Publications

ABSTRACT Importance Estimating global lives and life-years saved is important to put into perspective the benefits of COVID-19 vaccination. Prior studies have focused mainly on the pre-Omicron period or only on specific regions, lack crucial life-year calculations, and often depend on strong modeling assumptions with unaccounted uncertainty. Observations We aimed to calculate the lives and life-years saved by COVID-19 vaccination worldwide from the onset of the vaccination campaigns and until October 2024. We considered different strata according to age; community-dwelling and long-term care residence status; pre-Omicron and Omicron periods; and vaccination before and after a SARS-CoV-2 infection. In the main analysis, 2.533 million deaths were averted (1 death averted per 5,400 vaccine doses administered). Eighty-two percent were among people vaccinated before any infection, 57% were in the Omicron period, and 90% pertained to people 60 years and above. Sensitivity analyses suggested 1.4 to 4.0 million lives saved. Some sensitivity analyses showed preponderance of the benefit during the pre-Omicron period. We estimated 14.8 million life-years saved (1 life-year saved per 900 vaccine doses administered). Sensitivity range was 7.4-23.6 million life-years. Most life-years saved (76%) were in people over 60 years old, but long-term care residents contributed only 2% of the total. Children and adolescents (0.01% of lives saved and 0.1% of life-years saved) and young adults 20-29 years old (0.07% of lives saved and 0.3% of life-years saved) had very small contributions to the total benefit. Conclusions and relevance Based on a number of assumptions, these estimates are substantially more conservative than previous calculations focusing mostly on the first year of vaccination, but they still clearly demonstrate a major overall benefit from COVID-19 vaccination during 2020-2024. The vast majority of benefit in lives and life-years saved was secured for a portion of the elderly minority of the global population.

Data continue to accumulate indicating that many systematic reviews are methodologically flawed, biased, redundant, or uninformative. Some improvements have occurred in recent years based on empirical methods research and standardization of appraisal tools; however, many authors do not routinely or consistently apply these updated methods. In addition, guideline developers, peer reviewers, and journal editors often disregard current methodological standards. Although extensively acknowledged and explored in the methodological literature, most clinicians seem unaware of these issues and may automatically accept evidence syntheses (and clinical practice guidelines based on their conclusions) as trustworthy. A plethora of methods and tools are recommended for the development and evaluation of evidence syntheses. It is important to understand what these are intended to do (and cannot do) and how they can be utilized. Our objective is to distill this sprawling information into a format that is understandable and readily accessible to authors, peer reviewers, and editors. In doing so, we aim to promote appreciation and understanding of the demanding science of evidence synthesis among stakeholders. We focus on well‐documented deficiencies in key components of evidence syntheses to elucidate the rationale for current standards. The constructs underlying the tools developed to assess reporting, risk of bias, and methodological quality of evidence syntheses are distinguished from those involved in determining overall certainty of a body of evidence. Another important distinction is made between those tools used by authors to develop their syntheses as opposed to those used to ultimately judge their work. Exemplar methods and research practices are described, complemented by novel pragmatic strategies to improve evidence syntheses. The latter include preferred terminology and a scheme to characterize types of research evidence. We organize best practice resources in a Concise Guide that can be widely adopted and adapted for routine implementation by authors and journals. Appropriate, informed use of these is encouraged, but we caution against their superficial application and emphasize their endorsement does not substitute for in‐depth methodological training. By highlighting best practices with their rationale, we hope this guidance will inspire further evolution of methods and tools that can advance the field.

Abstract Genome‐wide testing platforms are increasingly used to promote “agnostic” approaches to the discovery of gene variants associated with the risk of many common diseases and quantitative traits. The early track record of genome‐wide association (GWA) studies suggests that some proposed associations are replicated quite consistently with large‐scale subsequent evidence from multiple studies, others have a more inconsistent replication record, some have failed to be replicated by independent investigators and many more early proposed associations await further replication. An important question is how to calibrate the credibility of these postulated associations. A simple Bayesian method is applied here to achieve such calibration. The variability of the estimated credibility is examined under different assumptions. Empirical examples are drawn from existing GWA studies. It is demonstrated that the credibility of different proposed associations can cover a very wide range. The credibility of specific associations usually remains relatively robust when different plausible assumptions are made (within a reasonable range) for the prior odds of an association being true, or the magnitude of the anticipated effect size for genetic associations. Heterogeneity and bias assumptions can have a more major impact on the credibility estimates and thus they need very careful consideration in each case. Credibility calibration may be used in conjunction with qualitative criteria for the appraisal of the cumulative evidence that take into consideration the amount, consistency, and protection from bias in the data. © 2008 Wiley‐Liss, Inc.

