Contra-Analysis: Prioritizing Meaningful Effect Size in Scientific Research

At every phase of scientific research, scientists must decide how to allocate limited resources to pursue the research inquiries with the greatest potential. This prioritization dictates which controlled interventions are studied, awarded funding, published, reproduced with repeated experiments, investigated in related contexts, and translated for societal use. There are many factors that influence this decision-making, but interventions with larger effect size are often favored because they exert the greatest influence on the system studied. To inform these decisions, scientists must compare effect size across studies with dissimilar experiment designs to identify the interventions with the largest effect. These studies are often only loosely related in nature, using experiments with a combination of different populations, conditions, timepoints, measurement techniques, and experiment models that measure the same phenomenon with a continuous variable. We name this assessment contra-analysis and propose to use credible intervals of the relative difference in means to compare effect size across studies in a meritocracy between competing interventions. We propose a data visualization, the contra plot, that allows scientists to score and rank effect size between studies that measure the same phenomenon, aid in determining an appropriate threshold for meaningful effect, and perform hypothesis tests to determine which interventions have meaningful effect size. We illustrate the use of contra plots with real biomedical research data. Contra-analysis promotes a practical interpretation of effect size and facilitates the prioritization of scientific research.Comment: 4 figures, 8000 word

Vascular Expression of Hemoglobin Alpha in Antarctic Icefish Supports Iron Limitation as Novel Evolutionary Driver

Frigid temperatures of the Southern Ocean are known to be an evolutionary driver in Antarctic fish. For example, many fish have reduced red blood cell (RBC) concentration to minimize vascular resistance. Via the oxygen-carrying protein hemoglobin, RBCs contain the vast majority of the body’s iron, which is known to be a limiting nutrient in marine ecosystems. Since lower RBC levels also lead to reduced iron requirements, we hypothesize that low iron availability was an additional evolutionary driver of Antarctic fish speciation. Antarctic Icefish of the family Channichthyidae are known to have an extreme alteration of iron metabolism due to loss of RBCs and two iron-binding proteins, hemoglobin and myoglobin. Loss of hemoglobin is considered a maladaptive trait allowed by relaxation of predator selection since extreme adaptations are required to compensate for the loss of oxygen-carrying capacity. However, iron dependency minimization may have driven hemoglobin loss instead of a random evolutionary event. Given the variety of functions that hemoglobin serves in the endothelium, we suspected the protein corresponding to the 3’ truncated Hbα fragment (Hbα-3’f) that was not genetically excluded by icefish may still be expressed as a protein. Using whole mount confocal microscopy, we show that Hbα-3’f is expressed in the vascular endothelium of icefish retina, suggesting this Hbα fragment may still serve an important role in the endothelium. These observations support a novel hypothesis that iron minimization could have influenced icefish speciation with the loss of the iron-binding portion of Hbα in Hbα-3’f, as well as hemoglobin β and myoglobin

Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1

Lipid regulation of ion channels is largely explored using in silico modeling with minimal experimentation in intact tissue; thus, the functional consequences of these predicted lipid-channel interactions within native cellular environments remain elusive. The goal of this study is to investigate how lipid regulation of endothelial Kir2.1 - an inwardly rectifying potassium channel that regulates membrane hyperpolarization - contributes to vasodilation in resistance arteries. First, we show that phosphatidylserine (PS) localizes to a specific subpopulation of myoendothelial junctions (MEJs), crucial signaling microdomains that regulate vasodilation in resistance arteries, and in silico data have implied that PS may compete with phosphatidylinositol 4,5-bisphosphate (PIP2) binding on Kir2.1. We found that Kir2.1-MEJs also contained PS, possibly indicating an interaction where PS regulates Kir2.1. Electrophysiology experiments on HEK cells demonstrate that PS blocks PIP2 activation of Kir2.1 and that addition of exogenous PS blocks PIP2-mediated Kir2.1 vasodilation in resistance arteries. Using a mouse model lacking canonical MEJs in resistance arteries (Elnfl/fl/Cdh5-Cre), PS localization in endothelium was disrupted and PIP2 activation of Kir2.1 was significantly increased. Taken together, our data suggest that PS enrichment to MEJs inhibits PIP2-mediated activation of Kir2.1 to tightly regulate changes in arterial diameter, and they demonstrate that the intracellular lipid localization within the endothelium is an important determinant of vascular function

Compositional variability in a cold-water scleractinian, Lophelia pertusa : new insights into “vital effects”

Author Posting. © American Geophysical Union, 2006. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 7 (2006): Q12004, doi:10.1029/2006GC001354.We analyzed Sr/Ca and Mg/Ca ratios in the thecal wall of Lophelia pertusa, a cold-water coral, using SIMS ion microprobe techniques. The wall grows by simultaneous upward extension and outward thickening. Compositional variability displays similar trends along the upward and outward growth axes. Sr/Ca and Mg/Ca ratios oscillate systematically and inversely. The sensitivity of Lophelia Sr/Ca ratios to the annual temperature cycle (−0.18 mmol · mol−1/°C) is twice as strong as that exhibited by tropical reef corals, and four times as strong as the temperature dependence of Sr/Ca ratios of abiogenic aragonites precipitated experimentally from seawater. A comparison of the skeletal composition of Lophelia with results from precipitation calculations carried out using experimentally determined partition coefficients suggests that both temperature-dependent element partitioning and seasonal changes in the mass fraction of aragonite precipitated from the calcifying fluid influence the composition of Lophelia skeleton. Results from calculations that combine these effects reproduce both the exaggerated amplitude of the Sr/Ca and Mg/Ca oscillations and the inverse relationship between Sr/Ca and Mg/Ca ratios.This study was supported in part by a WHOI Ocean Life Institute fellowship to ALC, by NSF grant OCE-0527350 to G.A.G. and A.L.C., and by the EU 6FP project HERMES, EC contract GOCE-CT-2005-511234 to T.L

