Multivariate Dose-Response Meta-Analysis: The dosresmeta R Package

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

Novel methods for dose-response meta-analysis

Dose–response meta-analysis is a statistical procedure for combining and contrasting the evidence on the association between a continuous exposure and the risk of a health outcome. Different papers refined selected aspects of the methodology, such as implementation of flexible strategies and extensions to multivariate meta-analysis. However, there were still several relevant questions that needed to be addressed. This thesis aims to address these issues by developing and implementing new strategies and ad-hoc measures (Paper I), including tools for evaluating the goodness-of-fit (Paper II), a new measure for quantifying the impact of heterogeneity (Paper III), a strategy to deal with differences in the exposure range across studies (Paper IV), and a one-stage approach to estimate complex models without excluding relevant studies (Paper V). In Paper I, we described the implementation of the main aspects of the methodology in the dosresmeta R package available on CRAN. Dedicated functions were written to facilitate specific tasks such as definition of the design matrix and prediction of the pooled results. We illustrated how to estimate both linear and non-linear curves, conduct test of hypotheses, and present the results in a tabular and graphical format reanalyzing published aggregated dose–response data. In Paper II, we discussed how to evaluate the goodness-of-fit. The proposed solutions consist of descriptive measures to summarize the agreement between fitted and observed data (the deviance and the coefficient of determination), and graphical tools to visualize the fit of the model (decorrelated residuals-versus-exposure plot). A reanalysis of two published meta-analyses exemplified how these tools can improve the practice of quantitative synthesis of aggregated dose–response data. In Paper III, we proposed and characterized a new measure, Rˆb, to quantify the proportion of the variance of the pooled estimate attributable to the between-study heterogeneity. Contrary to the available measures of heterogeneity, Rˆb does not make any assumption about the distribution of the within-study error variances, nor does it require specification of a typical value for these quantities. The performance of the proposed measure was evaluated in an extensive simulation study. We demonstrated how to present and interpret the Rˆb -analyzing three published meta-analyses. In Paper IV, we extended a point-wise approach to dose–response meta-analysis of aggregated data. The strategy consists of combining predicted relative risks for a fine grid of exposure values based on potentially different dose–response models. A point-wise approach can improve the flexibility in modeling the study-specific curves and may limit the impact of extrapolation by predicting the studyspecific relative risks based on the observe exposure range. We illustrated the methodology using both individual and aggregated participant data. In Paper V, we formalized a one-stage approach for dose–response meta-analysis in terms of a linear mixed model. We explained the main aspects of the methodology and how to address the same questions frequently answered in a two-stage analysis. Using both hypothetical and real data, we showed how the one-stage approach can facilitate the assessment of heterogeneity over the exposure range, model comparison, and prediction of individual dose–response associations. The main advantage is that flexible curves can be estimated regardless of the number of data-points in the individual analyses. In conclusion, the methods presented in this thesis enrich the set of tools available for applying dose–response meta-analyses and for addressing specific questions including goodness-of-fit evaluation (Paper II) and quantification of heterogeneity (Paper III). In addition, we presented alternative models for pooling results in case of heterogeneous exposure range (Paper IV) and for estimating complex models without excluding relevant studies (Paper V). The proposed methods have been illustrated using real data and implemented in user-friendly R packages available on CRAN (Paper I)

Risk of childhood leukemia and exposure to outdoor air pollution. Updated review and dose-response meta-analysis

Leukemia is the most frequent malignant disease of childhood. Most epidemiologic studies have suggested that exposure to traffic pollutants may increase the risk of childhood leukemia. We updated our previous review and metaanalysis as some recent studies have now available, and we also performed a dose-response metaanalysis using traffic estimators

Transperineal template saturation and conventional biopsy for stage prediction in prostate cancer

