Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, although down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci; the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses were found robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who generate and share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers\' use of the summary statistics.

BACKGROUND: Cardiomyocytes differentiated from human induced pluripotent stem cells (iPSC-CMs) can be used to study genetic cardiac diseases. In patients these diseases are manifested e.g. with impaired contractility and fatal cardiac arrhythmias, and both of these can be due to abnormal calcium transients in cardiomyocytes. Here we classify different genetic cardiac diseases using Ca2+ transient data and different machine learning algorithms.
METHODS: By studying calcium cycling of disease-specific iPSC-CMs and by using calcium transients measured from these cells it is possible to classify diseases from each other and also from healthy controls by applying machine learning computation on the basis of peak attributes detected from calcium transient signals.
RESULTS: In the current research we extend our previous study having Ca-transient data from four different genetic diseases by adding data from two additional diseases (dilated cardiomyopathy and long QT Syndrome 2). We also study, in the light of the current data, possible differences and relations when machine learning modelling and classification accuracies were computed by using either leave-one-out test or 10-fold cross-validation.
CONCLUSIONS: Despite more complex classification tasks compared to our earlier research and having more different genetic cardiac diseases in the analysis, it is still possible to attain good disease classification results. As excepted, leave-one-out test and 10-fold cross-validation achieved virtually equal results.

Ultimate force of the proximal human femur can be predicted using Finite Element Analysis (FEA), but the models rely on 3D computed tomography images. Landmark-based statistical appearance models (SAM) and B-Spline transformation-based statistical deformation models (SDM) have been used to estimate 3D images from 2D projections, which facilitates model generation and reduces the radiation dose. However, there is no literature on the accuracy of SDM-based FEA models of bones with respect to experimental results. In this study, a methodology for an enhanced SDM with textural information is presented. The statistical deformation and texture models (SDTMs) are based on a set of 37 quantitative CT (QCT) images. They were used to estimate 3D images from two or one projections of the set in a leave-one-out setup. These estimations where then used to create FEA models. The ultimate force predicted by FEA models estimated from two or one projection using the SDTMs were compared to the experimental ultimate force from a previous study on the same femora and to the results of standard QCT-based FEA models. High correlations between predictions and experimental measurements were found for FEA models reconstructed from 2D projections with R2=0.835 when based on two projections and R2=0.724 when using one projection. The correlations were comparable to those reached with standard QCT-based FE-models with the experimental results (R2=0.795). This study shows the high potential of SDTM-based 3D image reconstruction and FEA modelling from 2D projections to predict femoral ultimate force.

UNASSIGNED: Data about herpesvirus microRNA motifs on human circular RNAs suggested the following statistical question. Consider independent random counts, not necessarily identically distributed. Conditioned on the sum, decide whether one of the counts is unusually large. Exact computation of the p-value leads to a specific algorithmic problem. Given n elements g 0 , g 1 , … , g n - 1 in a set G with the closure and associative properties and a commutative product without inverses, compute the jackknife (leave-one-out) products g ¯ j = g 0 g 1 ⋯ g j - 1 g j + 1 ⋯ g n - 1 ( 0 ≤ j < n ).
UNASSIGNED: This article gives a linear-time Jackknife Product algorithm. Its upward phase constructs a standard segment tree for computing segment products like g i , j = g i g i + 1 ⋯ g j - 1 ; its novel downward phase mirrors the upward phase while exploiting the symmetry of g j and its complement g ¯ j . The algorithm requires storage for 2 n elements of G and only about 3 n products. In contrast, the standard segment tree algorithms require about n products for construction and log 2 n products for calculating each g ¯ j , i.e., about n log 2 n products in total; and a naïve quadratic algorithm using n - 2 element-by-element products to compute each g ¯ j requires n n - 2 products.
UNASSIGNED: In the herpesvirus application, the Jackknife Product algorithm required 15 min; standard segment tree algorithms would have taken an estimated 3 h; and the quadratic algorithm, an estimated 1 month. The Jackknife Product algorithm has many possible uses in bioinformatics and statistics.

A key goal of model-based cognitive neuroscience is to estimate the trial-by-trial fluctuations of cognitive model parameters in order to link these fluctuations to brain signals. However, previously developed methods are limited by being difficult to implement, time-consuming, or model-specific. Here, we propose an easy, efficient and general approach to estimating trial-wise changes in parameters: Leave-One-Trial-Out (LOTO). The rationale behind LOTO is that the difference between parameter estimates for the complete dataset and for the dataset with one omitted trial reflects the parameter value in the omitted trial. We show that LOTO is superior to estimating parameter values from single trials and compare it to previously proposed approaches. Furthermore, the method makes it possible to distinguish true variability in a parameter from noise and from other sources of variability. In our view, the practicability and generality of LOTO will advance research on tracking fluctuations in latent cognitive variables and linking them to neural data.

