Publications

ABSTRACT Excess death estimates have great value in public health, but they can be sensitive to analytical choices. Here we propose a multiverse analysis approach that considers all possible different time periods for defining the reference baseline and a range of 1 to 4 years for the projected time period for which excess deaths are calculated. We used data from the Human Mortality Database on 33 countries with detailed age-stratified death information on an annual basis during the period 2009-2021. The use of different time periods for reference baseline led to large variability in the absolute magnitude of the exact excess death estimates. However, the relative ranking of different countries compared to others for specific years remained largely unaltered. The relative ranking of different years for the specific country was also largely independent of baseline. Averaging across all possible analyses, distinct time patterns were discerned across different countries. Countries had declines between 2009 and 2019, but the steepness of the decline varied markedly. There were also large differences across countries on whether the COVID-19 pandemic years 2020-2021 resulted in an increase of excess deaths and by how much. Consideration of longer projected time windows resulted in substantial shrinking of the excess deaths in many, but not all countries. Multiverse analysis of excess deaths over long periods of interest can offer a more unbiased approach to understand comparative mortality trends across different countries, the range of uncertainty around estimates, and the nature of observed mortality peaks.

Reproducibility concerns in biomedical research have persisted for more than a decade, with large-scale assessments revealing significant challenges in replicating findings. Despite widespread acknowledgment of these issues, responses remain inconsistent, and proposed solutions often lack rigorous evaluation. This review examines the factors that contribute to irreproducibility in conducting, reporting, and reviewing research and assesses the effectiveness and desirability of interventions aimed at improving reproducibility. It highlights the need for balanced scientific reforms that strengthen reproducibility without stifling innovation or introducing unintended consequences. A critical appraisal of the role of meta-research is essential to ensure sustainable improvements in research quality.

Abstract Annual vaccination is widely recommended for influenza and SARS‐CoV‐2. In this essay, we analyse and question the prevailing policymaking approach to these respiratory virus vaccines, especially in the United States. Every year, licensed influenza vaccines are reformulated to include specific strains expected to dominate in the season ahead. Updated vaccines are rapidly manufactured and approved without further regulatory requirement of clinical data. Novel vaccines (i.e. new products) typically undergo clinical trials, though generally powered for clinically unimportant outcomes (e.g. lab‐confirmed infections, regardless of symptomatology or antibody levels). Eventually, the current and future efficacy of influenza and COVID‐19 vaccines against hospitalization or death carries considerable uncertainty. The emergence of highly transmissible SARS‐CoV‐2 variants and waning vaccine‐induced immunity led to plummeting vaccine effectiveness, at least against symptomatic infection, and booster doses have since been widely recommended. No further randomized trials were performed for clinically important outcomes for licensed updated boosters. In both cases, annual vaccine effectiveness estimates are generated by observational research, but observational studies are particularly susceptible to confounding and bias. Well‐conducted experimental studies, particularly randomized trials, are necessary to address persistent uncertainties about influenza and COVID‐19 vaccines. We propose a new research framework which would render results relevant to the current or future respiratory viral seasons. We demonstrate that experimental studies are feasible by adopting a more pragmatic approach and provide strategies on how to do so. When it comes to implementing policies that seriously impact people's lives, require substantial public resources and/or rely on widespread public acceptance, high evidence standards are desirable.

Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

This article proposes a completion-detection method for efficiently implementing Boolean functions as self-timed logic structures. Current-Sensing Completion Detection, CSCD, allows self-timed circuits to be designed using single-rail variable encoding (one signal...

This draft describes an architecture for security policy management for IPSEC based on the principle of ``compliance checking.'' We describe a two-level policy hierarchy, in which security association policy is managed by a highly flexible policy language, which in turn provides input to packet policies that are managed by a fast packet filtering language. We provide a sample SA policy language, based on KeyNote, and describe interoperability issues for this architecture.

Clock skew is an increasing concern for high-speed circuit designers. Circuit designers use transparent latches and skew-tolerant domino circuits to hide clock skew from the critical path and take advantage of shared portions of the clock network to budget less skew between nearby elements than across the entire die, but current timing analysis algorithms do not handle correlated clock skews. This paper extends the Sakallah-Mudge-Olukotun (SMO) latch-based timing analysis to include different amounts of clock skew between different elements. The key change is that departure times from each latch must be defined with respect to launching clocks so that the skew between the launching and receiving clocks can be determined at each receiver. The exact analysis leads to an explosion in the number of timing constraints, but most constraints are not tight in practical situations and a modified version of the Szymanski-Shenoy relaxation algorithm gives exact results with only a small increase in runtime. The timing analysis formulation also captures the effects of skew on edge-triggered flip-flops, domino circuits, and min-delay constraints. Our exact algorithm, applied to a supercomputer node controller with over 12000 clocked elements, finds the system can run 50-90 ps faster than a single skew analysis would predict and requires searching fewer than 4% more latch departures than conventional algorithms. With the less conservative skew budgets enabled by better timing analysis, we expect clocked systems will remain viable to multi-GHz frequencies.

The increasing speed of new generation processors will exacerbate the already large difference between CPU cycle times and main memory access times. As this difference grows, it will be increasingly difficult to build single-level caches that are both fast enough to match these fast cycle times and large enough to effectively hide the slow main memory access times. One solution to this problem is to use a multi-level cache hierarchy. This paper examines the relationship between cache organization and program execution time for multi-level caches. We show that a first-level cache dramatically reduces the number of references seen by a second-level cache, without having a large effect on the number of second-level cache misses. This reduction in the number of second-level cache hits changes the optimal design point by decreasing the importance of the cycle-time of the second-level cache relative to its size. The lower the first-level cache miss rate, the less important the second-level cycle time becomes. This change in relative importance of cycle time and miss rate makes associativity more attractive and increases the optimal cache size for second-level caches over what they would be for an equivalent single-level cache system.