OBJECTIVE To evaluate the performance of risk calculators (RCs) predicting lymph node invasion (LNI) and extraprostatic extension (EPE) in men undergoing transperineal magnetic resonance imaging/transrectal ultrasound (TRUS)-fusion template saturation biopsy (TTSB) and conventional systematic TRUS-guided biopsy (SB). PATIENTS AND METHODS The RCs were tested in a consecutive cohort of 645 men undergoing radical prostatectomy with extended pelvic LN dissection between 2005 and 2019. TTSB was performed in 230 (35.7%) and SB in 415 (64.3%) men. Risk of LNI and EPE was calculated using the available RCs. Discrimination, calibration, and clinical usefulness stratified by different biopsy techniques were assessed. RESULTS Lymph node invasion was observed in 23 (10%) and EPE in 73 (31.8%) of cases with TTSB and 53 (12.8%) and 158 (38%) with SB, respectively. RCs showed an excellent discrimination and acceptable calibration for prediction of LNI based on TTSB (area under the curve [AUC]/risk estimation: Memorial Sloan Kettering Cancer Center [MSKCC]-RC 0.79/-4%, Briganti (2012)-RC 0.82/-4%, Gandaglia-RC 0.81/+6%). These were comparable in SB (MSKCC-RC 0.78/+2%; Briganti (2012)-RC 0.77/-3%). Decision curve analysis (DCA) revealed a net benefit at threshold probabilities between 3% and 6% when TTSB was used. For prediction of EPE based on TTSB an inferior discrimination and variable calibration were observed (AUC/risk estimation: MSKCC-RC 0.71/+8% and Martini (2018)-RC 0.69/+2%) achieving a net benefit on DCA only at risk thresholds of >17%. Performance of RCs for prediction of LNI and EPE based on SB showed comparable results with a better performance in the DCA for LNI (risk thresholds 1-2%) and poorer performance for EPE (risk threshold >20%). This study is limited by its retrospective single-institution design. CONCLUSIONS The potentially more accurate grading ability of TTSB did not result in improved performance of preoperative RCs. Prediction tools for LNI proved clinical usefulness while RCs for EPE did not

Some new well-posedness results for continuity and transport equations, and applications to the chromatography system

We obtain various new well-posedness results for continuity and transport equations, among them an existence and uniqueness theorem (in the class of strongly continuous solutions) in the case of nearly incompressible vector fields, possibly having a blow-up of the BV norm at the initial time. We apply these results (valid in any space dimension) to the k x k chromatography system of conservation laws and to the k x k Keyfitz and Kranzer system, both in one space dimension.Comment: 33 pages, minor change

Meta-Analysis of Potassium Intake and the Risk of Stroke

Background-—The possibility that lifestyle factors such as diet, specifically potassium intake, may modify the risk of stroke has been suggested by several observational cohort studies, including some recent reports. We performed a systematic review and meta-analysis of existing studies and assessed the dose–response relation between potassium intake and stroke risk. Methods and Results-—We reviewed the observational cohort studies addressing the relation between potassium intake, and incidence or mortality of total stroke or stroke subtypes published through August 6, 2016. We carried out a meta-analysis of 16 cohort studies based on the relative risk (RR) of stroke comparing the highest versus lowest intake categories. We also plotted a pooled dose–response curve of RR of stroke according to potassium intake. Analyses were performed with and without adjustment for blood pressure. Relative to the lowest category of potassium intake, the highest category of potassium intake was associated with a 13% reduced risk of stroke (RR=0.87, 95% CI 0.80–0.94) in the blood pressure–adjusted analysis. Summary RRs tended to decrease when original estimates were unadjusted for blood pressure. Analysis for stroke subtypes yielded comparable results. In the spline analysis, the pooled RR was lowest at 90 mmol of potassium daily intake (RRs=0.78, 95% CI 0.70–0.86) in blood pressure–adjusted analysis, and 0.67 (95% CI 0.57–0.78) in unadjusted analysis. Conclusions-—Overall, this dose–response meta-analysis confirms the inverse association between potassium intake and stroke risk, with potassium intake of 90 mmol (!3500 mg)/day associated with the lowest risk of stroke

Estimates of Mortality Benefit From Ideal Cardiovascular Health Metrics: A Dose Response Meta-Analysis

Background Several studies have shown an inverse relationship between ideal cardiovascular health (CVH) and mortality. However, there are no studies that pool these data to show the shape of the relationship and quantify the mortality benefit from ideal CVH. Methods and Results We conducted a systematic internet literature search of multiple databases including MEDLINE, Web of Science, Embase, CINAHL, and Scopus for longitudinal studies assessing the relationship between ideal CVH and mortality in adults, published between January 1, 2010, and May 31, 2017. We included studies that assessed the relationship between ideal CVH and mortality in populations that were initially free of cardiovascular disease. We conducted a dose‐response meta‐analysis generating both study‐specific and pooled trends from the correlated log hazard ratio estimates of mortality across categories of ideal CVH metrics. A total of 6 studies were included in the meta‐analysis. All of the studies indicated a linear decrease in (cardiovascular disease and all‐cause) mortality with increasing ideal CVH metrics. Overall, each unit increase in CVH metrics was associated with a pooled hazard ratio for cardiovascular disease mortality of 0.81 (95% confidence interval, 0.75–0.87), while each unit increase in ideal CVH metrics was associated with a pooled hazard ratio of 0.89 (95% confidence interval, 0.86–0.93) for all‐cause mortality. Conclusions Our meta‐analysis showed a strong inverse linear dose‐response relationship between ideal CVH metrics and both all‐cause and cardiovascular disease–related mortality. This study suggests that even modest improvements in CVH is associated with substantial mortality benefit, thus providing a strong public health message advocating for even the smallest improvements in lifestyle

