Large-scale machine learning-based phenotyping significantly improves genomic discovery for optic nerve head morphology.

Genome-wide association studies (GWASs) require accurate cohort phenotyping, but expert labeling can be costly, time intensive, and variable. Here, we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; p ≤ 5 × 10-8) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 93 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR: select loci near genes involved in neuronal and synaptic biology or harboring variants are known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort

Support vector machine model for diagnosis of lymph node metastasis in gastric cancer with multidetector computed tomography: a preliminary study

<p>Abstract</p> <p>Background</p> <p>Lymph node metastasis (LNM) of gastric cancer is an important prognostic factor regarding long-term survival. But several imaging techniques which are commonly used in stomach cannot satisfactorily assess the gastric cancer lymph node status. They can not achieve both high sensitivity and specificity. As a kind of machine-learning methods, Support Vector Machine has the potential to solve this complex issue.</p> <p>Methods</p> <p>The institutional review board approved this retrospective study. 175 consecutive patients with gastric cancer who underwent MDCT before surgery were included. We evaluated the tumor and lymph node indicators on CT images including serosal invasion, tumor classification, tumor maximum diameter, number of lymph nodes, maximum lymph node size and lymph nodes station, which reflected the biological behavior of gastric cancer. Univariate analysis was used to analyze the relationship between the six image indicators with LNM. A SVM model was built with these indicators above as input index. The output index was that lymph node metastasis of the patient was positive or negative. It was confirmed by the surgery and histopathology. A standard machine-learning technique called k-fold cross-validation (5-fold in our study) was used to train and test SVM models. We evaluated the diagnostic capability of the SVM models in lymph node metastasis with the receiver operating characteristic (ROC) curves. And the radiologist classified the lymph node metastasis of patients by using maximum lymph node size on CT images as criterion. We compared the areas under ROC curves (AUC) of the radiologist and SVM models.</p> <p>Results</p> <p>In 175 cases, the cases of lymph node metastasis were 134 and 41 cases were not. The six image indicators all had statistically significant differences between the LNM negative and positive groups. The means of the sensitivity, specificity and AUC of SVM models with 5-fold cross-validation were 88.5%, 78.5% and 0.876, respectively. While the diagnostic power of the radiologist classifying lymph node metastasis by maximum lymph node size were only 63.4%, 75.6% and 0.757. Each SVM model of the 5-fold cross-validation performed significantly better than the radiologist.</p> <p>Conclusions</p> <p>Based on biological behavior information of gastric cancer on MDCT images, SVM model can help diagnose the lymph node metastasis preoperatively.</p

Magnetic resonance imaging of the knee in Norway 2002–2004 (national survey): rapid increase, older patients, large geographic differences

<p>Abstract</p> <p>Background</p> <p>Magnetic resonance imaging (MRI) of the knee is the second most common MRI examination in Norway after head/brain MRI. Little has been published internationally on trends in the use of knee MRI after 1999. This study aimed to describe levels and trends in ambulant knee MRI utilisation in Norway 2002–2004 in relation to type of radiology service, geographic regions, number of MRI-scanners, patient age and gender, and type of referring health care provider.</p> <p>Methods</p> <p>We analysed administrative data on all claims for reimbursement of ambulant knee MRI performed in Norway in 2002, 2003 and 2004 and noted nominal reimbursement. We also recorded the referring health care provider from clinical requests of ambulant knee MRI done consecutively during two months in 2004 at one private institute and three hospitals. Number of MRI-scanners was given by manufacturers and radiology services.</p> <p>Results</p> <p>In Norway, the rate of knee MRI claims for 2004 was 15.6 per 1000 persons. This rate was 74% higher in East than in North region (18.4 vs. 10.6), slightly higher for men than women (16.4 vs. 14.7) and highest for ages 50–59 years (29.0) and 60–69 years (21.2). Most claims (76% for 2004) came from private radiology services. In 2004, the referring health care provider was a general practitioner in 63% of claims (unspecified in 24%) and in 83.5% (394/472) of clinical requests. From 2002 to 2004, the rate of knee MRI claims increased 64%. In the age group 50 years or above the increase was 86%. Rate of MRI-scanners increased 43% to 21 scanners per million persons in 2004. Reimbursement for knee MRI claims (nominal value) increased 80% to 70 million Norwegian kroner in 2004.</p> <p>Conclusion</p> <p>Ambulant knee MRI utilisation in Norway increases rapidly especially for patients over 50, and shows large geographic differences. Evaluation of clinical outcomes of this activity is needed together with clinical guidelines for use of knee MRI.</p

Lattice Boltzmann simulations of soft matter systems

This article concerns numerical simulations of the dynamics of particles immersed in a continuum solvent. As prototypical systems, we consider colloidal dispersions of spherical particles and solutions of uncharged polymers. After a brief explanation of the concept of hydrodynamic interactions, we give a general overview over the various simulation methods that have been developed to cope with the resulting computational problems. We then focus on the approach we have developed, which couples a system of particles to a lattice Boltzmann model representing the solvent degrees of freedom. The standard D3Q19 lattice Boltzmann model is derived and explained in depth, followed by a detailed discussion of complementary methods for the coupling of solvent and solute. Colloidal dispersions are best described in terms of extended particles with appropriate boundary conditions at the surfaces, while particles with internal degrees of freedom are easier to simulate as an arrangement of mass points with frictional coupling to the solvent. In both cases, particular care has been taken to simulate thermal fluctuations in a consistent way. The usefulness of this methodology is illustrated by studies from our own research, where the dynamics of colloidal and polymeric systems has been investigated in both equilibrium and nonequilibrium situations.Comment: Review article, submitted to Advances in Polymer Science. 16 figures, 76 page

Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed