Multivariate Random-effects Meta-analysis Research Articles

Individual participant data meta-analysis to examine linear or non-linear treatment-covariate interactions at multiple time-points for a continuous outcome.

Individual participant data (IPD) meta-analysis projects obtain, harmonise, and synthesise original data from multiple studies. Many IPD meta-analyses of randomised trials are initiated to identify treatment effect modifiers at the individual level, thus requiring statistical modelling of interactions between treatment effect and participant-level covariates. Using a two-stage approach, the interaction is estimated in each trial separately and combined in a meta-analysis. In practice, two complications often arise with continuous outcomes: examining non-linear relationships for continuous covariates and dealing with multiple time-points. We propose a two-stage multivariate IPD meta-analysis approach that summarises non-linear treatment-covariate interaction functions at multiple time-points for continuous outcomes. A set-up phase is required to identify a small set of time-points; relevant knot positions for a spline function, at identical locations in each trial; and a common reference group for each covariate. Crucially, the multivariate approach can include participants or trials with missing outcomes at some time-points. In the first stage, restricted cubic spline functions are fitted and their interaction with each discrete time-point is estimated in each trial separately. In the second stage, the parameter estimates defining these multiple interaction functions are jointly synthesised in a multivariate random-effects meta-analysis model accounting for within-trial and across-trial correlation. These meta-analysis estimates define the summary non-linear interactions at each time-point, which can be displayed graphically alongside confidence intervals. The approach is illustrated using an IPD meta-analysis examining effect modifiers for exercise interventions in osteoarthritis, which shows evidence of non-linear relationships and small gains in precision by analysing all time-points jointly.

Association between ambient temperature and influenza prevalence: A nationwide time-series analysis in 201 Chinese cities from 2013 to 2018

BackgroundTemperature affects influenza transmission; however, currently, limited evidence exists about its effect in China at the national and city levels as well as how temperature can be integrated into influenza interventions. MethodsMeteorological, pollutant, and influenza data from 201 cities in mainland China between 2013 and 2018 were analyzed at both the city and national levels to investigate the relationship between temperature and influenza prevalence. We examined the impact of temperature on the time-varying reproduction number (Rt) using generalized additive quasi-Poisson regression models combined with the distributed lag nonlinear model. Threshold temperatures were determined for seven regions based on the early warning threshold of serious influenza outbreaks, set at Rt = 1.2. A multivariate random-effects meta-analysis was employed to assess region-specific associations. The excess risk (ER) index was defined to investigate the correlation between Rt and temperature, modified based on seasonal and regional characteristics. ResultsAt the national level and in the central, northern, northwestern, and southern regions, temperature was found to be negatively correlated with relative risk, whereas the shapes of the data curves for the eastern, southwestern, and northeastern regions were not well defined. Low temperatures had an observable effect on influenza prevalence; however, the effects of high temperatures were not obvious. At an Rt of 1.2, the threshold temperatures for reaching a warning for serious influenza outbreaks were − 24.3 °C in the northeastern region, 16.6 °C in the northwestern region, and between 1℃ and 10 °C in other regions. ConclusionThe study findings revealed that temperature had a varying effect on influenza transmission trends (Rt) across different regions in China. By identifying region-specific temperature thresholds at Rt = 1.2, more effective early warning systems for influenza outbreaks could be tailored. These findings emphasize the significance of the region-specific adaptation of influenza prevention and control measures.

Meta-Analysis of Social Presence Effects on Stroop Task Performance.

In this paper, we conducted a meta-analytic review to examine the impact of social presence on individuals' performance on the Stroop task, shedding light on the cognitive processes underlying social facilitation. We followed PRISMA guidelines to identify and include 33 relevant studies in a multivariate random-effects meta-analysis. Our results show that social presence reliably modulates Stroop interference (a measure of cognitive control); specifically, participants exhibit lower Stroop interference when performing the task in the presence of others compared to performing it in isolation. We also found that the strength of the effect varies depending on the type of social presence: it is stronger with an attentive audience compared to an inattentive one, and null with an evaluative audience. Additionally, different features of the Stroop task itself moderate the effect; the effect is stronger for the classic version of the task compared to the semantic version, and for experiments that use mixed within-block trials compared to those with homogenous blocks. We also observed a negative relationship between the number of trials and the magnitude of the effect. Overall, these findings provide insights into the mechanisms by which the presence of others affects performance on the Stroop task, and how they align with social facilitation theories.