Association between Outdoor Air Pollution and Childhood Leukemia: A Systematic Review and Dose-Response Meta-Analysis.

BackgroundA causal link between outdoor air pollution and childhood leukemia has been proposed, but some older studies suffer from methodological drawbacks. To the best of our knowledge, no systematic reviews have summarized the most recently published evidence and no analyses have examined the dose-response relation.ObjectiveWe investigated the extent to which outdoor air pollution, especially as resulting from traffic-related contaminants, affects the risk of childhood leukemia.MethodsWe searched all case-control and cohort studies that have investigated the risk of childhood leukemia in relation to exposure either to motorized traffic and related contaminants, based on various traffic-related metrics (number of vehicles in the closest roads, road density, and distance from major roads), or to measured or modeled levels of air contaminants such as benzene, nitrogen dioxide, 1,3-butadiene, and particulate matter. We carried out a meta-analysis of all eligible studies, including nine studies published since the last systematic review and, when possible, we fit a dose-response curve using a restricted cubic spline regression model.ResultsWe found 29 studies eligible to be included in our review. In the dose-response analysis, we found little association between disease risk and traffic indicators near the child's residence for most of the exposure range, with an indication of a possible excess risk only at the highest levels. In contrast, benzene exposure was positively and approximately linearly associated with risk of childhood leukemia, particularly for acute myeloid leukemia, among children under 6 y of age, and when exposure assessment at the time of diagnosis was used. Exposure to nitrogen dioxide showed little association with leukemia risk except at the highest levels.DiscussionOverall, the epidemiologic literature appears to support an association between benzene and childhood leukemia risk, with no indication of any threshold effect. A role for other measured and unmeasured pollutants from motorized traffic is also possible. https://doi.org/10.1289/EHP4381

Morbidity and mortality after robot-assisted radical cystectomy with intracorporeal urinary diversion in octogenarians: results from the European Association of Urology Robotic Urology Section Scientific Working Group

OBJECTIVES: To evaluate the postoperative complication and mortality rate following laparoscopic radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in octogenarians. PATIENTS AND METHODS: We conducted a retrospective analysis comparing postoperative complication and mortality rates depending on age in a consecutive series of 1890 patients who underwent RARC with ICUD for bladder cancer between 2004 and 2018 in 10 European centres. Outcomes of patients aged <80 years and those aged ≥80 years were compared with regard to postoperative complications (Clavien–Dindo grading) and mortality rate. Cancer-specific mortality (CSM) and other-cause mortality (OCM) after surgery were calculated using the non-parametric Aalen-Johansen estimator. RESULTS: A total of 1726 patients aged <80 years and 164 aged ≥80 years were included in the analysis. The 30- and 90-day rate for high-grade (Clavien–Dindo grades III–V) complications were 15% and 21% for patients aged <80 years compared to 11% and 13% for patients aged ≥80 years (P = 0.2 and P = 0.03), respectively. In a multivariable logistic regression analysis adjusting for pre- and postoperative variables, age ≥80 years was not an independent predictor of high-grade complications (odds ratio 0.6, 95% confidence interval 0.3–1.1; P = 0.12). The non-cancer-related 90-day mortality was 2.3% for patients aged ≥80 years and 1.8% for those aged <80 years, respectively (P = 0.7). The estimated 12-month CSM and OCM rates for those aged <80 years were 8% and 3%, and for those aged ≥80 years, 15% and 8%, respectively (P = 0.009 and P < 0.001). CONCLUSIONS: The minimally invasive approach to RARC with ICUD for bladder cancer in well-selected elderly patients (aged ≥80 years) achieved a tolerable high-grade complication rate; the 90-day postoperative mortality rate was driven by cancer progression and the non-cancer-related rate was equivalent to that of patients aged <80 years. However, an increased OCM rate in this elderly group after the first year should be taken into account. These results will support clinicians and patients when balancing cancer-related vs treatment-related risks and benefits