Hierarchical Random-effects Model Research Articles

The anterior and medial open approaches yield superior outcomes compared to the lateral and posterior open approaches in supracondylar humerus fractures in children: a systematic review and network meta-analysis.

This study aimed to perform a systematic review and network meta-analysis (NMA) to examine which open approach is superior in terms of outcomes and complications in the treatment of pediatric supracondylar humerus fractures. MEDLINE/PubMed, Embase, Web of Science, Clinicaltrials.gov, and Cochrane Library were searched from database inception to December 2022 and screened for relevant studies. Data were collected regarding patient demographics, Flynn's functional and cosmetic outcomes, and complications. Unsatisfactory Flynn's and complications were considered negative events. Comparisons of outcomes from aggregate data from each surgical approach using relative risk (RR) with a 95% confidence interval (95% CI) were performed. The NMA of overall negative events was conducted using a Bayesian hierarchical random-effects model analysis. A total of 26 studies involving 1461 patients were included; 459 (31.4%) patients underwent a closed reduction and percutaneous pinning (CRPP), 84 (5.7%) an anterior approach, 240 (16.4%) a medial, 220 (15%) a lateral, and 458 (31.3%) a posterior. The lateral and posterior approaches demonstrate a higher risk of negative event in the NMA compared to CRPP [RR = 2 (1.03, 3.85); RR = 2.63 (1.96, 3.57), respectively], anterior approach [RR = 3.33 (1.11, 10); RR = 4.35 (1.49, 12.5), respectively], and medial approach [RR = 1.82 (1.16, 2.86); RR = 2.38 (1.23, 4.76), respectively]. The medial approach resulted in a similar negative event rate compared to the anterior [RR = 1.82 (0.58, 5.88)]. The anterior and medial open approaches yield superior functional and cosmetic outcomes with fewer complications compared to the lateral and posterior.

Extracorporeal cardiopulmonary resuscitation versus standard treatment for refractory out-of-hospital cardiac arrest: a Bayesian meta-analysis

BackgroundThe outcomes of several randomized trials on extracorporeal cardiopulmonary resuscitation (ECPR) in patients with refractory out-of-hospital cardiac arrest were examined using frequentist methods, resulting in a dichotomous interpretation of results based on p-values rather than in the probability of clinically relevant treatment effects. To determine such a probability of a clinically relevant ECPR-based treatment effect on neurological outcomes, the authors of these trials performed a Bayesian meta-analysis of the totality of randomized ECPR evidence.MethodsA systematic search was applied to three electronic databases. Randomized trials that compared ECPR-based treatment with conventional CPR for refractory out-of-hospital cardiac arrest were included. The study was preregistered in INPLASY (INPLASY2023120060). The primary Bayesian hierarchical meta-analysis estimated the difference in 6-month neurologically favorable survival in patients with all rhythms, and a secondary analysis assessed this difference in patients with shockable rhythms (Bayesian hierarchical random-effects model). Primary Bayesian analyses were performed under vague priors. Outcomes were formulated as estimated median relative risks, mean absolute risk differences, and numbers needed to treat with corresponding 95% credible intervals (CrIs). The posterior probabilities of various clinically relevant absolute risk difference thresholds were estimated.ResultsThree randomized trials were included in the analysis (ECPR, n = 209 patients; conventional CPR, n = 211 patients). The estimated median relative risk of ECPR for 6-month neurologically favorable survival was 1.47 (95%CrI 0.73–3.32) with a mean absolute risk difference of 8.7% (− 5.0; 42.7%) in patients with all rhythms, and the median relative risk was 1.54 (95%CrI 0.79–3.71) with a mean absolute risk difference of 10.8% (95%CrI − 4.2; 73.9%) in patients with shockable rhythms. The posterior probabilities of an absolute risk difference > 0% and > 5% were 91.0% and 71.1% in patients with all rhythms and 92.4% and 75.8% in patients with shockable rhythms, respectively.ConclusionThe current Bayesian meta-analysis found a 71.1% and 75.8% posterior probability of a clinically relevant ECPR-based treatment effect on 6-month neurologically favorable survival in patients with all rhythms and shockable rhythms. These results must be interpreted within the context of the reported credible intervals and varying designs of the randomized trials.RegistrationINPLASY (INPLASY2023120060, December 14th, 2023, https://doi.org/10.37766/inplasy2023.12.0060).

Ecological and anthropogenic drivers of waterfowl productivity are synchronous across species, space, and time.

