populations where the correlation between the exposures is smaller.
The associations of diastolic blood pressure (DBP) with stroke and with coronary heart disease (CHD) were investigated in nine major prospective observational studies: total 420,000 individuals, 843 strokes, and 4856 CHD events, 6-25 (mean 10) years of follow-up. The combined results demonstrate positive, continuous, and apparently independent associations, with no significant heterogeneity of effect among different studies. Within the range of DBP studied (about 70-110 mm Hg), there was no evidence of any "threshold" below which lower levels of DBP were not associated with lower risks of stroke and of CHD. Previous analyses have described the uncorrected associations of DBP measured just at "baseline" with subsequent disease rates. But, because of the diluting effects of random fluctuations in DBP, these substantially underestimate the true associations of the usual DBP (ie, an individual's long-term average DBP) with disease. After correction for this "regression dilution" bias, prolonged differences in usual DBP of 5, 7.5, and 10 mm Hg were respectively associated with at least 34%, 46%, and 56% less stroke and at least 21%, 29%, and 37% less CHD. These associations are about 60% greater than in previous uncorrected analyses. (This regression dilution bias is quite general, so analogous corrections to the relations of cholesterol to CHD or of various other risk factors to CHD or to other diseases would likewise increase their estimated strengths.) The DBP results suggest that for the large majority of individuals, whether conventionally "hypertensive" or "normotensive", a lower blood pressure should eventually confer a lower risk of vascular disease.
In a study of human immunodeficiency virus type 1 (HIV-1)-uninfected African prostitutes, 83 (67%) of 124 seroconverted to HIV-1. Oral contraceptive use (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-8.6; P less than .03), genital ulcers (mean annual episodes, 1.32 +/- 0.55 in seroconverting women vs. 0.48 +/- 0.21 in seronegative women; P less than .02) and Chlamydia trachomatis infections (OR, 3.6; CI, 1.3-11.0; P less than .02) were associated with increased risk of HIV-1 infection. Condom use reduced the risk of HIV-1 infection (OR, 0.11; CI, 0.05-0.27; P less than .0001). Stepwise logistic regression analysis confirmed independent associations between HIV-1 infection and oral contraceptive use, condom use, genital ulcers, and C. trachomatis. The presence of other sexually transmitted diseases may in part explain the heterosexual HIV-1 epidemic in Africa and may represent important targets for intervention to control HIV-1 infection.
Clinical and administrative databases are increasingly used for clinical research. Descriptive studies and analyses of prognostic factors are established research uses of databases, but using them to compare therapies remains controversial. Such comparisons may be possible when a validated model of prognosis can account for the effect of clinically recognized variables on outcome. Models meeting these criteria have been developed using the Duke Cardiovascular Disease Database. They were applied to compare medical therapy to surgical therapy for coronary artery disease. Predictions from these models agreed well with the results of the three major randomized trials of bypass surgery versus medical therapy. These findings indicate that when data is reliable and understanding of factors affecting prognosis is good, researchers can use statistical techniques to minimize the bias due to non-random treatment assignment. Carefully performed analyses of observational clinical data can complement and extend randomized studies.
Over 30 epidemiologic studies have evaluated cancer risks associated with formaldehyde exposure. Excesses were reported for several sites, leukemia and cancers of the nasal cavities, nasopharynx, lung, and brain generating the greatest interest. The excesses of leukemia and brain and colon cancer found among professionals may not be related to formaldehyde exposure, since similar excesses were not observed among industrial workers. Inconsistencies among and within studies impede assigning formaldehyde a convincing causal role for the excesses of lung cancer found among industrial workers. A causal role for formaldehyde is the most probable for cancers of the nasopharynx and, to a less extent, the nasal cavities. Evidence of exposure-response relationships, the fact that direct contact with formaldehyde may occur at these upper respiratory sites, and the consistency of these findings with experimental studies make this assumption highly probable.
Many substances used in daily life, such as coffee, alcohol, and pharmaceutical treatment for hypertension, have been accused
of "menace" in causing cancer or other major diseases. Although some of the accusations have subsequently been refuted or
withdrawn, they have usually been based on statistical associations in epidemiologic studies that could not be done with the
customary experimental methods of science. With these epidemiologic methods, however, the fundamental scientific standards
used to specify hypotheses and groups, get high-quality data, analyze attributable actions, and avoid detection bias may also
be omitted. Despite peer-review approval, the current methods need substantial improvement to produce trustworthy scientific
evidence.
The efficacy of Auto-Immune Buccal Urine Therapy (AIBUT) against allergic symptoms depends upon sublingual administration of the correct dose of urine as determined by bio-assay in individual patients. Succeeding effective turn-off doses occur at the troughs of a sinusoidal dose-response curve. Efficacy of the administered dose is confirmed by reduction in the severity and duration of Cold-water-induced Raynaud symptoms after administration of effective doses of unboiled urine in AIBUT. Boiled urine does not affect the Raynaud phenomenon.