Abstract Plantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5×10−8) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). The indel chr5:118704153:D is located within TNFAIP8 (encodes a protein induced by TNF alpha) and rs62051384 is located within WWP2 (which is involved in proteasomal degradation). These DNA variants may be informative in explaining why some individuals are at higher risk for plantar fascial disorders than others.

Abstract Background: Until recently a typical rule that has often been used for the endorsement of new medications by the Food and Drug Administration has been the existence of at least two statistically significant clinical trials favoring the new medication. This rule has consequences for the true positive (endorsement of an effective treatment) and false positive rates (endorsement of an ineffective treatment). Methods: In this paper, we compare true positive and false positive rates for different evaluation criteria through simulations that rely on (1) conventional p-values; (2) confidence intervals based on meta-analyses assuming fixed or random effects; and (3) Bayes factors. We varied threshold levels for statistical evidence, thresholds for what constitutes a clinically meaningful treatment effect, and number of trials conducted. Results: Our results show that Bayes factors, meta-analytic confidence intervals, and p-values often have similar performance. Bayes factors may perform better when the number of trials conducted is high and when trials have small sample sizes and clinically meaningful effects are not small, particularly in fields where the number of non-zero effects is relatively large. Conclusions: Thinking about realistic effect sizes in conjunction with desirable levels of statistical evidence, as well as quantifying statistical evidence with Bayes factors may help improve decision-making in some circumstances.

This paper explores a standard-cell design methodology based on netlist partitioning as a solution for the problem of lack of convergence in the conventional methodology in deep submicron technologies. A synthesized design block is partitioned along unpredictable nets that are identified from the netlist structure. The size of each partition is restricted so that the longest possible local net in a partition can be sufficiently driven by an average library gate, hence allowing statistical wire-load modeling for the local nets. The block is resynthesized using a hybrid wire-load model that takes into account accurate wire-load information on the unpredictable nets derived after floorplanning the partitions, and uses custom statistical wire-load models within each partition. Final placement is restricted to respect the initial floorplan. The methodology was implemented using existing commercial tools for synthesis and layout. Experimental results show high correlation between synthesis estimates and post-placement measurements of wire-loads and gate delays with the new methodology. The trade-offs of partitioning, current limitations of the methodology and future work to overcome these limitations are also discussed.

