The standard two-stage approach for estimating non-linear dose–response curves based on aggregated data typically excludes those studies with less than three exposure groups. We develop the one-stage ...method as a linear mixed model and present the main aspects of the methodology, including model specification, estimation, testing, prediction, goodness-of-fit, model comparison, and quantification of between-studies heterogeneity. Using both fictitious and real data from a published meta-analysis, we illustrated the main features of the proposed methodology and compared it to a traditional two-stage analysis. In a one-stage approach, the pooled curve and estimates of the between-studies heterogeneity are based on the whole set of studies without any exclusion. Thus, even complex curves (splines, spike at zero exposure) defined by several parameters can be estimated. We showed how the one-stage method may facilitate several applications, in particular quantification of heterogeneity over the exposure range, prediction of marginal and conditional curves, and comparison of alternative models. The one-stage method for meta-analysis of non-linear curves is implemented in the dosresmeta R package. It is particularly suited for dose–response meta-analyses of aggregated where the complexity of the research question is better addressed by including all the studies.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
An increasing number of quantitative reviews of epidemiological data includes a doseresponse analysis. Aims of this paper are to describe the main aspects of the methodology and to illustrate the ...novel R package dosresmeta developed for multivariate dose-response meta-analysis of summarized data. Specific topics covered are reconstructing covariances of correlated outcomes; pooling of study-specific trends; flexible modeling of the exposure; testing hypothesis; assessing statistical heterogeneity; and presenting in either a graphical or tabular way the overall dose-response association.
Aims/hypothesis
Inverse associations between physical activity (PA) and type 2 diabetes mellitus are well known. However, the shape of the dose–response relationship is still uncertain. This review ...synthesises results from longitudinal studies in general populations and uses non-linear models of the association between PA and incident type 2 diabetes.
Methods
A systematic literature search identified 28 prospective studies on leisure-time PA (LTPA) or total PA and risk of type 2 diabetes. PA exposures were converted into metabolic equivalent of task (MET) h/week and marginal MET (MMET) h/week, a measure only considering energy expended above resting metabolic rate. Restricted cubic splines were used to model the exposure–disease relationship.
Results
Our results suggest an overall non-linear relationship; using the cubic spline model we found a risk reduction of 26% (95% CI 20%, 31%) for type 2 diabetes among those who achieved 11.25 MET h/week (equivalent to 150 min/week of moderate activity) relative to inactive individuals. Achieving twice this amount of PA was associated with a risk reduction of 36% (95% CI 27%, 46%), with further reductions at higher doses (60 MET h/week, risk reduction of 53%). Results for the MMET h/week dose–response curve were similar for moderate intensity PA, but benefits were greater for higher intensity PA and smaller for lower intensity activity.
Conclusions/interpretation
Higher levels of LTPA were associated with substantially lower incidence of type 2 diabetes in the general population. The relationship between LTPA and type 2 diabetes was curvilinear; the greatest relative benefits are achieved at low levels of activity, but additional benefits can be realised at exposures considerably higher than those prescribed by public health recommendations.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective:The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought ...to fill this gap by conducting dose-response meta-analyses.Methods:A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.Results:Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.Conclusions:In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.
Several studies have analyzed the relationship between coffee consumption and mortality, but the shape of the association remains unclear. We conducted a dose-response meta-analysis of prospective ...studies to examine the dose-response associations between coffee consumption and mortality from all causes, cardiovascular disease (CVD), and all cancers. Pertinent studies, published between 1966 and 2013, were identified by searching PubMed and by reviewing the reference lists of the selected articles. Prospective studies in which investigators reported relative risks of mortality from all causes, CVD, and all cancers for 3 or more categories of coffee consumption were eligible. Results from individual studies were pooled using a random-effects model. Twenty-one prospective studies, with 121,915 deaths and 997,464 participants, met the inclusion criteria. There was strong evidence of nonlinear associations between coffee consumption and mortality for all causes and CVD (P for nonlinearity < 0.001). The largest risk reductions were observed for 4 cups/day for all-cause mortality (16%, 95% confidence interval: 13, 18) and 3 cups/day for CVD mortality (21%, 95% confidence interval: 16, 26). Coffee consumption was not associated with cancer mortality. Findings from this meta-analysis indicate that coffee consumption is inversely associated with all-cause and CVD mortality.