A total of 6194 female doctors who in 1951 replied to a questionnaire about their smoking habits were followed up prospectively for 22 years. During that time 1094 died. Ischaemic heart disease, lung cancer, and chronic obstructive lung disease were all significantly (p < 0.001) related to smoking, though the absolute excess risks were lower than in male doctors smoking equivalent amounts. Female smokers born before the first world war were less likely to describe themselves as inhalers or as having started to smoke while young than were female smokers who were born later. In these respects this younger group resembled male smokers, and as they move into their 60s and 70s their absolute risk of lung disease and relative risk of ischaemic heart disease will probably come to resemble the risks for men smoking the same numbers of cigarettes. These findings show only that cigarette smoking causes lung cancer, chronic obstructive lung disease, and heart disease in women as in men. Whether the proportional increase in mortality from these diseases is as great in women as in men might be estimated directly from new case-control studies on men and women born since 1920.
Case control studies on the association between sunlight exposure and melanoma risk show considerable differences in design; this could be responsible for the variation in study results. In an attempt to resolve the controversy between study results, the results of 25 publications on case control studies were evaluated using meta-analytical techniques. Comparison of odds ratios between subgroups of studies revealed that the range of odds ratios was far greater for hospital-based studies than for population-based studies. For the latter type of studies, the odds ratios were homogeneous and the pooled odds ratios were 1.57 (95% confidence interval [CI], 1.29-1.91) for intermittent sunlight exposure and 0.73 (95% CI, 0.60-0.89) for chronic exposure. However, among other problems, the lack of standardized measures for sunlight exposure warrants cautious interpretation of these results. It is concluded that evidence to support the intermittent sunlight theory is still far from complete.
The objectives of the study were to assess whether the epidemiologic data support a relation between dietary calcium intake and blood pressure, to obtain a quantitative estimate of the difference in blood pressure for a given difference in dietary calcium intake, and to assess the public health implications. A meta-analysis of published data (January 1983 to November 1993) that investigated the association between dietary calcium intake and blood pressure in different populations around the world was performed. Of 63 population studies identified, 23 were suitable for a quantitative overview (total n = 38,950). Unadjusted regression coefficients (95% confidence intervals) were obtained. Pooled unadjusted regression coefficients (95% confidence intervals) were then computed weighting each individual study by the inverse of its variance. Tests of heterogeneity and sensitivity analysis were carried out, and the possibility of publication bias was assessed. The regression coefficients ranged between -9.40 and 1.63 mmHg/100 mg calcium for systolic blood pressure and between -4.90 and 0.47 for diastolic blood pressure. In men (11 studies, n = 7,271), the pooled regression coefficients were -0.010 and -0.009 mmHg/100 mg calcium for systolic and diastolic pressures, respectively (p < 0.001 and p < 0.05). In women (six studies, n = 8,507), they were -0.15 and -0.057 mmHg/100 mg calcium (p < 0.001 and p < 0.02), and in men and women combined (six studies, n = 23,172 for systolic pressure and four studies, n = 3,215 for diastolic pressure) they were -0.061 and -0.061 mmHg/100 mg calcium (p < 0.001 and p < 0.05). In those studies that used the 24-hour recall method, the pooled regression coefficients were -0.06 and -0.09 mmHg/100 mg calcium (p < 0.005 and p = 0.07), whereas in those that used the food frequency questionnaire, they were -0.15 and -0.05 mmhg/100 mg calcium (p < 0.001 and p < 0.03). These data are consistent with an inverse association between dietary calcium intake and blood pressure. However, the size of the estimate, the observed heterogeneity among studies, and the possibility of confounding and publication bias indicate that an increase in calcium intake above the Recommended Dietary Allowance is not recommended at population level for the prevention and treatment of high blood pressure.
Editor‘s note
This and the following two commentaries (pages 779 and 783) are based on presentations made at the symposium “Meta-analysis of Observational Studies” at the 26th Annual Meeting of the Society for Epidemiologic Research, Keystone, Colorado, June 16—18, 1993. Dr. Shapiro‘s response to Drs. Petitti and Greenland follows on page 788.
A total of 44,290 men and 24,535 women aged 35-49 have been followed with respect to different causes of death during 13.3 years on average. A detailed history of smoking, together with other important risk factors, were recorded in a standardized way. Compared with the classical American and British studies, the excess mortality for the smokers was largely the same for the majority of causes. The exceptions were cerebrovascular mortality and suicides and accidents, which were more strongly related to smoking in this study. Furthermore, men who smoked only pipe, had nearly the same coronary heart disease mortality as men who smoked only cigarettes. The same applies to lung cancer mortality. Among men who had quit cigarette smoking, the coronary heart disease mortality decreased with time since quitting to almost the level of the never cigarette smokers after 5 years or more.
Experiments in animals, international correlation comparisons, and case-control studies support an association between dietary fat intake and the incidence of breast cancer. Most cohort studies do not corroborate the association, but they have been criticized for involving small numbers of cases, homogeneous fat intake, and measurement errors in estimates of fat intake.