Countrywide analysis of heat- and cold-related mortality trends in the Czech Republic: growing inequalities under recent climate warming.

Only little is known about trends in temperature-mortality associations among the most vulnerable subgroups, especially in the areas of central and eastern Europe, which are considered major climatic hotspots in terms of heatwave exposure. Thus, we aimed to assess trends in temperature-related mortality in the Czech Republic by sex, age and cause of death, and to quantify the temporal evolution of possible inequalities. We collected daily time series of all-cause (1987-2019) and cause-specific (1994-2019) mortality by sex and age category, and population-weighted daily mean 2-metre temperatures for each region of the Czech Republic. We applied a quasi-Poisson regression model to estimate the trends in region-specific temperature-mortality associations, with distributed lag non-linear models and multivariate random-effects meta-analysis to derive average associations across the country. We then calculated mortality attributable to non-optimal temperatures and implemented the indicator of sex- and age-dependent inequalities. We observed a similar risk of mortality due to cold temperatures for men and women. Conversely, for warm temperatures, a higher risk was observed for women. Results by age showed a clear pattern of increasing risk due to non-optimum temperatures with increasing age category. The relative risk (RR) related to cold was considerably attenuated in most of the studied subgroups during the study period, whereas an increase in the RR associated with heat was seen in the overall population, in women, in the age category 90+ years and with respect to respiratory causes. Moreover, underlying sex- and age-dependent inequalities experienced substantial growth. Our findings suggest ongoing adaptation to cold temperatures. Mal/adaptation to hot temperatures occurred unequally among population subgroups and resulted in growing inequalities between the sexes and among age categories.

Comparative effects of warming systems applied to different parts of the body on hypothermia in adults undergoing abdominal surgery: A systematic review and network meta-analysis of randomized controlled trials

Study objectiveThe prevention of perioperative hypothermia after anesthesia induction is a critical concern in patients undergoing abdominal surgery. The effectiveness of various warming systems for preventing hypothermia and shivering when applied to specific areas of the body remains undetermined. DesignSystematic review and network meta-analysis. SettingOperating room. InterventionFive electronic databases were searched, including only randomized control trials (RCTs) reporting the effects of warming systems applied to specific body sites on the intraoperative core temperature and postoperative risk of shivering in adults undergoing abdominal surgery. A multivariate random-effects network meta-analysis with a frequentist framework was implemented for data analysis. MeasurementsThe primary outcome was the core body temperature 60 and 120 min after anesthesia induction for abdominal surgery. The secondary outcome was the incidence of postoperative shivering. ResultsThis review comprised a total of 24 RCTs including 1119 patients. At 60 and 120 min after anesthesia induction, a forced-air warming system applied to the upper body (0.3 °C and 95% confidence intervals = [0.3 to 0.4], 1.0 °C [0.7 to 1.3]), lower body (0.4 °C [0.3 to 0.5], 0.9 °C [0.5 to 1.2]), and underbody (0.5 °C [0.5 to 0.6], 1.2 °C [0.9 to 1.6]) was superior to passive insulation in terms of core body temperature regulation. Compared with passive insulation, the forced-air warming system applied to the lower body (odds ratio = 0.06) or underbody (0.44) and the electric heating blanket to the lower body (0.02) or the whole body (0.07) significantly reduced the risk of shivering. ConclusionsThe results of this NMA revealed that forced-air warming with an underbody blanket effectively elevates core body temperatures in 60 and 120 min after induction of anesthesia and prevents shivering in patients recovering from abdominal surgery.

A meta-analytic review of the effectiveness of psychological treatment of functional/dissociative seizures on non-seizure outcomes in adults.

