In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.
The language and conceptual framework of "research reproducibility" are nonstandard and unsettled across the sciences.In this Perspective, we review an array of explicit and implicit definitions of reproducibility and related terminology, and discuss how to avoid potential misunderstandings when these terms are used as a surrogate for "truth.
Domino circuits are widely used in high-performance CMOS microprocessors. However, textbook domino pipelines suffer significant timing overhead from clock skew, latch delay, and the inability to borrow time. To eliminate this overhead, some designers provide multiple overlapping clock phases such that domino gates are always ready for evaluation by the time critical inputs arrive and do not precharge until the next gate consumes the result. This paper describes a systematic framework, called skew-tolerant domino circuits, for understanding and analyzing domino circuits with overlapping clocks. Simulations confirm that a speedup of 25% or more can be achieved over textbook domino circuits in high-speed systems.
Abstract The scientific endeavor pivots on the accurate reporting of experimental and theoretical findings, and consequently scientific publication is immensely important. As the number of active scientists continues to increase, there is concern that rewarding scientists chiefly on publication creates a perverse incentive where careless and fraudulent research can thrive. This is compounded by the predisposition of top-tier journals towards novel or positive findings rather than negative results or investigations that merely confirm a null hypothesis, despite their intrinsic value, potentially compounding a reproducibility crisis in several fields. This is a serious problem for both science and public trust in scientific findings. To date, there has been comparatively little mathematical modeling on the factors that influence science trustworthiness, despite the importance of quantifying the problem. In this work, we present a simple phenomenological model with cohorts of diligent, careless and unethical scientists with funding allocated based on published outputs. The results of this analysis suggest that trustworthiness of published science in a given field is strongly influenced by the false positive rate and the pressures from journals for positive results, and that decreasing available funding has negative consequences for the resulting trustworthiness. We also examine strategies to combat propagation of irreproducible science, including increasing fraud detection and awarding diligence, discussing the implications of these findings.
In 2004, the International Committee of Medical Journal Editors (ICMJE)10 issued guidelines requiring registration of all clinical trials that initiated recruitment after July 1, 2005. Clinical trials were to be registered in one of the primary registries in the WHO Registry Network (16 registries as of April 2014) or in ClinicalTrials.gov. Key information about each study, including eligibility criteria and primary outcome measures, are recorded in the registry before the trial starts recruiting participants. The impetus for this action was to improve the ethical standards in the conduct and reporting of research and to assist the biomedical publishing community in the production and distribution of accurate and unbiased articles. Although ICMJE has targeted only clinical trials, publication bias and selective reporting are recognized problems throughout the entire biomedical literature. Positive findings are more likely to be reported than negative ones. Some authors of studies with negative findings perform multiple comparisons and numerous subgroup analyses not defined in the study protocol, to generate positive results, while failing to report the negative observations. Reported outcomes and primary hypotheses differ from those defined in the study protocol. Authors and sponsors, rather than journal editors, appear to be primarily responsible for the reporting bias, a practice that distorts the practice of evidence-based medicine and diminishes the value of systematic reviews and metaanalyses. Selective and incomplete reporting and the failure to report negative findings lead to unnecessary duplication of efforts. Such practices corrupt the validity of literature-based estimates of the risk–benefit ratio of interventions and of the performance of medical tests and, ultimately, can erode public trust in the biomedical research community. On the basis of these considerations a movement has started that is gaining momentum toward expanding the registration of studies involving human study participants beyond clinical trials. In this Q&A, the issue …
Abstract One of the biggest challenges in treating chronic kidney disease (CKD) is that 80 – 90% of people with this disease are undiagnosed, and thus do not access healthcare promptly. The problem arises because early stage CKD has no overt symptoms and the current policy is to perform diagnostic tests (e.g. glomerular filtration rate and urinary albumin to creatinine ratio) only when accompanied by risk factors such as old age, hypertension and diabetes. Genetic testing may be useful to identify those most likely to have CKD and who therefore may benefit from screening. This work describes the development of an algorithm termed RICK (for RIsk for Chronic Kidney disease) that employs a polygenic risk score for CKD plus clinical risk factors to identify people at risk. In data from the UK biobank, those in the top decile of RICK have a 4.4-fold increased risk of CKD, and about 34% of all those with CKD are included in this decile. Using RICK to selectively test those in the general population with highest risk may help in early identification of CKD and thereby facilitate early access to renal healthcare. Lay Summary One of the biggest challenges in renal health is that 80 – 90% of people with Chronic Kidney Disease (CKD) are undiagnosed, and thus do not access healthcare promptly. The problem arises because early stage CKD has no overt symptoms and the current policy is to perform diagnostic tests (e.g. glomerular filtration rate and urinary albumin to creatinine ratio) only when accompanied by risk factors such as old age, hypertension and diabetes. This work describes the development of an algorithm termed RICK (for RIsk for Chronic Kidney disease) that employs a genetic test for CKD plus clinical risk factors to identify people at risk and who therefore may benefit from screening. Those in the top ten percentile of RICK have a 15-fold increased risk of stage 3 CKD. Diagnostic testing of the top decile would capture about 43% of the undiagnosed stage 3 CKD cases. Thus, using RICK to selectively test those with highest risk could have an immense impact on renal health by facilitating early identification of CKD and thereby enabling access to healthcare.