Knowledge of interspecific and spatiotemporal variation in demography-environment relationships is key for understanding the population dynamics of sympatric species and developing multispecies conservation strategies. We used hierarchical random-effects models to examine interspecific and spatial variation in annual productivity in six migratory ducks (i.e., American wigeon [Mareca americana], blue-winged teal [Spatula discors], gadwall [Mareca strepera], green-winged teal [Anas crecca], mallard [Anas platyrhynchos] and northern pintail [Anas acuta]) across six distinct ecostrata in the Prairie Pothole Region of North America. We tested whether breeding habitat conditions (seasonal pond counts, agricultural intensification, and grassland acreage) or cross-seasonal effects (indexed by flooded rice acreage in primary wintering areas) better explained variation in the proportion of juveniles captured during late summer banding. The proportion of juveniles (i.e., productivity) was highly variable within species and ecostrata throughout 1961-2019 and generally declined through time in blue-winged teal, gadwall, mallard, pintail, and wigeon, but there was no support for a trend in green-winged teal. Productivity in Canadian ecostrata declined with increasing agricultural intensification and increased with increasing pond counts. We also found a strong cross-seasonal effect, whereby more flooded rice hectares during winter resulted in higher subsequent productivity. Our results suggest highly consistent environmental and anthropogenic effects on waterfowl productivity across species and space. Our study advances our understanding of current year and cross-seasonal effects on duck productivity across a suite of species and at finer spatial scales, which could help managers better target working-lands conservation programs on both breeding and wintering areas. We encourage other researchers to evaluate environmental drivers of population dynamics among species in a single modeling framework for a deeper understanding of whether conservation plans should be generalized or customized given limited financial resources.

How much do conservation cropping practices mitigate runoff and soil erosion under Western European conditions: A focus on conservation tillage, tied ridging and winter cover crops

AbstractConservation farming practices are known for their capacity to mitigate runoff and erosion, but the magnitude of their effectiveness is highly variable across studies. In order to better understand the contribution of environmental and management factors to their effectiveness, up to 37 studies reporting 271 individual trials were collated for a quantitative review regarding 3 common conservation agriculture‐related practices, at the plot scale and in a Western European context. Two different methods suitable for hierarchically structured data sets were used for the meta‐analyses—hierarchical nonparametric bootstrapping and linear random effects models—, yielding nearly identical average outcomes but differing in terms of confidence intervals. We found that, on average, winter cover crops reduce cumulative seasonal (autumn‐winter) runoff by 68% and soil losses by 72% compared with a bare soil. The occurrence and intensity of stubble tillage on the control plot is a key explanatory variable for the mitigation effect of winter cover crops. In potato crops, tied ridging reduces cumulative seasonal (spring–summer) runoff by a mean of 70% and soil erosion by 92%. Conservation (non‐inversion) tillage techniques alleviate cumulative seasonal overland flow by 27% and associated sediments losses by 66%, but strong evidence of publication bias was detected for this farming practice, probably leading to an overestimation of its effectiveness. These mitigation effects are shown to be much greater for spring crops than for winter crops, and to increase with time since ploughing was stopped. The type of conservation tillage scheme strongly affects the ability to attenuate surface flows. Intensive non‐inversion tillage systems relying on repeated use of (powered) tillage operations appear to be the least effective for reducing both water and sediment losses. The best performing scheme against runoff would be a deep (non‐inversion) tillage (−61%), while against erosion it would be a no‐till system (−82%). Although several explanatory factors were identified, there remains a high (unexplained) variability between trials effect sizes, thus not attributable to pure sampling variability. Meanwhile, this review provides farm advisors or policy makers with guidance on the contexts in which implementation of such conservation practices should be supported so as to maximize expected benefits.

Bayesian meta-analysis of penetrance for cancer risk.

Multi-gene panel testing allows many cancer susceptibility genes to be tested quickly at a lower cost making such testing accessible to a broader population. Thus, more patients carrying pathogenic germline mutations in various cancer-susceptibility genes are being identified. This creates a great opportunity, as well as an urgent need, to counsel these patients about appropriate risk-reducing management strategies. Counseling hinges on accurate estimates of age-specific risks of developing various cancers associated with mutations in a specific gene, ie, penetrance estimation. We propose a meta-analysis approach based on a Bayesian hierarchical random-effects model to obtain penetrance estimates by integrating studies reporting different types of risk measures (eg, penetrance, relative risk, odds ratio) while accounting for the associated uncertainties. After estimating posterior distributions of the parameters via a Markov chain Monte Carlo algorithm, we estimate penetrance and credible intervals. We investigate the proposed method and compare with an existing approach via simulations based on studies reporting risks for two moderate-risk breast cancer susceptibility genes, ATM and PALB2. Our proposed method is far superior in terms of coverage probability of credible intervals and mean square error of estimates. Finally, we apply our method to estimate the penetrance of breast cancer among carriers of pathogenic mutations in the ATM gene.