Psychological therapies are considered the treatment of choice for functional/dissociative seizures (FDSs). Although most previous studies have focused on seizure persistence or frequency, it has been argued that well-being or health-related quality of life outcomes may actually be more meaningful. This study contributes by summarizing and meta-analyzing non-seizure outcomes to quantify the effectiveness of psychological treatment in this patient group. A pre-registered systematic search identified treatment studies (e.g., cohort studies, controlled trials) in FDSs. Data from these studies were synthesized using multi-variate random-effects meta-analysis. Moderators of treatment effect were examined using treatment characteristics, sample characteristics, and risk of bias. A total of 171 non-seizure outcomes across 32 studies with a pooled sample size of N = 898 yielded a pooled effect-size of d = .51 (moderate effect size). The outcome domain assessed and the type of psychological treatment were significant moderators of reported outcomes. Greater rates of improvement were demonstrated for outcomes assessing general functioning. Behavioral treatments emerged as particularly effective interventions. Psychological interventions are associated with clinical improvements across a broad array of non-seizure outcomes, over and above seizure frequency, in adults with FDSs.

Exploring the association between precipitation and hospital admission for mental disorders in Switzerland between 2009 and 2019.

While several studies proved the relationship between increasing temperatures and poor mental health, limited evidence exists on the effect of other weather factors, such as precipitation. This study assessed the impact of precipitation on hospital admissions for mental disorders in Switzerland between 2009-2019. We defined different precipitation events based on the duration (daily precipitation ≥1mm for 2, 3, or 4 days; PP.2/PP.3/PP.4) and intensity (≥90th percentile for 2 consecutive days; PEP90.2). First, we conducted aggregated time-stratified case-crossover analysis in eight main Swiss cities with distributed lag models to assess the association up to 3 days after the exposure. Then, we pooled the estimates in each city using a multivariate random effects meta-analysis for all hospital admissions and by subgroups (sex, age, diagnosis). Evidence of an association between precipitation and hospital admission for mental disorders was not found in Switzerland (PP.2: 1.003[0.978-1.029]; PP.3: 1.005[0.985-1.026]; PP.4: 0.994[0.960-1.030]; PEP90.2: 1.000[0.953-1.050]). Although the results were highly uncertain, we found an indication of increasing risks of hospital admission with increasing intensity of precipitation in warmer seasons (PP.2: 1.001[0.971-1.032] vs PEP90.2: 1.014[0.955-1.078]), while the risks of hospital admission slightly increased by the duration in colder season (PP.2: 1.009[0.981-1.039]; PP.3: 1.008[0.980-1.036]; PP.4: 1.017[0.956-1.081]). Overall, risks tend to be higher in people aged < 65 years. Duration of the events may influence more than intensity in females, while opposite patterns were observed in males. Risks tended to be larger but still uncertain for schizophrenia, mood disorders, and adult personality disorders. An indication of a negative association was found in neurotic disorders and null risks in the remaining groups. Although our findings did not show a clear association between precipitation and mental disorders, further research is required to clarify the role of precipitation and the potential implications of climate change and extreme precipitation events on mental health.

Ambient temperature and nervous system diseases-related mortality in Japan from 2010 to 2019: A time-stratified case-crossover analysis

