Accurate modeling of replication rates in genome-wide association studies by accounting for Winner's Curse and study-specific heterogeneity.

Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex human traits, but only a fraction of variants identified in discovery studies achieve significance in replication studies. Replication in genome-wide association studies has been well-studied in the context of Winner's Curse, which is the inflation of effect size estimates for significant variants due to statistical chance. However, Winner's Curse is often not sufficient to explain lack of replication. Another reason why studies fail to replicate is that there are fundamental differences between the discovery and replication studies. A confounding factor can create the appearance of a significant finding while actually being an artifact that will not replicate in future studies. We propose a statistical framework that utilizes genome-wide association studies and replication studies to jointly model Winner's Curse and study-specific heterogeneity due to confounding factors. We apply this framework to 100 genome-wide association studies from the Human Genome-Wide Association Studies Catalog and observe that there is a large range in the level of estimated confounding. We demonstrate how this framework can be used to distinguish when studies fail to replicate due to statistical noise and when they fail due to confounding.

Cognitive impairment is associated with sarcopenia mainly related to attention and calculation in hospitalized Chinese elderly men.

BACKGROUND AND OBJECTIVES: Sarcopenia and cognitive impairment are the most prevalent causes of disability in older individuals. The aim of this study was to assess the prevalence of sarcopenia and the association between cognitive impairment and sarcopenia in older patients. METHODS AND STUDY DESIGN: A cross-sectional study was undertaken, comprised 250 male patients aged 65 and over. Sarcopenia was defined using the diagnostic recommended consensus by the Asian Working Group for sarcopenia, and the participants were classified into the sarcopenia and non-sarcopenia groups according to this definition. The cognitive functions of older patients were assessed using the Mini-Mental State Examination (MMSE). After bivariate analyses, a multivariate logistic regression model was constructed to determine the association of study variables with sarcopenia. RESULTS: The prevalence of sarcopenia and cognitive impairment was 20.8% and 19.6% respectively. Additionally, we found 10.8% patients had nutritional risk, 19.6% patients had cognitive impairment in this study. Multivariate analysis identified age (OR: 1.11, 95% Cl 1.03, 1.19, p=0.008), cognitive impairment (OR: 4.06, 95% Cl 1.42, 11.6, p=0.009) and nutritional risk (OR: 13.7, 95% Cl 3.06, 61.2, p=0.001) were significantly associated with sarcopenia. The prevalence of sarcopenia significantly increased stepwise with lower MMSE score. Additionally, the score on the attention and calculation (OR=0.68, 95% Cl: 0.51, 0.91, p=0.009) subsection of the MMSE was associated with the presence of sarcopenia. MMSE score was correlated with the fat free mass, handgrip strength (p<0.05). CONCLUSIONS: Cognitive impairment, especially in the calculation and attention, and nutritional risk, are associated with sarcopenia in hospitalized Chinese male elderly. Adequate nutritional support may be the key to solving these diseases.

DGL-LifeSci: An Open-Source Toolkit for Deep Learning on Graphs in Life Science.

Graph neural networks (GNNs) constitute a class of deep learning methods for graph data. They have wide applications in chemistry and biology, such as molecular property prediction, reaction prediction, and drug-target interaction prediction. Despite the interest, GNN-based modeling is challenging as it requires graph data preprocessing and modeling in addition to programming and deep learning. Here, we present Deep Graph Library (DGL)-LifeSci, an open-source package for deep learning on graphs in life science. Deep Graph Library (DGL)-LifeSci is a python toolkit based on RDKit, PyTorch, and Deep Graph Library (DGL). DGL-LifeSci allows GNN-based modeling on custom datasets for molecular property prediction, reaction prediction, and molecule generation. With its command-line interfaces, users can perform modeling without any background in programming and deep learning. We test the command-line interfaces using standard benchmarks MoleculeNet, USPTO, and ZINC. Compared with previous implementations, DGL-LifeSci achieves a speed up by up to 6×. For modeling flexibility, DGL-LifeSci provides well-optimized modules for various stages of the modeling pipeline. In addition, DGL-LifeSci provides pretrained models for reproducing the test experiment results and applying models without training. The code is distributed under an Apache-2.0 License and is freely accessible at https://github.com/awslabs/dgl-lifesci.

A Survey of Clinical Opinions and Preferences on the Non-surgical Management of Intermittent Exotropia in China.

PURPOSE: This study reports clinical opinions and preferences on the non-surgical management of intermittent exotropia (IXT) among practitioners in China. METHODS: An online survey was developed and distributed through professional bodies. The study was conducted from July 25th to August 3rd, 2019. A total of 300 ophthalmologists and 188 optometrists responded. RESULTS: Of 488 participants, 257 (53%) considered fusion defects as the main cause of IXT, and 299 (61%) took IXT as a progressive disorder. Two hundred and seventy-one (56%) participants considered orthoptic exercises as the most effective non-surgical intervention for IXT. Likewise, 245 (50%) participants reported that orthoptic exercises were their most frequent non-surgical option, followed by observation (178, 37%). There are discrepancies between ophthalmologists and optometrists. A greater proportion of ophthalmologists (201, 67%) shared the view that IXT worsens over time (98, 52%) (p = .001). Additionally, ophthalmologists (121, 40%) tended to prefer observation compared with optometrists (57, 30%) (p = .021). CONCLUSIONS: This study shows that there is no general consensus on the non-surgical management of IXT in China. Given the lack of robust evidence, the findings from this study highlight the need for future randomized clinical trials to validate the effectiveness of non-surgical interventions, orthoptic exercises in particular, and to establish treatment guidelines accordingly.