Arsenic in drinking water and lung cancer: A systematic review of 35 years of evidence

The association between higher arsenic concentrations in drinking water and lung cancer is well-established. However, the risk associated with lower levels of arsenic exposure remains uncertain. This systematic review and meta-analysis summarizes the evidence on the relationship between exposure to arsenic in drinking water and lung cancer outcomes as measured over a broad range of exposures, including lower levels. A total of 51 studies were included in the review and 15 met criteria for inclusion in meta-analysis. Risk estimates for lung cancer incidence and mortality were pooled and analyzed separately using Bayesian hierarchical random-effects models with a Gaussian observation submodel for log(Risk), computed using the “brms” R package. For lung cancer incidence, the predicted posterior mean relative risks (RRs) at arsenic concentrations of 10, 50 and 150 μg/L were 1.11 (0.86–1.43), 1.67 (1.27–2.17) and 2.21 (1.61–3.02), respectively, with posterior probabilities of 79%, 100% and 100%, respectively, for the RRs to be >1. The posterior mean mortality ratios at 20, 50 and 150 μg/L were 1.22 (0.83–1.78), 2.10 (1.62–2.71) and 2.41 (1.88–3.08), respectively, with posterior probabilities being above 80%. In addition to observing the dose-response relationship, these findings demonstrate that individuals exposed to low to moderate levels of arsenic (<150 μg/L) were at an elevated risk of developing or dying from lung cancer. Given the widespread exposure to lower levels of arsenic, there is an urgent need for vigilance and potential revisions to regulatory guidelines to protect people from the cancer risks associated with arsenic exposure.

Surgeon- and hospital-level variation in wait times for scheduled non-urgent surgery in Ontario, Canada: A cross-sectional population-based study.

Canadian health systems fare poorly in providing timely access to elective surgical care, which is crucial for quality, trust, and satisfaction. We conducted a cross-sectional analysis of surgical wait times for adults receiving non-urgent cataract surgery, knee arthroplasty, hip arthroplasty, gallbladder surgery, and non-cancer uterine surgery in Ontario, Canada, between 2013 and 2019. We obtained data from the Wait Times Information System (WTIS) database. Inter- and intra-hospital and surgeon variations in wait time were described graphically with caterpillar plots. We used non-nested 3-level hierarchical random effects models to estimate variation partition coefficients, quantifying the proportion of wait time variance attributable to surgeons and hospitals. A total of 942,605 procedures at 107 healthcare facilities, conducted by 1,834 surgeons, were included in the analysis. We observed significant intra- and inter-provider variations in wait times across all five surgical procedures. Inter-facility median wait time varied between six-fold for gallbladder surgery and 15-fold for knee arthroplasty. Inter-surgeon variation was more pronounced, ranging from a 17-fold median wait time difference for cataract surgery to a 216-fold difference for non-cancer uterine surgery. The proportion of variation in wait times attributable to facilities ranged from 6.2% for gallbladder surgery to 23.0% for cataract surgery. In comparison, surgeon-related variation ranged from 16.0% for non-cancer uterine surgery to 28.0% for cataract surgery. There is extreme variability in surgical wait times for five common, high-volume, non-urgent surgical procedures. Strategies to address surgical wait times must address the variation between service providers through better coordination of supply and demand. Approaches such as single-entry models could improve surgical system performance.

Efficacy of Pharmacotherapy for Seasonal Influenza in Young and Middle-aged Adults: A Systematic Review and Network Meta-analysis.