BackgroundDespite the substantial disease burden caused by nervous system diseases, few studies have examined the association between ambient temperature and nervous system diseases, especially during cold seasons. Evidence for specific disease subgroups such as Alzheimer's and Parkinson's is also lacking. ObjectivesThis study examined the association between short-term changes in ambient temperature and nervous system diseases-related mortality in ten Japanese prefectures from 1 January 2010 to 31 December 2019. MethodsA two-stage analysis based on a time-stratified case-crossover study design was conducted. A conditional quasi-Poisson regression model with a distributed lag non-linear model for temperature was applied followed by a multivariate random-effects meta-analysis to obtain average associations. Mortality due to all and cause-specific nervous system diseases (major neurodegenerative diseases, Alzheimer's, and Parkinson's) were analyzed, with consideration for sex and age (0–84 and 85+ years old) subgroups. ResultsWe analyzed 162,315 death cases due to nervous system diseases. Cold was associated with all categories of nervous system diseases-related mortality, but not heat. The estimated relative risks for cold, obtained by comparing the 2.5th percentile of daily mean temperature distribution to the minimum mortality temperature (MMT), were 1.43 (95 % CI: 1.28–1.60), 1.37 (95 % CI: 1.17–1.59), 1.53 (95 % CI: 1.07–2.01), and 1.54 (95 % CI: 1.13–2.10) for all nervous system diseases, major neurodegenerative diseases, Alzheimer's, and Parkinson's, respectively. These associations were also observed in the sex and age subgroups in general but without evidence of effect modification. Heat (the 97.5th percentile of daily mean temperature distribution vs. MMT) was associated with Parkinson’s disease-related mortality among those aged 85 years and over. DiscussionCold was associated with an increased risk of nervous system disease-related mortality. The effect of heat was not observed, except for mortality among the elderly aged 85 years and older with Parkinson's disease.

Respiratory support strategy in adults with acute hypoxemic respiratory failure: a systematic review and network meta-analysis.

IntroductionNetwork meta-analyses (NMAs) of respiratory management strategies for acute hypoxemic respiratory failure (AHRF) have been reported, but no previous study has compared noninvasive ventilation (NIV), high-flow nasal oxygen (HFNO), standard oxygenation therapy (SOT), and invasive mechanical ventilation (IMV) for de novo AHRF. Therefore, we conducted an NMA to assess the effectiveness of these four respiratory strategies in patients with de novo AHRF.MethodsThe Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Ichushi databases were searched. Studies including adults aged ≥18 years with AHRF and RCTs that compared two different oxygenation techniques (SOT, NIV, HFNO, or IMV) were selected. A frequentist-based approach with multivariate random-effects meta-analysis was used. The outcomes were mortality and intubation rates.ResultsAmong the 14,263 records initially identified, 25 studies (3302 patients) were included. In the analysis of mortality, compared to SOT, NIV (risk ratio [RR], 0.76; 95% confidence interval [CI], 0.61–0.95) reduced mortality; however, IMV (RR, 1.01; 95% CI, 0.57–1.78) and HFNO (RR, 0.89; 95% CI, 0.66–1.20) did not. For assessments of the intubation incidence, compared to SOT, NIV use (RR, 0.63; 95% CI, 0.51–0.79) was associated with a reduction in intubation, but HFNO (RR, 0.82; 95% CI, 0.61–1.11) was not significant.ConclusionsOur NMA demonstrated that only NIV showed clinical benefits compared with SOT as an initial respiratory strategy for de novo AHRF. Further investigation, especially comparison with HFNO, is warranted.Trial registrationPROSPERO (registration number: CRD42020213948, 11/11/2020).Supplementary InformationThe online version contains supplementary material available at 10.1186/s40981-022-00525-4.

Trajectory of Antidepressant Effects after Single- or Two-Dose Administration of Psilocybin: A Systematic Review and Multivariate Meta-Analysis.

We examined the cardiovascular safety, acceptability, and trajectory of the antidepressant effects of psilocybin after single- or two-dose administration. Four major electronic databases were systematically searched. Data were pooled using a multivariate random-effects meta-analysis. Primary outcomes were changes in depressive symptoms. Secondary outcomes were cardiovascular safety and acceptability. Ten studies were included. The estimated effect sizes (standardized mean difference (SMD) with 95% confidence intervals) for psilocybin were −0.75 (−1.15 to −0.35) on day 1, −1.74 (−2.15 to −1.32) at 1 week, −1.35 (−1.77 to −0.93) at 1 month, −0.91 (−1.31 to −0.51) at 3 months, and −1.12 (−1.56 to −0.68) at 6 months. Higher doses and two sessions of psilocybin treatment were significantly associated with superior antidepressant effects. The all-cause discontinuation and heart rate after psilocybin administration were comparable to placebo; meanwhile, psilocybin increased systolic and diastolic blood pressure by 19.00 mmHg and 8.66 mmHg, respectively. There were no significant differences between SMD derived from placebo-controlled trials compared to those from pre–post changes and SMD in randomized controlled trials (RCTs) compared to those in non-RCTs. The present study demonstrates that single- or two-dose psilocybin administration has rapid and sustained antidepressant effects for up to 6 months, with favorable cardiovascular safety and acceptability.