Purpose Thoracic electrical bioimpedance (TEB) is an alternative to invasive monitoring of hemodynamic parameters including cardiac output, stroke volume, and cardiac index. The Centers for Medicare and Medicaid Services (CMS) requested a technology assessment by the Agency for Health Care Research and Quality (AHRQ) to evaluate data on the clinical effectiveness of thoracic electrical bioimpedance (TEB) for several cardiovascular applications. The Tufts-New England Medical Center was asked to conduct a technology assessment on the literature published since an earlier report published in 1992 by the Agency for Health Care Policy and Research (now AHRQ). Materials and Methods We conducted a systematic review and meta-analysis of the TEB literature. We searched MEDLINE® using synonyms for “impedance cardiography;” the search strategy was restricted to the English language, to human subjects, and was conducted for the period from 1966 through January 2002. This search yielded more than 8000 articles. An updated search was performed on July 22, 2002. Inclusion criteria for articles included date of publication 1991 and onward, reporting on the methodology of TEB as a diagnostic and/or monitoring tool or TEB in comparison to another diagnostic technique for the clinical indications of interest. Seventy-seven articles were included in the evidence tables of this report. We performed meta-analyses by constructing subgroups (i.e., inpatient, outpatient, emergency department, and years of publication – to account for most recent technology) for selected comparison techniques, equations used by the devices and hemodynamic parameters --- cardiac output, cardiac index, and stroke volume. Accuracy of bioimpedance devices The overwhelming majority of studies reported only the correlation coefficient of bioimpedance when compared to alternative techniques, such as thermodilution (TD). Correlation coefficients were in the range of −0.01 to 0.97. Correlation coefficients have serious limitations when used to summarize diagnostic test data, and there are no methodologic crosswalks which can allow correlation coefficients to reflect well-established parameters of accuracy, such as sensitivity and specificity. There was significant between-study heterogeneity due to factors other than the factors that we used to stratify studies. The majority of the studies were done on the NCCOM device, a device that is no longer commercially produced. There is wide variation in results across the instruments; the variation could be due to differences in instrument performance, but there is not enough data available on any one instrument to draw conclusions about this. We also reported the bias (systematic error) and limits of agreement (random variation) in studies of TEB. The test for heterogeneity across studies was statistically significant for bias and limits of agreement for cardiac output for TD, suggesting that there may be patient populations where TEB measurements can be much farther from the TD measurement than the combined limits of agreement indicate. Errors in placement of the leads, and clinical factors such as patient weight and presence of pulmonary edema, have been reported to affect results of measurements. Data on the effect of these factors have not been adequately reported in published literature with currently available commercial devices on the outpatient population of interest. MONITORING IN PATIENTS WITH SUSPECTED OR KNOWN CARDIOVASCULAR DISEASE No studies provided information on health outcomes, patient management, or on clinical endpoints to address the usefulness of TEB in monitoring or management. ACUTE DYSPNEA No studies were found that evaluated the clinical impact on patient management and/or improved health outcomes from the use of TEB monitoring for the differentiation of cardiogenic from pulmonary causes of acute dyspnea. PACEMAKERS There were no well-designed studies for this indication that provided information on the clinical impact on patient management or improved health outcomes. For example, since none of the studies reported health outcomes after adjustment of the atrioventricular delay (AV) setting, the evidence is insufficient to conclude whether TEB optimization of the AV delay improves health outcomes. INOTROPIC THERAPY No studies were found that evaluated the clinical impact on patient management and/or improved health outcomes from the use of TEB monitoring of patients in need of inotropic therapy. POST-HEART TRANSPLANT EVALUATION Only one study reported sensitivity and specificity of TEB as a diagnostic test. In this study, TEB had a sensitivity and specificity of 71% and 100%, respectively, for detecting rejection in heart transplant patients, suggesting that, if this finding were replicated, TEB might be a useful adjunct to the standard test, myocardial biopsy. CARDIAC PATIENTS WITH A NEED FOR FLUID MANAGEMENT Several studies were identified which assessed congestive heart failure patients with a need for fluid management with whole body impedance, but no such studies involving TEB were found. HYPERTENSION Only one study reported patient outcomes, and this was a randomized study of the use of TEB compared to specialist care in guiding management of patients with resistant hypertension. In this study, patients who were monitored with TEB had a small, but statistically significant, lower blood pressure at the end of the study, compared to patients treated using clinical judgment. Blood pressure is a well-accepted intermediate result for health outcomes of interest such as lower rates of stroke. Despite the randomized design, the TEB group had a lower average blood pressure at the beginning of the study. The difference in blood pressure between groups at the end of the study was not much larger than the difference at the beginning. Patients in both the control and TEB groups had large reductions in blood pressure compared to their starting pressures, suggesting that the majority of the benefit may have been due to intensive management by expert specialists. The results may not be generalizable to community practice. Conclusion Due to limitations in the studies, no meaningful conclusions can be drawn about the accuracy of TEB, compared to alternative measures of hemodynamic parameters. There is also little conclusive evidence regarding TEB’s usefulness in the specific clinical areas addressed. This was largely due to the lack of focus on clinical outcomes by researchers in this area. The clinical reports on the use of TEB for a variety of clinical indications in reports published from 1991 onwards suggested that this non-invasive method is of interest and may potentially support some of these indications, but there is little evidence that directly addressed how this monitoring technique can affect patient outcomes.