Background Seasonal influenza affects healthcare demand. However, the efficacy of anti-influenza drugs, particularly among young patients at a low risk of complications, has rarely been evaluated. Therefore, we evaluated the efficacy of anti-influenza drugs against seasonal influenza in healthy young and middle-aged adults. Methods A systematic review and network meta-analysis were conducted. The Cochrane Central Register of Controlled Trials and Medical Literature Analysis and Retrieval System Online were searched for original articles reporting double-blind, randomized controlled trials published up to the end of July 2023. Clinical trials that tested the efficacy of anti-influenza drugs in young and middle-aged patients with seasonal influenza were also included. The primary outcome was time to fever alleviation. The efficacy and adverse effects of these treatments were estimated using a Bayesian hierarchical random-effects model and a Markov chain Monte Carlo simulation. Results In total, 24 articles with 34 treatments and 8,949 individuals were included. Oseltamivir (300 mg/day for 5 days) showed the largest reduction in time to fever alleviation by -19.1 (95% confidence interval [CI]: -29.4, -10.7) h compared with a placebo. Baloxavir marboxil (40 mg/day) reduced the time to symptom alleviation by -28.2 (95% CI: -42.7, -13.7) h, and peramivir (300 mg/day) administered by intravenous infusion for 1 day reduced the time to resumption of usual activities by -43.5 (95% CI: -72.8, -14.2) h. Conclusion Several pharmaceutical treatments were able to reduce the recovery time for fever and symptom alleviation and resumption of usual activities in young and middle-aged adults with seasonal influenza without increasing the risk of complications.

The Efficacy and Safety of Regimens for Helicobacter pylori Eradication Treatment in China: A Systemic Review and Network Meta-Analysis.

With Helicobacter pylori's increasing antibiotic resistance, evidence of more effective treatments is lacking in China, where H. pylori prevalence is nearly 50%. Thus, we performed a network meta-analysis to compare therapeutic regimens. Data extracted from eligible randomized controlled trials from January 2000 to September 2021 were entered into a Bayesian hierarchical random-effects model to evaluate the efficacy and safety of H. pylori eradication regimens. This study included 101 trials involving 21,745 patients. Vonoprazan-bismuth-containing quadruple therapy (VBQT) ranked the highest [surfaces under cumulative ranking curve (SUCRA), 83.64%], followed by high-dose amoxicillin dual therapy (HDDT) [SUCRA, 79.70%, odds ratio (OR)=1.31, 95% credible interval (CrI) (0.36, 4.72)] and proton pump inhibitor-based bismuth-containing quadruple therapy (BQT) [SUCRA, 63.59%, OR=1.59, 95% CrI (0.48, 5.24)]. HDDT [OR=2.47, 95% CrI (1.51, 4.06)], BQT [OR=2.04, 95% CrI (1.69, 2.47)], concomitant quadruple nonbismuth therapy (CT) [OR=1.93, 95% CrI (1.19, 3.15)], and sequential therapy (ST) [OR=1.86, 95% CrI (1.50, 2.32)] had higher eradication rates than standard triple therapy (TT). ST (SUCRA, 82.52%) and VBQT (SUCRA, 83.89%) had the highest eradication rate before and after 2010 in the effectiveness ranking, respectively. Furthermore, the H. pylori eradication rate of patients receiving 14-day BQT treatment was higher than that of 10-day BQT regimen [OR=2.55, 95% CI (1.84, 3.53)] and 7-day BQT regimen [OR=3.64, 95% CI (2.64, 5.01)]. The TT regimen was not an optimal choice in China for H. pylori eradication; VBQT, HDDT, and BQT showed better efficacy. After 2010, there is a trend toward significance that VBQT provided a higher H. pylori eradication rate in China, but with only 1 randomized controlled trial. Thus, more supportive real-world data are needed to confirm its effectiveness.

A Systematic Review and Bayesian Network Meta-Analysis on the Effect of Different Anticoagulants on the Prophylaxis of Post-Thrombotic Syndrome after Deep Venous Thrombosis