Association of noninvasive respiratory support with mortality and intubation rates in acute respiratory failure: a systematic review and network meta-analysis

BackgroundNoninvasive respiratory support devices may reduce the tracheal intubation rate compared with conventional oxygen therapy (COT). To date, few studies have compared high-flow nasal cannula (HFNC) use with noninvasive positive-pressure ventilation (NPPV). We conducted a network meta-analysis to compare the effectiveness of three respiratory support devices in patients with acute respiratory failure.MethodsThe Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Ichushi databases were searched. Studies including adults aged ≥ 16 years with acute hypoxic respiratory failure and randomized-controlled trials that compared two different oxygenation devices (COT, NPPV, or HFNC) before tracheal intubation were included. A frequentist-based approach with a multivariate random-effects meta-analysis was used. The network meta-analysis was performed using the GRADE Working Group approach. The outcomes were short-term mortality and intubation rate.ResultsAmong 5507 records, 27 studies (4618 patients) were included. The main cause of acute hypoxic respiratory failure was pneumonia. Compared with COT, NPPV and HFNC use tended to reduce mortality (relative risk, 0.88 and 0.93, respectively; 95% confidence intervals, 0.76–1.01 and 0.80–1.08, respectively; both low certainty) and lower the risk of endotracheal intubation (0.81 and 0.78; 0.72–0.91 and 0.68–0.89, respectively; both low certainty); however, short-term mortality or intubation rates did not differ (0.94 and 1.04, respectively; 0.78–1.15 and 0.88–1.22, respectively; both low certainty) between NPPV and HFNC use.ConclusionNPPV and HFNC use are associated with a decreased risk of endotracheal intubation; however, there are no significant differences in short-term mortality.Trial registrationPROSPERO (registration number: CRD42020139105, 01/21/2020)

Revised estimates of leprosy disability weights for assessing the global burden of disease: A systematic review and individual patient data meta-analysis.

Leprosy is a chronic bacterial infection caused by Mycobacterium leprae, which may lead to physical disability, stigma, and discrimination. The chronicity of the disease and disabilities are the prime contributors to the disease burden of leprosy. The current figures of the disease burden in the 2017 global burden of disease study, however, are considered to be under-estimated. In this study, we aimed to systematically review the literature and perform individual patient data meta-analysis to estimate new disability weights for leprosy, using Health-Related Quality of Life (HRQOL) data. The search strategy included all major databases with no restriction on language, setting, study design, or year of publication. Studies on human populations that have been affected by leprosy and recorded the HRQOL with the Short form tool, were included. A consortium was formed with authors who could share the anonymous individual-level data of their study. Mean disability weight estimates, sorted by the grade of leprosy disability as defined by WHO, were estimated for individual participant data and pooled using multivariate random-effects meta-analysis. Eight out of 14 studies from the review were included in the meta-analysis due to the availability of individual-level data (667 individuals). The overall estimated disability weight for grade 2 disability was 0.26 (95%CI: 0.18-0.34). For grade 1 disability the estimated weight was 0.19 (95%CI: 0.13-0.26) and for grade 0 disability it was 0.13 (95%CI: 0.06-0.19). The revised disability weight for grade 2 leprosy disability is four times higher than the published GBD 2017 weights for leprosy and the grade 1 disability weight is nearly twenty times higher. The global burden of leprosy is grossly underestimated. Revision of the current disability weights and inclusion of disability caused in individuals with grade 0 leprosy disability will contribute towards a more precise estimation of the global burden of leprosy.