We identified seven prospective studies in four countries that met specific criteria and analyzed the primary data in a standardized manner. Pooled estimates of the relation of fat intake to the risk of breast cancer were calculated, and data from study-specific validation studies were used to adjust the results for measurement error.
Information about 4980 cases from studies including 337,819 women was available. When women in the highest quintile of energy-adjusted total fat intake were compared with women in the lowest quintile, the multivariate pooled relative risk of breast cancer was 1.05 (95 percent confidence interval, 0.94 to 1.16). Relative risks for saturated, monounsaturated, and polyunsaturated fat and for cholesterol, considered individually, were also close to unity. There was little overall association between the percentage of energy intake from fat and the risk of breast cancer, even among women whose energy intake from fat was less than 20 percent. Correcting for error in the measurement of nutrient intake did not materially alter these findings.
We found no evidence of a positive association between total dietary fat intake and the risk of breast cancer. There was no reduction in risk even among women whose energy intake from fat was less than 20 percent of total energy intake. In the context of the Western lifestyle, lowering the total intake of fat in midlife is unlikely to reduce the risk of breast cancer substantially.
To examine the relationship between beta carotene plasma concentration and beta carotene supplementation and risk of death from major disease causes.
Cohort study of plasma concentrations; randomized, controlled clinical trial of supplementation.
Medical school-affiliated dermatology practices.
A total of 1188 men and 532 women with mean age of 63.2 years, who had enrolled in a randomized clinical trial of beta carotene supplementation to prevent nonmelanoma skin cancer.
Oral beta carotene, 50 mg per day for a median of 4.3 years.
All-cause mortality and mortality from cardiovascular disease and cancer.
During a median follow-up period of 8.2 years, there were 285 deaths. Persons whose initial plasma beta carotene concentrations were in the highest quartile (>0.52 micromol/L [27.7 microg/dL]) had a lower risk of death from all causes (adjusted relative rate [RR], 0.52; 95% confidence interval [CI] 0.44 to 0.87) and from cardiovascular diseases (adjusted RR, 0.57; 95% CI, 0.34 to 0.95) compared with persons with initial concentrations in the lowest quartile (<0.21 micromol/L [11.2 microg/dL]). Patients randomly assigned to beta carotene supplementation showed no reduction in relative mortality rates from all causes (adjusted RR, 1.03; 95% CI, 0.82 to 1.30) or from cardiovascular disease (adjusted RR, 1.16; 95% CI, 0.82 to 1.64). There was no evidence of lower mortality following supplementation among patients with initial beta carotene concentrations below the median for the study group.
These analyses provide no support for a strong effect of supplemental beta carotene in reducing mortality from cardiovascular disease or other causes. Although the possibility exists that beta carotene supplementation produces benefits that are too small or too delayed to have been detected in this study, noncausal explanations should be sought for the association between plasma concentrations of beta carotene and diminished risk of death.
Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation.
In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene.
Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points.
In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.
The view is widely held that experimental methods (randomised controlled trials) are the "gold standard" for evaluation and that observational methods (cohort and case control studies) have little or no value. This ignores the limitations of randomised trials, which may prove unnecessary, inappropriate, impossible, or inadequate. Many of the problems of conducting randomised trials could often, in theory, be overcome, but the practical implications for researchers and funding bodies mean that this is often not possible. The false conflict between those who advocate randomised trials in all situations and those who believe observational data provide sufficient evidence needs to be replaced with mutual recognition of the complementary roles of the two approaches. Researchers should be united in their quest for scientific rigour in evaluation, regardless of the method used.
The number of papers published on meta-analyses in medical research has increased sharply in the past 10 years (fig 1). The merits and perils of the somewhat mysterious procedure of meta-analysis, however, continue to be debated in the medical community.1 23 What, then, is meta-analysis? A useful definition was given by Huque: “A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be ‘combinable.’” 4 The terminology, however, is still debated, and expressions used concurrently include “overview,” “pooling,” and “quantitative synthesis.” We believe that the term meta-analysis should be used to describe the statistical integration of separate studies, whereas “systematic review” is most appropriate for denoting any review of a body of data that uses clearly defined methods and criteria (box). Systematic reviews can include meta-analyses, appraisals of single trials, and other sources of evidence.6 In this article we examine the potentials and promise of meta-analysis of randomised controlled trials. In later articles of this series we will consider the practical steps involved in meta-analysis,7 examine various extensions beyond the calculation of a combined estimate,8 address potential biases and discuss strategies to detect and minimise the influence of these in meta-analysis of randomised trials9 and of observational studies.10 We will conclude with a discussion of unresolved issues and future developments.11 Details of relevant software will appear on the BMJ's website at the end of the series.
Fig 1
Number of publications about meta-analysis, 1987–96 (results from Medline search using text word and medical subject heading “meta-analysis”)
#### What's in a name? The case for “meta-analysis”
The term meta-analysis for statistically combining and analysing data from separate studies is appropriate because:
MARK HUDSON Education and debate from clinical trials in acute myocardial infarction
MARK HUDSON
Education and debate
from clinical trials in acute myocardial infarction. JAMA 1992;268:
1417-22.