Background: Postthrombotic syndrome (PTS) has a major impact on the quality of life after deep venous thrombosis (DVT). From clinical practice and related trials, anticoagulants show potential for reducing the occurrence and alleviating the symptoms of PTS. Methods: A systematic review and Bayesian network meta-analysis (NMA) were conducted by combing the literature from the databases of MEDLINE, Embase, Web of Science, Cochrane Libraries, and ClinicalTrials, through a variety of medical subject headings (Mesh) and PTS keywords. With regard to PTS prophylaxis, all anticoagulant-related randomized controlled trials (RCTs) and observational studies were assessed. The network model was conducted through the R software, and further comparisons were conducted using the Bayesian hierarchical random effects model. The odds ratio (OR) and the corresponding 95% CI were calculated for analysis. Results: Data from two RCTs and nine non-randomized studies meeting the selection criteria were included in the Bayesian analysis model, which incorporated seven anticoagulants. Edoxaban (OR: 0.42, 95% CI: 0.18–1.0) and rivaroxaban (OR: 0.54, 95% CI: 0.38–0.76) were significantly more effective than warfarin in the prevention of PTS (Villalta score ≥ 5). A subgroup analysis based on the severity of PTS showed that rivaroxaban was more effective than warfarin, with OR: 0.59, 95% CI: 0.41–0.84 (Villalta score 5 to 14) and OR: 0.48, 95% CI: 0.22–0.9 (Villalta score ≥ 15, ulceration), respectively. Edoxaban had the highest probability (80.1%) of providing preventive benefits for PTS. For mild/moderate and severe PTS, rivaroxaban provided the highest benefits in preventing PTS (89.3% and 85.6%, respectively). Conclusion: Edoxaban demonstrated a better prophylactic effect on PTS (Villalta score &gt; 5), while rivaroxaban displayed a better effect against mild/moderate (Villalta score 5 to 14) and severe PTS (Villalta score ≥ 15, ulceration).

Implantable arterial doppler efficacy in free flap reconstruction: A systematic review and meta-analysis.

The implantable arterial doppler (IAD) is frequently used to postoperatively monitor free flaps with high accuracy, but there are no guidelines for its use. Bedside exam is used adjunctively to determine necessary intervention. This systematic review seeks to discover why the doppler is used adjunctively despite its established record of accuracy. Criteria for inclusion and exclusion were established. In total, 280 articles were found on PubMed and Web of Science, then screened accordingly. Data from 22 articles were analyzed using a bivariate hierarchical random effects model. Twenty-two studies yielded 2996 total patients undergoing 3127 free flap procedures. The meta-analysis found a high sensitivity of 0.809 (95% CI = 0.709, 0.880) and specificity of 0.966 (95% CI = 0.947, 0.979). False-positive rate was found to be 0.034 (95% CI = 0.021, 0.053). Positive and negative predictive values were 0.711 (95% CI = 0.581, 0.817) and 0.979 (95% CI = 0.966, 0.988). Positive and negative likelihood ratios were 24.7 (95% CI = 14.5, 39.5) and 0.20 (95% CI = 0.12, 0.30). The established efficacy of the IAD is supported by this study. Clinical exams may remain as the final adjunct due to the risks of inaccurate IAD signals. Further studies are warranted to optimize its use for future practice guidelines.

A Bayesian adaptive design for dual-agent phase I-II oncology trials integrating efficacy data across stages.

Combination of several anticancer treatments has typically been presumed to have enhanced drug activity. Motivated by a real clinical trial, this paper considers phase I-II dose finding designs for dual-agent combinations, where one main objective is to characterize both the toxicity and efficacy profiles. We propose a two-stage Bayesian adaptive design that accommodates a change of patient population in-between. In stage I, we estimate a maximum tolerated dose combination using the escalation with overdose control (EWOC) principle. This is followed by a stage II, conducted in a new yet relevant patient population, to find the most efficacious dose combination. We implement a robust Bayesian hierarchical random-effects model to allow sharing of information on the efficacy across stages, assuming that the related parameters are either exchangeable or nonexchangeable. Under the assumption of exchangeability, a random-effects distribution is specified for the main effects parameters to capture uncertainty about the between-stage differences. The inclusion of nonexchangeability assumption further enables that the stage-specific efficacy parameters have their own priors. The proposed methodology is assessed with an extensive simulation study. Our results suggest a general improvement of the operating characteristics for the efficacy assessment, under a conservative assumption about the exchangeability of the parameters apriori.

Racial, gender, and psychosocial disparities in viral suppression trends among people receiving coordinated HIV care in Los Angeles County.

To longitudinally evaluate differences in HIV viral suppression (<200 copies/ml) by intersections of race/ethnicity, gender, and psychosocial issues in people with HIV in the Los Angeles County Medical Care Coordination Program. We analyzed 74 649 viral load measurements over 10 184 people with HIV enrolled in the Medical Care Coordination Program between January 1, 2013 and March 1, 2020.Methods: We fit Bayesian logistic hierarchical random effects models to test interactions between gender, race/ethnicity, and a psychosocial acuity score on viral suppression over time from 1 year prior to program enrollment to 24 months after enrollment. The probability of viral suppression declined prior to enrollment, then increased and stabilized by 6 months after enrollment. Black/African American patients with low and moderate psychosocial acuity scores did not achieve the same increase in percentage of viral suppression as those in other racial/ethnic groups. Transgender women with high psychosocial acuity scores took longer (about 1 year) to achieve the same percentage of viral suppression as clients of other gender identities. Some racial/ethnic and gender disparities in viral suppression persisted after enrollment in the Los Angeles County Medical Care Coordination Program while accounting for psychosocial acuity score, which may be explained by factors not assessed in the program.