Epidemiology of depressive disorders in people living with hypertension in Africa: a systematic review and meta-analysis

ObjectivesBetter knowledge of epidemiology of depressive disorders in people living with hypertension can help to implement pertinent strategies to address its burden. The objective was to estimate the prevalence of...

Association of Non-Invasive Respiratory Support with Mortality and Intubation Rates in Acute Respiratory Failure: A Systematic Network Meta-Analysis

Background: Non-invasive respiratory support devices may reduce the tracheal intubation rate compared with conventional oxygen therapy (COT). To date, few studies have compared high-flow nasal cannula (HFNC) use with non-invasive positive-pressure ventilation(NPPV). We conducted a network meta-analysis (NMA) to compare the effectiveness of three respiratory support devices in patients with acute respiratory failure. Methods: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Ichushi databases were searched. Adults ≥16 years of age with acute hypoxic respiratory failure and randomised controlled trials that compared two different respiratory support devices(COT,NPPV, or HFNC) before tracheal intubation were included. NMA was performed using a frequentist-based approach with multivariate random effects meta-analysis. The meta-analysis was performed using the GRADE Working Group Approach for an NMA. The primary outcome was short-term mortality, and the secondary outcome was the rate of intubation. Findings: Among 5,093 records, 25 studies (4,372 patients) were included. Compared with COT, NPPV and HFNC tended to reduce mortality (relative risk, 0·88 and 0·92; 95% confidence interval 0·76–1.01 and 0·80–1·07; low and moderate certainties, respectively); however, a significantly lower risk of endotracheal intubation(0·81 and 0·79; 0·71–0·91 and 0·69–0·91; low and moderate certainty, respectively) was observed. There were no significant differences in short-term mortality or endotracheal intubation (0·95 and 1·02;0·78–1·16 and0·86–1·20; respectively; both low certainty) for NPPV and HFNC use. Interpretation: NPPV and HFNC are associated with decreased endotracheal intubation risk, but there are no significant differences in short-term mortality. Funding: None. Declaration of Interests: The authors declare no competing interests.

Contrasting patterns of temperature related mortality and hospitalization by cardiovascular and respiratory diseases in 52 Spanish cities

BackgroundClimate change is a severe public health challenge. Understanding to what extent fatal and non-fatal consequences of specific diseases are associated with temperature may help to improve the effectiveness of preventive public health efforts. This study examines the effects of temperature on deaths and hospital admissions by cardiovascular and respiratory diseases, empathizing the difference between mortality and morbidity. MethodsDaily counts for mortality and hospital admissions by cardiovascular and respiratory diseases were collected for the 52 provincial capital cities in Spain, between 1990 and 2014. The association with temperature in each city was investigated by means of distributed lag non-linear models using quasi-Poisson regression. City-specific exposure-response curves were pooled by multivariate random-effects meta-analysis to obtain countrywide risk estimates of mortality and hospitalizations due to heat and cold, and attributable fractions were computed. ResultsHeat and cold exposure were identified to be associated with increased risk of cardiovascular and respiratory mortality. Heat was not found to have an impact on hospital admissions. The estimated fraction of mortality attributable to cold was of greater magnitude in hospitalizations (17.5% for cardiovascular and 12.5% for respiratory diseases) compared to deaths (9% and 2.7%, respectively). ConclusionsThere were noteworthy differences between temperature-related mortality and hospital admissions regarding cardiovascular and respiratory diseases, hence reinforcing the convenience of cause-specific measures to prevent temperature-related deaths.

