Publications

An overview of recommendations and translational milestones for genomic tests in cancer

Markov Random Field Based Automatic Image Alignment for ElectronTomography

Cryo electron tomography (cryo-ET) is the primary method for obtaining 3D reconstructions of intact bacteria, viruses, and complex molecular machines ([7],[2]). It first flash freezes a specimen in a thin layer of ice, and then rotates the ice sheet in a transmission electron microscope (TEM) recording images of different projections through the sample. The resulting images are aligned and then back projected to form the desired 3-D model. The typical resolution of biological electron microscope is on the order of 1 nm per pixel which means that small imprecision in the microscope's stage or lenses can cause large alignment errors. To enable a high precision alignment, biologists add a small number of spherical gold beads to the sample before it is frozen. These beads generate high contrast dots in the image that can be tracked across projections. Each gold bead can be seen as a marker with a fixed location in 3D, which provides the reference points to bring all the images to a common frame as in the classical structure from motion problem. A high accuracy alignment is critical to obtain a high resolution tomogram (usually on the order of 5-15nm resolution). While some methods try to automate the task of tracking markers and aligning the images ([8],[4]), they require user intervention if the SNR of the image becomes too low. Unfortunately, cryogenic electron tomography (or cryo-ET) often has poor SNR, since the samples are relatively thick (for TEM) and the restricted electron dose usually results in projections with SNR under 0 dB. This paper shows that formulating this problem as a most-likely estimation task yields an approach that is able to automatically align with high precision cryo-ET datasets using inference in graphical models. This approach has been packaged into a publicly available software called RAPTOR-Robust Alignment and Projection estimation for Tomographic Reconstruction.

Hardware Abstractions and Hardware Mechanisms to Support Multi-Task Execution on Coarse-Grained Reconfigurable Arrays

Domain-specific accelerators are used in various computing systems ranging from edge devices to data centers. Coarse-grained reconfigurable arrays (CGRAs) represent an architectural midpoint between the flexibility of an FPGA and the efficiency of an ASIC and are a promising candidate for servicing multi-tasked workloads within an application domain. Unfortunately, scheduling multiple tasks onto a CGRA is challenging. CGRAs lack abstractions that capture hardware resources, leaving workload schedulers unable to reason about performance, energy, and utilization for different schedules. This work first proposes a CGRA architecture that can flexibly partition key resources, including the global buffer memory capacity, the global buffer memory bandwidth, and the compute resources. Partitioned resources serve as hardware abstractions that decouple compilation and resource allocation. The compiler uses these abstractions for coarse-grained resource mapping, and the scheduler uses them for flexible resource allocation at run time. We then propose two hardware mechanisms to support multi-task execution. A flexible-shape execution region increases the overall resource utilization by mapping multiple tasks with different resource requirements. Dynamic partial reconfiguration (DPR) enables a CGRA to update the hardware configuration as the scheduler makes decisions rapidly. We show that our abstraction can help automatic and efficient scheduling of multi-tasked workloads onto our target CGRA with high utilization, resulting in 1.05x-1.24x higher throughput and a 23-28% lower latency in a multi-tasked cloud workload and 60.8% reduced latency in an autonomous system workload when compared to a baseline CGRA running single tasks at a time.

PREDIMED trial of Mediterranean diet: retracted, republished, still trusted?

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Transparent Communication of Radiology Research

Genetic associations: false or true?

STrengthening the REporting of Genetic Association Studies (STREGA)— An Extension of the STROBE Statement

This FAIRsharing record describes: The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies.

Por qué la mayoría de los resultados de investigación publicados son falsos

Most healthcare interventions tested in Cochrane Reviews are not effective according to high quality evidence: a systematic review and meta-analysis

The importance of independent risk‐factors for long‐term mortality prediction after cardiac surgery

Abstract Background The purpose of the present study was to determine independent predictors for long‐term mortality after cardiac surgery. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was developed to score in‐hospital mortality and recent studies have shown its ability to predict long‐term mortality as well. We compared forecasts based on EuroSCORE with other models based on independent predictors. Methods Medical records of patients with cardiac surgery who were discharged alive ( n = 4852) were retrospectively reviewed. Their operative surgical risks were calculated according to EuroSCORE. Patients were randomly divided into two groups: training dataset ( n = 3233) and validation dataset ( n = 1619). Long‐term survival data (mean follow‐up 5·1 years) were obtained from the National Death Index. We compared four models: standard EuroSCORE (M1); logistic EuroSCORE (M2); M2 and other preoperative, intra‐operative and post‐operative selected variables (M3); and selected variables only (M4). M3 and M4 were determined with multivariable Cox regression analysis using the training dataset. Results The estimated five‐year survival rates of the quartiles in compared models in the validation dataset were: 94·5%, 87·8%, 77·1%, 64·9% for M1; 95·1%, 88·0%, 80·5%, 64·4% for M2; 93·4%, 89·4%, 80·8%, 64·1% for M3; and 95·8%, 90·9%, 81·0%, 59·9% for M4. In the four models, the odds of death in the highest‐risk quartile was 8·4‐, 8·5‐, 9·4‐ and 15·6‐fold higher, respectively, than the odds of death in the lowest‐risk quartile ( P < 0·0001 for all). Conclusions EuroSCORE is a good predictor of long‐term mortality after cardiac surgery. We developed and validated a model using selected preoperative, intra‐operative and post‐operative variables that has better discriminatory ability.