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The cover image is based on the Research Article Hierarchical random-effects model for the insurance pricing of vehicles belonging to a fleet by Denise Desjardins et al., https://doi.org/10.1002/jae.2949.

Transcriptional Responses as Biomarkers of General Toxicity: A Systematic Review and Meta-analysis on Metal-Exposed Bivalves.

Through a systematic review and a series of meta-analyses, we evaluated the general responsiveness of putative transcriptional biomarkers of general toxicity and chemical stress. We targeted metal exposures performed on bivalves under controlled laboratory conditions and selected six transcripts associated with general toxicity for evaluation: catalase, glutathione-S-transferase, heat shock proteins 70 and 90, metallothionein, and superoxide dismutase. Transcriptional responses (n = 396) were extracted from published scientific articles (k = 22) and converted to log response ratios (lnRRs). By estimating toxic units, we normalized different metal exposures to a common scale, as a proxy of concentration. Using Bayesian hierarchical random effect models, we then tested the effects of metal exposure on lnRR, both for metal exposure in general and in meta-regressions using toxic unit and exposure time as independent variables. Corresponding analyses were also repeated with transcript and tissue as additional moderators. Observed patterns were similar for general and for transcript- and tissue-specific responses. The expected overall response to arbitrary metal exposure was an lnRR of 0.50, corresponding to a 65% increase relative to a nonexposed control. However, when accounting for publication bias, the estimated "true" response showed no such effect. Furthermore, expected response magnitude increased slightly with exposure time, but there was little support for general monotonic concentration dependence with regard to toxic unit. Altogether, the present study reveals potential limitations that need consideration prior to applying the selected transcripts as biomarkers in environmental risk assessment. Environ Toxicol Chem 2023;42:628-641. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

The salience of social context, opioid antagonist use, and prior opioid exposure as determinants of fatal and non-fatal opioid overdoses.

This study examines the salience of social context for opioid overdoses in Boston from 2014 to 2019. Longitudinal negative binomial models with random effects indicated that higher levels of concentrated disadvantage, residential instability, and illicit drug activity increased annual block group counts of opioid overdoses. Logistic hierarchical and cross-classified random effects models indicated that the use of Narcan and greater exposure to drugs through previous opioid overdose and contextual lillicit drug crime activity reduced the odds of fatal opioid overdose relative to non-fatal opioid overdose. The findings suggest that the accurate tracking of both fatal and non-fatal overdoses, and a consideration of the broader social context, can facilitate effective public health resource allocation to reduce opioid overdoses.

Diagnostic accuracy and added value of blood-based protein biomarkers for pancreatic cancer: A meta-analysis of aggregate and individual participant data.

Novel blood-based protein biomarkers may be of value for efficient, accurate, and non-invasive diagnosis of pancreatic cancer. This study assesses the diagnostic accuracy of newly recognized blood-based protein biomarkers for detecting pancreatic cancer, and investigates their added value to CA19-9, the common blood-based biomarker in clinical use for pancreatic cancer. PubMed, Embase, Web of Science, and the Wiley/Cochrane Library were systematically searched from inception until June 2022. A meta-analysis of aggregate and individual participant data was conducted using frequentist and Bayesian hierarchical random-effects models. The added clinical utility of protein biomarkers was investigated using bootstrap bias-corrected decision curve analyses. Aggregate data from 28 primary studies (6127 participants) were included, of which 8 studies (1790 participants) provided individual participant data. CA19-9 was significantly more accurate than MIC-1 for distinguishing pancreatic cancer from benign disease (AUC, 0.83 vs 0.74; relative diagnostic odds ratio [rDOR], 2.10 [95% CI, 0.98-4.48]; p=0.002), THBS2 (AUC, 0.87 vs 0.69; rDOR, 4.53 [2.16-9.39]; p<0.0001), TIMP-1 (AUC, 0.91 vs 0.70; rDOR, 8.00 [3.81-16.9]; p<0.0001), OPN (AUC, 0.89 vs 0.74; rDOR, 4.22 [1.13-15.6]; p<0.0001), ICAM-1 (AUC, 0.91 vs 0.68; rDOR 9.30 [0.87-99.5]; p<0.0001), and IGFBP2 (AUC, 0.91 vs 0.68; rDOR, 4.48 [0.78-24.3]; p<0.0001). The addition of these novel protein biomarkers to CA19-9 did not significantly improve the AUC, and resulted in minor increases or limited decreases in clinical utility. Novel protein biomarkers have moderate diagnostic accuracy, do not outperform CA19-9 in differentiating pancreatic cancer from benign disease, and show limited added clinical value to CA19-9. We propose recommendations to aid the development of minimally invasive diagnostic tests with sufficient clinical utility to improve the management of patients with suspected pancreatic cancer. Bennink Foundation, Dutch Cancer Foundation (KWF Kankerbestrijding), and AIRC.