Network Analysis of Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement for Stenotic Bicuspid Aortic Valves According to Valve Type

BackgroundIt is currently unknown if outcomes after transcatheter aortic valve replacement (TAVR) differ according to the prosthetic valve deployed in patients with bicuspid aortic valves (BAV). ObjectivesThis study evaluated valve-specific outcomes post-TAVR in patients with BAV. MethodsLiterature search was performed using the Cochrane databases, PubMed, ClinicalTrials, SCOPUS and EMBASE databases from inception until July 2018. We computed risk ratios and their 95% confidence intervals for all outcomes of interest. For each outcome, the data were pooled using a multivariate random-effects meta-analysis including multiple treatment as well as direct and indirect comparisons. ResultsTen studies enrolling a total of 1547 BAV patients undergoing TAVR using 6 different prosthetic valve types were analyzed. There were no significant differences in 30-day all-cause mortality, life-threatening bleeding and device success among the diverse prosthetic valve types implanted. However, 2nd generation balloon-expandable valves had consistently lower risk of moderate-to-severe prosthetic valve regurgitation. ConclusionIn patients with BAV, there were no significant differences in 30-day all-cause mortality after TAVR among the various prosthetic valve types.

Reduction in mortality risk with opioid agonist therapy: a systematic review and meta‐analysis

Opioid agonist therapies are effective medications that can greatly improve the quality of life of individuals with opioid use disorder. However, there is significant uncertainty about the risks of cause-specific mortality in and out of treatment. This systematic review and meta-analysis explored the association between methadone and buprenorphine with cause-specific mortality among opioid-dependent persons. We searched six online databases to identify relevant cohort studies, calculating all-cause and overdose-specific mortality rates during periods in and out of treatment. We pooled mortality estimates using multivariate random effects meta-analysis of the crude mortality rate per 1000 person-years of follow-up as well as relative risks comparing mortality in vs. out of treatment. A total of 32 cohort studies (representing 150235 participants, 805423.6 person-years, and 9112 deaths) met eligibility criteria. Crude mortality rates were substantially higher among methadone cohorts than buprenorphine cohorts. Relative risk reduction was substantially higher with methadone relative to buprenorphine when time in-treatment was compared to time out-of-treatment. Furthermore, the greatest mortality reduction was conferred during the first 4weeks of treatment. Mortality estimates were substantially heterogeneous and varied significantly by country, region, and by the nature of the treatment provider. Precautions are necessary for the safer implementation of opioid agonist therapy, including baseline assessments of opioid tolerance, ongoing monitoring during the induction period, education of patients about the risk of overdose, and coordination within healthcare services.

Trends in temperature-related age-specific and sex-specific mortality from cardiovascular diseases in Spain: a national time-series analysis

Climate change driven by human activities has increased annual temperatures in Spain by around 1°C since 1980. However, little is known regarding the extent to which the association between temperature and mortality has changed among the most susceptible population groups as a result of the rapidly warming climate. We aimed to assess trends in temperature-related cardiovascular disease mortality in Spain by sex and age, and we investigated the association between climate warming and changes in the risk of mortality. We did a country-wide time-series analysis of 48 provinces in mainland Spain and the Balearic Islands between Jan 1, 1980, and Dec 31, 2016. We extracted daily cardiovascular disease mortality data disaggregated by sex, age, and province from the Spanish National Institute of Statistics database. We also extracted daily mean temperatures from the European Climate Assessment and Dataset project. We applied a quasi-Poisson regression model for each province, controlling for seasonal and long-term trends, to estimate the temporal changes in the province-specific temperature-mortality associations with distributed lag non-linear models. We did a multivariate random-effects meta-analysis to derive the best linear unbiased prediction of the temperature-mortality association and the minimum mortality temperature in each province. Heat-attributable and cold-attributable fractions of death were computed by separating the contributions from days with temperatures warmer and colder than the minimum mortality temperature, respectively. Between 1980 and 2016, 4 576 600 cardiovascular deaths were recorded. For warm temperatures, the increase in relative risk (RR) of death from cardiovascular diseases was higher for women than men and higher for older individuals (aged ≥90 years) than younger individuals (aged 60-74 years), whereas for cold temperatures, RRs were higher for men than women, with no clear pattern by age group. The heat-attributable fraction of cardiovascular deaths was higher for women in all age groups, and the cold-attributable fraction was larger in men. The heat-attributable fraction increased with age for both sexes, whereas the cold-attributable fraction increased with age for men and decreased for women. Overall minimum mortality temperature increased from 19·5°C between 1980 and 1994 to 20·2°C between 2002 and 2016, which is similar in magnitude to, and occurred in parallel with, the observed mean increase of 0·77°C that occurred in Spain between these two time periods. In general, between 1980 and 2016, the risk and attributable fraction of cardiovascular deaths due to warm and cold temperatures decreased for men and women across all age groups. For all the age groups combined, between 1980-94 and 2002-16, the heat-attributable fraction decreased by -42·06% (95% empirical CI -44·39 to -41·06) for men and -36·64% (-36·70 to -36·04) for women, whereas the cold-attributable fraction was reduced by -30·23% (-30·34 to -30·05) for men and -44·87% (-46·77 to -42·94) for women. In Spain, the observed warming of the climate has occurred in parallel with substantial adaptation to both high and low temperatures. The reduction in the RR and the attributable fraction associated with heat would be compatible with an adaptive response specifically addressing the negative consequences of climate change. Nevertheless, the simultaneous reduction in the RR and attributable fraction of cold temperatures also highlights the importance of more general factors such as socioeconomic development, increased life expectancy and quality, and improved health-care services in the country. None.