Effect of the base-out recovery point as the surgical target for acute acquired comitant esotropia.

PURPOSE: To evaluate the treatment efficacy of the preoperative base-out recovery point as the surgical target angle for acute acquired comitant esotropia. METHODS: Prospective study. Twenty-two patients with acute acquired comitant esotropia (AACE) underwent strabismus surgery based on the target angle of the preoperative base-out recovery point. The postoperative deviation, positive fusional vergence, and negative fusional vergence were evaluated and compared with those of 23 normal individuals. RESULTS: The mean follow-up period was 18.68 ± 19.48 months. At the last follow-up, 19 (86.4%) of 22 subjects had orthophoria, whereas 3 (13.6%) had minimal esophoria. The postoperative angle of deviation was significantly smaller than the preoperative angle of deviation at near (P < 0.001) and distance (P < 0.001). Postoperative sensory fusion was significantly better than preoperative fusion at near (P < 0.001) and distance (P < 0.001). The postoperative stereoacuity improved significantly after the surgery at near (P < 0.001) and distance (P < 0.001). Compared with the controls, the convergence and divergence amplitudes in the AACE patients were similar at distance (P > 0.05) but were still narrower at near (P < 0.001). CONCLUSION: Good alignment and binocular balance were obtained with the surgical target angle of the base-out recovery point in AACE.

Can Clinical Measures of Postoperative Binocular Function Predict the Long-Term Stability of Postoperative Alignment in Intermittent Exotropia?

PURPOSE: To evaluate whether clinical measures of postoperative binocular functions could predict the long-term stability of postoperative ocular alignment in children with intermittent exotropia. METHODS: A retrospective study was performed in thirty-nine children (median: 7 years) who have been surgically treated from intermittent exotropia without overcorrection (less than 10 prism diopters [pd] of exodeviation at 1 month postoperatively). Angles of deviation and binocular functions were measured preoperatively and at 1 month, 6 months, and the final follow-up visit (≥24 months) postoperatively. We examined the relationships between postoperative drift (change of ocular alignment) and binocular functions (sensory fusion, fusional convergence amplitude, and stereoacuity). RESULTS: The surgical success rate (esophoria/tropia ≤5 pd to exophoria/tropia ≤10 pd) dropped to 76.9% at 6 months after surgery and to 53.8% at individuals' last visit (mean: 37 months). The mean exodrift was 7.7 ± 9.2 pd from the postoperative month 1 to the final visit (p < 0.001) on distance fixation. Distance stereoacuity, central fusion, and fusional convergence amplitude significantly improved following surgery (p < 0.05). However, no significant correlation was found between their binocular functions measured at the beginning of each follow-up period and the postoperative drift (all p > 0.13). CONCLUSION: Our findings suggest that the clinical measures of sensory fusion, fusional convergence amplitude, and stereoacuity cannot serve as a robust predictor for the long-term stability of postoperative ocular alignment in patients who underwent successful surgery without overcorrection at 1 month postoperatively.

Thickness of retinal layers in the foveas of children with anisometropic amblyopia.

PURPOSE: To use highly precise spectral-domain optical coherence tomography (SD-OCT) to determine whether there were structural abnormalities in the layers of different regions of the fovea in children with anisometropic amblyopia. METHODS: Eighteen children (mean age 7.8 years old; range 5-11 years) with unilateral anisometropic amblyopia and 18 age-matched control subjects participated. Foveal thickness was measured with an enhanced depth imaging system, SD-OCT and segmented into layers using custom developed software. The thickness of each layer of the fovea was compared among amblyopic eyes, fellow eyes and control eyes with optical magnification correction for axial length and statistical correction for age and sex. RESULTS: The total thickness and each intra-ocular layer of the central fovea were the same for each group. However, the amblyopic eyes were significantly thicker than the normal control eyes in 2 of 4 quadrants of the peripheral retina. Exploring intra-retinal layers in these two quadrants, the nasal nerve fiber layer (NFL) and inferior inner nuclear layer (INL)were significantly thicker in amblyopic eyes than in control eyes (p = 0.01 and 0.012, respectively, by ANCOVA). CONCLUSION: The SD-OCT data revealed marginal differences in some foveal layers at peripheral locations and indicated that structural differences might exist between individuals with amblyopia and visually normal control subjects. However, the differences were scattered and represented no identifiable pattern. More studies with large samples and precise locations of the retinal layers must be performed to extend the present results.

Tissue factor pathway inhibitor-2 inhibits the growth and invasion of hepatocellular carcinoma cells and is inactivated in human hepatocellular carcinoma.

Human tissue factor pathway inhibitor-2 (TFPI-2) is an extracellular matrix-associated Kunitz-type serine proteinase inhibitor that inhibits the plasmin- and trypsin-mediated activation of matrix metalloproteinases and inhibits tumor progression, invasion and metastasis. Previous studies have shown that TFPI-2 is downregulated in the progression of various tumors. The purpose of this study was to investigate the expression and function of TFPI-2 in hepatocellular carcinoma (HCC). In situ hybridization was used to detect human TFPI-2 mRNA and immunohistochemistry was performed to examine the role of TFPI-2 expression in hepatocarcinoma tissues. Cell proliferation was assessed using MTT assay. In situ hybridization and immunohistochemical analyses revealed that the expression of TFPI-2 in hepatocarcinoma tissues was markedly lower than that in tumor-adjacent normal hepatic tissues. Restored expression of TFPI-2 in HepG(2) cells inhibits cell proliferation and invasion. Taken together, the results suggest that TFPI-2 has a tumor-suppression action and its inactivation may contribute to HCC.