Systematic Review and Network Meta-Analysis of Frontline Targeted Therapy in Chronic Lymphocytic Leukemia Shows Comparable Efficacy but Distinct Toxicity

Introduction: Targeted therapies inhibiting Bruton Tyrosine Kinase (BTK) (ibrutinib, acalabrutinib, and zanubrutinib) and Bcl-2 (venetoclax) have improved survival when given first line (1L) to patients with chronic lymphocytic leukemia (CLL). However, no head-to-head trials of 1L targeted therapies exist to guide clinicians on selection of optimal therapy for their patients. We performed a systematic review and network meta-analysis (NMA) to understand the relative efficacy and toxicity of 1L CLL regimens, including newer regimens of ibrutinib/venetoclax (IV) and zanubrutinib not previously assessed in NMA. Methods: We performed a systematic literature search from 2009-2022 for randomized trials of treatment-naïve adults with CLL who were deemed unfit due to age or comorbidities. Endpoints were progression free survival (PFS) at 24 and 48 months, overall response rate (ORR), percentage of patients with grade 3 or higher adverse event (AE), discontinuation due to AE, and rates of AEs of clinical interest. We used a Bayesian hierarchical random-effects models for mixed multiple treatment comparisons to estimate the relative treatment effect of each intervention compared with a common comparator. Results: Our search yielded 12 clinical trials including 15 unique 1L regimens (Fig 1). PFS and ORR of common comparators were consistent across trials except 24-month PFS for chlorambucil/obinutuzumab (CO) which ranged from 31%-64% likely due to variable duration of chlorambucil and variable inclusion of patients with del(17p). Compared to CO, only acalabrutinib/obinutuzumab (AO) showed statistically significant improvement in 24-month PFS with hazard ratio (HR) 0.13 and 95% confidence interval (CI) 0.017-0.97 (Fig 1). In general, targeted therapies trended towards longer PFS compared to chemotherapy-based regimens, though there is insufficient power to demonstrate statistical significance. We found no statistically significant differences in 24-month PFS, 48-month PFS, or ORR between targeted therapies. Regarding toxicity, no statistically significant differences in proportion of patients experiencing grade 3 or higher AE were found across regimens, though single agent acalabrutinib and zanubrutinib trended toward less toxicity than CO with risk ratio (RR) 0.71, 95% CI 0.45-1.1 and RR 0.66, 95% CI 0.30-1.5, respectively. No statistically significant differences in discontinuation rates were found, though IV trended towards higher discontinuation rate than CO (RR 6.1, 95% CI 0.71-74). There were no statistically significant differences in rates of atrial fibrillation, infection, anemia, or neutropenia. However, grade 3 or higher thrombocytopenia was significantly lower with zanubrutinib than CO (RR 0.069, 95% CI 0.0048-0.92). Conclusions: Using NMA, we demonstrate that PFS is improved from the pre-targeted therapy standard of care by AO, but, amongst targeted therapies, no significant differences in efficacy were identified. Our results differ from previously published NMAs which have shown superior PFS with AO compared to other targeted therapies, likely due to inclusion of additional trials of common comparators (Foa et al, CLL5) as well as newer trials assessing IV and zanubrutinib (GLOW, SEQUOIA cohort 1) in this analysis. All four trials add heterogeneity to common comparator outcomes, resulting in widened confidence intervals and loss of statistical significance. This is the first assessment, to our knowledge, of relative rates of specific AEs, and we found that zanubrutinib showed lower rates of thrombocytopenia than pre-targeted therapy standard of care. Establishing the absence of significant difference in efficacy of frontline targeted therapies in CLL allows the clinician and patient to select therapy based on other factors, namely planned duration, toxicity profile, medication interactions, and cost. Figure 1. 24-month PFS Network and Forest Plot 1Chl = Chlorambucil; Acal = Acalabrutinib; Acal/Obin = Acalabrutinib/Obinutuzumab; BR = Bendamustine/Rituximab; Chl/Ofa = Chlorambucil/Ofatumumab; Chl/Ritux = Chlorambucil/Rituximab; Chl/Ritux + Mtn = Chlorambucil/Rituximab + maintenance Rituximab; Flu = Fludarabine; Ibr = Ibrutinib; Ibr/Obin = Ibrutinib/Obinutuzumab; Ibr/Ritux = Ibrutinib/Rituximab; Ibr/Ven = Ibrutinib/Venetoclax; Ven/Obin = Venetoclax/Obinutuzumab; Zan = Zanubrutinib Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Open vs. robot-assisted radical cystectomy with extracorporeal or intracorporeal urinary diversion for bladder cancer A pairwise meta-analysis of outcomes and a network meta-analysis of complications.