Assessment of extreme heat and hospitalizations to inform early warning systems.

Heat early warning systems and action plans use temperature thresholds to trigger warnings and risk communication. In this study, we conduct multistate analyses, exploring associations between heat and all-cause and cause-specific hospitalizations, to inform the design and development of heat-health early warning systems. We used a two-stage analysis to estimate heat-health risk relationships between heat index and hospitalizations in 1,617 counties in the United States for 2003-2012. The first stage involved a county-level time series quasi-Poisson regression, using a distributed lag nonlinear model, to estimate heat-health associations. The second stage involved a multivariate random-effects meta-analysis to pool county-specific exposure-response associations across larger geographic scales, such as by state or climate region. Using results from this two-stage analysis, we identified heat index ranges that correspond with significant heat-attributable burden. We then compared those with the National Oceanic and Atmospheric Administration National Weather Service (NWS) heat alert criteria used during the same time period. Associations between heat index and cause-specific hospitalizations vary widely by geography and health outcome. Heat-attributable burden starts to occur at moderately hot heat index values, which in some regions are below the alert ranges used by the NWS during the study time period. Locally specific health evidence can beneficially inform and calibrate heat alert criteria. A synchronization of health findings with traditional weather forecasting efforts could be critical in the development of effective heat-health early warning systems.

Efficient two-step multivariate random effects meta-analysis of individual participant data for longitudinal clinical trials using mixed effects models

BackgroundMixed effects models have been widely applied in clinical trials that involve longitudinal repeated measurements, which possibly contain missing outcome data. In meta-analysis of individual participant data (IPD) based on these longitudinal studies, joint synthesis of the regression coefficient parameters can improve efficiency, especially for explorations of effect modifiers that are useful to predict the response or lack of response to particular treatments.MethodsIn this article, we provide a valid and efficient two-step method for IPD meta-analyses using the mixed effects models that adequately addresses the between-studies heterogeneity using random effects models. The two-step method overcomes the practical difficulties of computations and modellings of the heterogeneity in the one-step method, and enables valid inference without loss of efficiency. We also show the two-step method can effectively circumvent the modellings of the between-studies heterogeneity of the variance-covariance parameters and provide valid and efficient estimators for the regression coefficient parameters, which are the primary objects of interests in the longitudinal studies. In addition, these methods can be easily implemented using standard statistical packages, and enable synthesis of IPD from different sources (e.g., from different platforms of clinical trial data sharing systems).ResultsTo assess the proposed method, we conducted simulation studies and also applied the method to an IPD meta-analysis of clinical trials for new generation antidepressants. Through the numerical studies, the validity and efficiency of the proposed method were demonstrated.ConclusionsThe two-step approach is an effective method for IPD meta-analyses of longitudinal clinical trials using mixed effects models. It can also effectively circumvent the modellings of the between-studies heterogeneity of the variance-covariance parameters, and enable efficient inferences for the regression coefficient parameters.