Replication and meta-analysis of TMEM132D gene variants in panic disorder

A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n = 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n = 1038 cases and n = 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.

A heuristic for optimizing stochastic activity networks with applications to statistical digital circuit sizing

A deterministic activity network (DAN) is a collection of activities, each with some duration, along with a set of precedence constraints, which specify th

Extremely large outlier treatment effects may be a footprint of bias in trials from less developed countries: randomized trials of gabapentinoids

Intent-leveraged optimization of analog circuits via homotopy

This paper proposes a circuit optimization approach that can ease the computational burden on the simulation-based circuit optimizers by leveraging simple design equations that reflect the designer's intent. The technique is inspired by continuation methods (a.k.a. homotopy) in numerical analysis where a hard problem is solved by constructing an easier problem first and gradually refining its solution to that of the hard problem. In a circuit optimization context, the designer's simplified equations for the circuit serve as the easier problem. These simplified design equations are easy to write as they need not be completely accurate and have intuitive, well-understood solutions. Nonetheless, in several circuit examples, it was found that the designer's equations serve as better guidance than the conventional, fixed-point equations. As a result, the proposed approach demonstrates the better convergence to the desired solution with less computational efforts.

Reproducibility in Science

Medical and scientific advances are predicated on new knowledge that is robust and reliable and that serves as a solid foundation on which further advances can be built. In biomedical research, we are in the midst of a revolution with the generation of new data and scientific publications at a previously unprecedented rate. However, unfortunately, there is compelling evidence that the majority of these discoveries will not stand the test of time. To a large extent, this reproducibility crisis in basic and preclinical research may be as a result of failure to adhere to good scientific practice and the desperation to publish or perish. This is a multifaceted, multistakeholder problem. No single party is solely responsible, and no single solution will suffice. Here we review the reproducibility problems in basic and preclinical biomedical research, highlight some of the complexities, and discuss potential solutions that may help improve research quality and reproducibility.

Calibrating the Scientific Ecosystem Through Meta-Research

While some scientists study insects, molecules, brains, or clouds, other scientists study science itself. Meta-research, or research-on-research, is a burgeoning discipline that investigates efficiency, quality, and bias in the scientific ecosystem, topics that have become especially relevant amid widespread concerns about the credibility of the scientific literature. Meta-research may help calibrate the scientific ecosystem toward higher standards by providing empirical evidence that informs the iterative generation and refinement of reform initiatives. We introduce a translational framework that involves ( a) identifying problems, ( b) investigating problems, ( c) developing solutions, and ( d) evaluating solutions. In each of these areas, we review key meta-research endeavors and discuss several examples of prior and ongoing work. The scientific ecosystem is perpetually evolving; the discipline of meta-research presents an opportunity to use empirical evidence to guide its development and maximize its potential.

Techniques for characterizing DRAMs with a 500 MHz interface

The advent of high-bandwidth DRAMs poses a number of new challenges for test and characterization. This paper describes a collection of techniques that were used in the design and characterization of a new DRAM architecture with 500 MHz I/O signals. Methods of fixturing and calibration are presented for achieving system accuracies of better than 100 ps. Laboratory techniques for measuring critical circuit parameters such as path delay, clock jitter, current source strength, and pin capacitances are shown as well. These techniques, along with on-chip test logic, which allows the DRAM core to be tested using conventional low-speed memory test equipment, enable full characterization of high bandwidth memories.

Physical activity and cancer: an umbrella review of the literature including 22 major anatomical sites and 770 000 cancer cases

Objective To provide an overview of the breadth and validity of claimed associations between physical activity and risk of developing or dying from cancer. Design Umbrella review. Data sources We searched Medline, Embase, Cochrane Database and Web of Science. Eligibility criteria for selecting studies Systematic reviews about physical activity and cancer incidence and cancer mortality in different body sites among general population. Results We included 19 reviews covering 22 cancer sites, 26 exposure-outcome pairs meta-analyses and 541 original studies. Physical activity was associated with lower risk of seven cancer sites (colon, breast, endometrial, lung, oesophageal, pancreas and meningioma). Only colon (a protective association with recreational physical activity) and breast cancer (a protective association with overall physical activity) were supported by strong evidence and highly suggestive evidence, respectively. Evidence from endometrial, lung, oesophageal, pancreas and meningioma presented hints of uncertainty and bias in the literature ( eg, not reaching P values<10 -6 ) showing large between-study heterogeneity and/or not demonstrating a definite direction for the effect when 95% prediction intervals were considered. Four of the 26 meta-analyses showed small study effects and 4 showed excess significance. Conclusion Physical activity is associated with a lower risk of several cancers, but only colon and breast cancer associations were supported by strong or highly suggestive evidence, respectively. Evidence from other cancer sites was less consistent, presenting hints of uncertainty and/or bias.