Cigarette smoking is an established risk factor for pancreatic cancer but an updated quantification of the association is lacking. Our aim is to provide the most accurate and updated estimate of the ...dose–response relationships between cigarette smoking and pancreatic cancer risk.
Using an innovative approach for the identification of original publications, we conducted a systematic review and meta-analysis of epidemiological studies published on the issue up to April 2017. Random effects models were used to provide pooled estimates for the cigarette smoking status; dose–risk relationships were evaluated using one-stage random effects models with restricted cubic splines.
Seventy-eight studies were included, providing a pooled relative risk (RR) of pancreatic cancer of 1.8 (95% confidence interval, CI: 1.7–1.9) for the current and 1.2 (95% CI: 1.1–1.2) for the former vs. never smokers. A sharp increase in pancreatic cancer risk was found already with a low number of cigarettes and up to 30 cigarettes/day (RR 2.2, 95% CI: 1.9–2.4). Similarly, the risk of pancreatic cancer steady increased after a few years of smoking up to 30 years (RR 1.8, 95% CI: 1.6–2.0). The risk rapidly decreased with increasing time since quitting and was 0.6 (95% CI: 0.5–0.7, for the former vs. current smokers) after 20 years of quitting.
The present meta-analysis indicates that pancreatic cancer risk sharply increases with a low number of cigarettes or after a few years of smoking and that it rapidly decreases a few years after cessation, although it takes almost 20 years to reach that of never smokers.
•An innovative methodology for the conduction of the systematic review was used.•The excess risk in pancreatic cancer is 82% for the current and 17% for ex-smokers.•Pancreatic cancer risk strongly increases already for a low number of cigarettes and duration of use.•The risk of ex-smokers rapidly declines, reaching that of never smokers after 20 years since quitting.•Avoiding smoking is a relevant measure for the prevention of this highly lethal neoplasm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background/objectives
Several epidemiological studies have analyzed the associations between red and processed meat and bladder cancer risk but the shape and strength of the associations are still ...unclear. Therefore, we conducted a dose–response meta-analysis to quantify the potential association between red and processed meat and bladder cancer risk.
Methods
Relevant studies were identified by searching the PubMed database through January 2016 and reviewing the reference lists of the retrieved articles. Results were combined using random-effects models.
Results
Five cohort studies with 3262 cases and 1,038,787 participants and 8 cases–control studies with 7009 cases and 27,240 participants met the inclusion criteria. Red meat was linearly associated with bladder cancer risk in case–control studies, with a pooled RR of 1.51 (95% confidence interval (CI) 1.13, 2.02) for every 100 g increase per day, while no association was observed among cohort studies (
P
heterogeneity across study design = 0.02). Based on both case–control and cohort studies, the pooled relative risk (RR) for every 50 g increase of processed meat per day was 1.20 (95% CI 1.06, 1.37) (
P
heterogeneity across study design = 0.22).
Conclusions
This meta-analysis suggests that processed meat may be positively associated with bladder cancer risk. A positive association between red meat and risk of bladder cancer was observed only in case–control studies, while no association was observe in prospective studies.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
The association between fish consumption and rheumatoid arthritis (RA) is unclear. The aim of this paper was to summarize the available evidence on the association between fish consumption and risk ...of RA using a dose-response meta-analysis.
Relevant studies were identified by a search of MEDLINE and EMBASE through December 2013, with no restrictions. A random-effects dose-response meta-analysis was conducted to combine study specific relative risks. Potential non-linear relation was investigated using restricted cubic splines. A stratified analysis was conducted by study design.