We present a method for image registration based on 3D scale- and rotation-invariant keypoints. The method extends the scale invariant feature transform (SIFT) to arbitrary dimensions by making key modifications to orientation assignment and gradient histograms. Rotation invariance is proven mathematically. Additional modifications are made to extrema detection and keypoint matching based on the demands of image registration. Our experiments suggest that the choice of neighborhood in discrete extrema detection has a strong impact on image registration accuracy. In head MR images, the brain is registered to a labeled atlas with an average Dice coefficient of 92%, outperforming registration from mutual information as well as an existing 3D SIFT implementation. In abdominal CT images, the spine is registered with an average error of 4.82 mm. Furthermore, keypoints are matched with high precision in simulated head MR images exhibiting lesions from multiple sclerosis. These results were achieved using only affine transforms, and with no change in parameters across a wide variety of medical images. This paper is freely available as a cross-platform software library.
Purpose: There is a sudden increase in the number of publications reporting on the use of the narrow band imaging (NBI) colonoscopy to differentiate neoplastic from hyperplastic colorectal polyps. These data would be valuable to allow us to understand its diagnostic operating characteristics, which, in turn, could provide insights of its potentials for clinical use. Methods: We extensively searched the literature using Medline, EMBASE and Cochrane Library databases and meeting abstracts; used an advanced bivariate meta-analysis to summarize the data, and a hierarchical model to synthesize the summary receiver-operating characteristic (ROC) curve. We calculated the summary sensitivity, specificity, and negative predictive value (NPV). Results: NBI diagnosis of colorectal polyps can be classified as an excellent test - the area under the ROC curve was 0.94 - based on 28 studies (18 manuscripts and 10 abstracts) involving 6,280 polyps in 3,036 patients. All studies reported the test to be worthwhile (Figure). The overall sensitivity was 91.0% (95% CI: 87.6-93.5%) and specificity was 82.6% (95% CI: 79.0-85.7%). In 6 studies (n=1567 polyps) that used high or low confidence diagnostic predictions, the overall sensitivity was 95.1% and specificity was 85% for a high confidence diagnosis, and the ROC area increased to 0.97. In the diagnosis of diminutive polyps (n=1850), including both high and low confidence predictions, NBI had a sensitivity of 89.4% (95%CI: 80.8-94.4%) and a specificity of 85.8% (95%CI=77.6-91.4%). The NPVs were 93.2, 90.1, and 86% for the proportion of neoplasms among polyps to be 40, 50 and 60%, respectively.Figure: [496] The Summary Receiver Operating Curve of the use of the Narrow Band Imaging to diagnose neoplastic and hyperplastic colorectal polyps. The size of the circles indicates the weight of each study.Conclusion: The accuracy of NBI diagnosis of neoplastic and hyperplastic colorectal polyps can be classified as excellent. It provides high (>90%) sensitivity and NPV for clinical implementation. Disclosure: Dr. McGill: nothing to disclose. Dr. Vangelis: nothing to disclose. Dr. Ioannides: nothing to disclose. Dr. Soetikno: consultant for Olympus Medical Systems Corporation, and has received research funding from Olympus America. Dr. Kaltenbach: consultant for Olympus Medical Systems Corporation, and has received research funding from Olympus America.Table: [496] Performance of real-time optical diagnosis with NBI colonoscopy
A technique often used in Positron Emission Tomography (PET) systems to readout pulse signals from detectors is to use a free-running ADC to digitize the pulse waveform and then use software to determine the time and energy of the pulse. The advantage of this technique over analog-based methods is the possibility of obtaining superior time resolution with software-based time discrimination algorithms and the flexibility of working with digitized values. Unfortunately, the digitized pulse waveform output from a free-running ADC is an inefficient representation of the signal. As illustrated in the paper, the rising edge, where we desire fine sampling for arrival time determination, ends up being sampled coarsely. The falling edge, which is only used for energy determination, can be coarsely sampled, but we fine sample it instead, so this solution is not cost or power optimal. The rest of this paper describes a chip which samples at user-defined voltage levels to overcome these issues.
Abstract Objective To appraise systematically randomized controlled trials (RCTs) on systemic sclerosis (SSc) in order to determine whether the parameter of study design and its quality may influence the reporting of efficacy for tested interventions. Methods Seventy RCTs were analyzed (1965–2000) in terms of design, patient characteristics, outcomes, and reported results. Results Median sample size was 28 patients. Fifty‐nine trials were double blind, but only 16 mentioned the randomization mode and only 7 described allocation concealment. There was sufficient information on withdrawals in 37 trials. Larger trials with longer followup scored higher on quality characteristics, but had higher withdrawal rates. Only 8 trials had a followup of more than 1 year. Significant efficacy was less likely to be reported in double‐blind studies ( P = 0.029) and in studies with larger rates of withdrawal ( P = 0.032). Specification of the following parameters improved over time: power calculations ( P = 0.0003), outcomes ( P = 0.001), and sample size per arm ( P = 0.011). Conclusions Several aspects of the quality of design and conduct of SSc RCTs can be improved. Adequately powered trials with longer followup and clear outcomes are needed.
<p>PDF - 104KB, Ascertainment and review of CEC papers for this analysis.</p>