Building a diverse workforce and thinkforce to reduce health disparities

The Research Centers in Minority Institutions (RCMI) Program was congressionally man-dated in 1985 to build research capacity at institutions that currently and historically recruit, train, and award doctorate degrees in the health professions and health-related sciences, primarily to individuals from underrepresented and minority populations. RCMI grantees share similar infrastructure needs and institutional goals. Of particular importance is the professional development of multidisciplinary teams of academic and community scholars (the “workforce”) and the harnessing of the heterogeneity of thought (the “thinkforce”) to reduce health disparities. The purpose of this report is to summarize the presentations and discussion at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019. The RCMI IDC Directors provided information about their professional development activities and Pilot Projects Programs and discussed barriers identified by new and early-stage investigators that limit effective career development, as well as potential solutions to overcome such obstacles. This report also proposes potential alignments of professional development activities, targeted goals and common metrics to track productivity and success

Reverse accumulation and accurate rounding error estimates for taylor series coefficient

Original article can be found at: http://www.informaworld.com/smpp/title~content=t713645924~db=all Copyright Taylor and Francis/ Informa.We begin by extending the technique of reverse accumulation so as to obtain gradients of univariate Taylor series coefficients. This is done by re-interpreting the same formulae used to reverse accumulategradients in the conventional (scalar) case. Thus a carefully written implementation of conventional reverse accumulation can be extended to the Taylor series valued case by (further) overloading of the appropriate operators. Next, we show how to use this extended reverse accumulation technique so as to construct accurate (i.e. rigorous and sharp) error bounds for the numerical values of the Taylor series coefficients of the target function, again by re-interpreting the corresponding conventional (scalar) formulae. This extension can also be implemented simply by re-engineering existing code. The two techniques (reverse accumulation of gradients and accurate error estimates) each require only a small multiple of the processing time required to compute the underlying Taylor series coefficients. Space "requirements are comparable to those for conventional (scalar) reverse accumulation, and can be simply managed. We concluded with a discussion of possible implementation strategies and the implications for the re-use of code.Peer reviewe

The Least Difference in Means: A Statistic for Effect Size Strength and Practical Significance

With limited resources, scientific inquiries must be prioritized for further study, funding, and translation based on their practical significance: whether the effect size is large enough to be meaningful in the real world. Doing so must evaluate a result's effect strength, defined as a conservative assessment of practical significance. We propose the least difference in means ($\delta_L$) as a two-sample statistic that can quantify effect strength and perform a hypothesis test to determine if a result has a meaningful effect size. To facilitate consensus, $\delta_L$ allows scientists to compare effect strength between related results and choose different thresholds for hypothesis testing without recalculation. Both $\delta_L$ and the relative $\delta_L$ outperform other candidate statistics in identifying results with higher effect strength. We use real data to demonstrate how the relative $\delta_L$ compares effect strength across broadly related experiments. The relative $\delta_L$ can prioritize research based on the strength of their results.Comment: 5 figures. arXiv admin note: substantial text overlap with arXiv:2201.0123

The Most Difference in Means: A Statistic for the Strength of Null and Near-Zero Results

Statistical insignificance does not suggest the absence of effect, yet scientists must often use null results as evidence of negligible (near-zero) effect size to falsify scientific hypotheses. Doing so must assess a result's null strength, defined as the evidence for a negligible effect size. Such an assessment would differentiate strong null results that suggest a negligible effect size from weak null results that suggest a broad range of potential effect sizes. We propose the most difference in means ($\delta_M$) as a two-sample statistic that can both quantify null strength and perform a hypothesis test for negligible effect size. To facilitate consensus when interpreting results, our statistic allows scientists to conclude that a result has negligible effect size using different thresholds with no recalculation required. To assist with selecting a threshold, $\delta_M$ can also compare null strength between related results. Both $\delta_M$ and the relative form of $\delta_M$ outperform other candidate statistics in comparing null strength. We compile broadly related results and use the relative $\delta_M$ to compare null strength across different treatments, measurement methods, and experiment models. Reporting the relative $\delta_M$ may provide a technical solution to the file drawer problem by encouraging the publication of null and near-zero results

Building a Diverse Workforce and Thinkforce to Reduce Health Disparities

The Research Centers in Minority Institutions (RCMI) Program was congressionally mandated in 1985 to build research capacity at institutions that currently and historically recruit, train, and award doctorate degrees in the health professions and health-related sciences, primarily to individuals from underrepresented and minority populations. RCMI grantees share similar infrastructure needs and institutional goals. Of particular importance is the professional development of multidisciplinary teams of academic and community scholars (the “workforce”) and the harnessing of the heterogeneity of thought (the “thinkforce”) to reduce health disparities. The purpose of this report is to summarize the presentations and discussion at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019. The RCMI IDC Directors provided information about their professional development activities and Pilot Projects Programs and discussed barriers identified by new and early-stage investigators that limit effective career development, as well as potential solutions to overcome such obstacles. This report also proposes potential alignments of professional development activities, targeted goals and common metrics to track productivity and success