Seven studies (four case-controls and three prospective cohorts) involving a total of 174 701 participants and 3346 cases were included in the meta-analysis. For each one serving per week increment in fish consumption, the relative risk (RR) of RA was 0.96 (95% confidence interval (CI) 0.91 to 1.01). Results did not change when stratifying by study design. No heterogeneity or publication bias was observed. When fish consumption was modeled using restricted cubic splines, the risk of RA was 20 to 24% lower for 1 up to 3 servings per week of fish (RR =0.76, 95% CI: 0.57 to 1.02) as compared to never consumption.
Results from this dose-response meta-analysis showed a non-statistically significant inverse association between fish consumption and RA.
Artificial intelligence (AI) as an independent reader of screening mammograms has shown promise, but there are few prospective studies. Our aim was to conduct a prospective clinical trial to examine ...how AI affects cancer detection and false positive findings in a real-world setting.
ScreenTrustCAD was a prospective, population-based, paired-reader, non-inferiority study done at the Capio Sankt Göran Hospital in Stockholm, Sweden. Consecutive women without breast implants aged 40–74 years participating in population-based screening in the geographical uptake area of the study hospital were included. The primary outcome was screen-detected breast cancer within 3 months of mammography, and the primary analysis was to assess non-inferiority (non-inferiority margin of 0·15 relative reduction in breast cancer diagnoses) of double reading by one radiologist plus AI compared with standard-of-care double reading by two radiologists. We also assessed single reading by AI alone and triple reading by two radiologists plus AI compared with standard-of-care double reading by two radiologists. This study is registered with ClinicalTrials.gov, NCT04778670.
From April 1, 2021, to June 9, 2022, 58 344 women aged 40–74 years underwent regular mammography screening, of whom 55 581 were included in the study. 269 (0·5%) women were diagnosed with screen-detected breast cancer based on an initial positive read: double reading by one radiologist plus AI was non-inferior for cancer detection compared with double reading by two radiologists (261 0·5% vs 250 0·4% detected cases; relative proportion 1·04 95% CI 1·00–1·09). Single reading by AI (246 0·4% vs 250 0·4% detected cases; relative proportion 0·98 0·93–1·04) and triple reading by two radiologists plus AI (269 0·5% vs 250 0·4% detected cases; relative proportion 1·08 1·04–1·11) were also non-inferior to double reading by two radiologists.
Replacing one radiologist with AI for independent reading of screening mammograms resulted in a 4% higher non-inferior cancer detection rate compared with radiologist double reading. Our study suggests that AI in the study setting has potential for controlled implementation, which would include risk management and real-world follow-up of performance.
Swedish Research Council, Swedish Cancer Society, Region Stockholm, and Lunit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Results from epidemiological studies of milk consumption and mortality are inconsistent. We conducted a systematic review and meta-analysis of prospective studies assessing the association of ...non-fermented and fermented milk consumption with mortality from all causes, cardiovascular disease, and cancer. PubMed was searched until August 2015. A two-stage, random-effects, dose-response meta-analysis was used to combine study-specific results. Heterogeneity among studies was assessed with the I² statistic. During follow-up periods ranging from 4.1 to 25 years, 70,743 deaths occurred among 367,505 participants. The range of non-fermented and fermented milk consumption and the shape of the associations between milk consumption and mortality differed considerably between studies. There was substantial heterogeneity among studies of non-fermented milk consumption in relation to mortality from all causes (12 studies; I² = 94%), cardiovascular disease (five studies; I² = 93%), and cancer (four studies; I² = 75%) as well as among studies of fermented milk consumption and all-cause mortality (seven studies; I² = 88%). Thus, estimating pooled hazard ratios was not appropriate. Heterogeneity among studies was observed in most subgroups defined by sex, country, and study quality. In conclusion, we observed no consistent association between milk consumption and all-cause or cause-specific mortality.
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