There are no meta-analyses of randomized controlled trials (RCTs) comparing open radical cystectomy (OR C) with robot-assisted radical cystectomy (RARC), inclusive of both intracorporeal (iRARC) and extracorporeal (hybrid RARC, hRARC) urinary reconstruction. MEDL INE, Embase, Scopus, the International Clinical Trials Registry Platform and ClinicalTrials.gov registries were searched in May 2022. Outcomes of interest included recurrence- or progression-free survival (RFS/PFS), margin status and lymph node yield, mean estimated blood loss (EBL) and operating room time (ORT ), hospital length of stay (LOS ), 90-day complications and readmissions, and quality of life (QoL). Pairwise meta-analyses and network meta-analyses were performed using random-effects models and Bayesian hierarchical random-effects models, respectively. We found no significant differences between RARC and OR C for oncological and most perioperative outcomes: RFS/PFS (hazard ratio [HR ] 0.91, 95% confidence interval [CI] 0.67-1.23); positive surgical margins (odds ratio [OR ] 1.05, 95% CI 0.60-1.85); lymph node yield (mean difference [MD ] -0.63, 95% CI -2.63-1.37); LOS (MD -0.22, 95% CI -1.10-0.65); overall complications (OR 0.81, 95% CI 0.61-1.07); major complications (OR 0.94, 95% CI 0.69-1.30); readmissions (OR 0.90, 95% CI 0.60-1.35); and QoL (standardized MD -0.02, 95% CI -0.17-0.14). We found significantly lower EBL for RARC compared to OR C (MD -312.61, 95% CI -447 to -178.22) at the expense of significantly prolonged ORT (MD 82.34 minutes, 95% CI 44.82-119.86). Network meta-analysis did not find significant differences in complications between hRARC and iRARC. This meta-analysis confirms the equivalence of RARC and OR C with respect to oncological outcomes.

Pregabalin administration in patients with fibromyalgia: a Bayesian network meta-analysis

Several studies investigated the effectiveness and the safety of different doses of pregabalin in fibromyalgia. However, the optimal protocol remains controversial. A Bayesian network meta-analysis comparing 300, 450, and 600 mg/daily of pregabalin for fibromyalgia was conducted. The literature search was conducted in January 2022. All the double-blind randomised clinical trials comparing two or more dose protocols of pregabalin for fibromyalgia were accessed. Studies enrolling less than 50 patients were not eligible, nor were those with a length of follow-up shorter than eight weeks. The outcomes of interests were: Fibromyalgia Impact Questionnaire (FIQ), sleep quality, and adverse events. The network meta-analyses were performed using the routine for Bayesian hierarchical random-effects model analysis, with log odd ratio (LOR) and standardized mean difference (SMD) effect measure. Data from 4693 patients (mean age 48.5 years) were retrieved. 93.1% (4370 of 4693 patients) were women. The median follow-up was 14.8 weeks. Pregabalin 450 mg/daily resulted in greater reduction in Fibromyalgia Impact Questionnaire (SMD − 1.83). Pregabalin 600 demonstrated the greatest sleep quality (SMD 0.15). Pregabalin 300 mg/daily evidenced the lowest rate of adverse events (LOR 0.12). The dose of pregabalin must be customised according to patients’ characteristics and main symptoms.