This study attempted to better understand the properties associated with the metabolic brain network in mild cognitive impairment (MCI) and Alzheimer\'s disease (AD). Graph theory was employed to investigate the topological organization of metabolic brain network among 86 patients with MCI, 89 patients with AD, and 97 normal controls (NCs) using 18F fluoro-deoxy-glucose positron emission tomography (FDG-PET) data. The whole brain was divided into 82 areas by Brodmann atlas to construct networks. We found that MCI and AD showed a loss of small-world properties and topological aberrations, and MCI showed an intermediate measurement between NC and AD. The networks of MCI and AD were vulnerable to attacks resulting from the altered topological pattern. Furthermore, individual contributions were correlated with Mini-Mental State Examination and Clinical Dementia Rating. The present study indicated that the topological patterns of the metabolic networks were aberrant in patients with MCI and AD, which may be particularly helpful in uncovering the pathophysiology underlying the cognitive dysfunction in MCI and AD.

We propose a method for visualizing genetic assignment data by characterizing the distribution of genetic profiles for each candidate source population. This method enhances the assignment method of Rannala and Mountain (1997) by calculating appropriate graph positions for individuals for which some genetic data are missing. An individual with missing data is positioned in the distributions of genetic profiles for a population according to its estimated quantile based on its available data. The quantiles of the genetic profile distribution for each population are calculated by approximating the cumulative distribution function (CDF) using the saddlepoint method, and then inverting the CDF to get the quantile function. The saddlepoint method also provides a way to visualize assignment results calculated using the leave-one-out procedure. This new method offers an advance upon assignment software such as geneclass2, which provides no visualization method, and is biologically more interpretable than the bar charts provided by the software structure. We show results from simulated data and apply the methods to microsatellite genotype data from ship rats (Rattus rattus) captured on the Great Barrier Island archipelago, New Zealand. The visualization method makes it straightforward to detect features of population structure and to judge the discriminative power of the genetic data for assigning individuals to source populations.

Forty anthraquinone derivatives have been downloaded from PubChem database and investigated in a quantitative structure-activity relationships (QSAR) study. The models describing log P and LD50 of this set were built up on the hypermolecule scheme that mimics the investigated receptor space; the models were validated by the leave-one-out procedure, in the external test set and in a new version of prediction by using similarity clusters. Molecular docking approach using Lamarckian Genetic Algorithm was made on this class of anthraquinones with respect to 3Q3B receptor. The best scored molecules in the docking assay were used as leaders in the similarity clustering procedure. It is demonstrated that the LD50 data of this set of anthraquinones are related to the binding energies of anthraquinone ligands to the 3Q3B receptor.

The performance of two QSAR methodologies, namely Multiple Linear Regressions (MLR) and Neural Networks (NN), towards the modeling and prediction of antitubercular activity was evaluated and compared. A data set of 173 potentially active compounds belonging to the hydrazide family and represented by 96 descriptors was analyzed. Models were built with Multiple Linear Regressions (MLR), single Feed-Forward Neural Networks (FFNNs), ensembles of FFNNs and Associative Neural Networks (AsNNs) using four different data sets and different types of descriptors. The predictive ability of the different techniques used were assessed and discussed on the basis of different validation criteria and results show in general a better performance of AsNNs in terms of learning ability and prediction of antitubercular behaviors when compared with all other methods. MLR have, however, the advantage of pinpointing the most relevant molecular characteristics responsible for the behavior of these compounds against Mycobacterium tuberculosis. The best results for the larger data set (94 compounds in training set and 18 in test set) were obtained with AsNNs using seven descriptors (R(2) of 0.874 and RMSE of 0.437 against R(2) of 0.845 and RMSE of 0.472 in MLRs, for test set). Counter-Propagation Neural Networks (CPNNs) were trained with the same data sets and descriptors. From the scrutiny of the weight levels in each CPNN and the information retrieved from MLRs, a rational design of potentially active compounds was attempted. Two new compounds were synthesized and tested against M. tuberculosis showing an activity close to that predicted by the majority of the models.

The 3-dimensional quantitative structure activity relationship (3D-QSAR) models were established from 21 anthocyanins based on their oxygen radical absorbing capacity (ORAC) and were applied to predict anthocyanins in eggplant and radish for their ORAC values. The cross-validated q(2)=0.857/0.729, non-cross-validated r(2) = 0.958/0.856, standard error of estimate = 0.153/0.134, and F = 73.267/19.247 were for the best QSAR (CoMFA/CoMSIA) models, where the correlation coefficient r(2)pred = 0.998/0.997 (>0.6) indicated a high predictive ability for each. Additionally, the contour map results suggested that structural characteristics of anthocyanins favourable for the high ORAC. Four anthocyanins from eggplant and radish have been screened based on the QSAR models. Pelargonidin-3-[(6\'\'-p-coumaroyl)-glucosyl(2 → 1)glucoside]-5-(6\'\'-malonyl)-glucoside, delphinidin-3-rutinoside-5-glucoside, and delphinidin-3-[(4\'\'-p-coumaroyl)-rhamnosyl(1 → 6)glucoside]-5-glucoside potential with high ORAC based the QSAR models were isolated and also confirmed for their relative high antioxidant ability, which might attribute to the bulky and/or electron-donating substituent at the 3-position in the C ring or/and hydrogen bond donor group/electron donating group on the R1 position in the B ring.