Structural Patterns in Chronic Disease Clinical Practice Guidelines Formalized for Clinical Decision Support.

Making recommendations from clinical practice guidelines (CPGs) computable for clinical decision support (CDS) has typically been a laborious and costly process. Identifying domain-specific regularities helps clinicians and knowledge engineers conceptualize, extract, and encode evidence-based recommendations. Based on our work to provide complex CDS in the management of multiple chronic diseases, we propose nine chronic disease CPG structural patterns, discuss considerations in representing the necessary knowledge, and illustrate them with the solutions that our CDS system provides.

Non-nucleoside inhibitors of HCV polymerase NS5B. Part 2: Synthesis and structure-activity relationships of benzothiazine-substituted quinolinediones.

A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.

Non-nucleoside inhibitors of HCV polymerase NS5B. Part 3: synthesis and optimization studies of benzothiazine-substituted tetramic acids.

Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.

Selecting Test Cases from the Electronic Health Record for Software Testing of Knowledge-Based Clinical Decision Support Systems.

Software testing of knowledge-based clinical decision support systems is challenging, labor intensive, and expensive; yet, testing is necessary since clinical applications have heightened consequences. Thoughtful test case selection improves testing coverage while minimizing testing burden. ATHENA-CDS is a knowledge-based system that provides guideline-based recommendations for chronic medical conditions. Using the ATHENA-CDS diabetes knowledgebase, we demonstrate a generalizable approach for selecting test cases using rules/ filters to create a set of paths that mimics the system's logic. Test cases are allocated to paths using a proportion heuristic. Using data from the electronic health record, we found 1,086 cases with glycemic control above target goals. We created a total of 48 filters and 50 unique system paths, which were used to allocate 200 test cases. We show that our method generates a comprehensive set of test cases that provides adequate coverage for the testing of a knowledge-based CDS.

Automating Guidelines for Clinical Decision Support: Knowledge Engineering and Implementation.

As utilization of clinical decision support (CDS) increases, it is important to continue the development and refinement of methods to accurately translate the intention of clinical practice guidelines (CPG) into a computable form. In this study, we validate and extend the 13 steps that Shiffman et al.5 identified for translating CPG knowledge for use in CDS. During an implementation project of ATHENA-CDS, we encoded complex CPG recommendations for five common chronic conditions for integration into an existing clinical dashboard. Major decisions made during the implementation process were recorded and categorized according to the 13 steps. During the implementation period, we categorized 119 decisions and identified 8 new categories required to complete the project. We provide details on an updated model that outlines all of the steps used to translate CPG knowledge into a CDS integrated with existing health information technology.

Automating Performance Measures and Clinical Practice Guidelines: Differences and Complementarities.

Through close analysis of two pairs of systems that implement the automated evaluation of performance measures (PMs) and guideline-based clinical decision support (CDS), we contrast differences in their knowledge encoding and necessary changes to a CDS system that provides management recommendations for patients failing performance measures. We trace the sources of differences to the implementation environments and goals of PMs and CDS.

Performance of 3D-database molecular docking studies into homology models.

The performance of docking studies into protein active sites constructed by homology model building was investigated using CDK2 and factor VIIa screening data sets. When the sequence identity between model and template near the binding site area is greater than approximately 50%, roughly 5 times more active compounds are identified than would be found randomly. This performance is comparable to docking to crystal structures.

Comparing performance of computational tools for combinatorial library design.

In using computational tools for library design it is necessary to understand the performance and limitations of available methods. This letter reports systematic comparisons of applying ligand-based and structure-based tools across therapeutic project-derived data sets. Included are assessments of performance in real-world iterative design applications and the utility of target structural information. The results suggest that combining screening and target structure information is robust; further, a well-designed screening library can compensate for lacking structural information.

Selection and characterization of replicon variants dually resistant to thumb- and palm-binding nonnucleoside polymerase inhibitors of the hepatitis C virus.

Multiple nonnucleoside inhibitor binding sites have been identified within the hepatitis C virus (HCV) polymerase, including in the palm and thumb domains. After a single treatment with a thumb site inhibitor (thiophene-2-carboxylic acid NNI-1), resistant HCV replicon variants emerged that contained mutations at residues Leu419, Met423, and Ile482 in the polymerase thumb domain. Binding studies using wild-type (WT) and mutant enzymes and structure-based modeling showed that the mechanism of resistance is through the reduced binding of the inhibitor to the mutant enzymes. Combined treatment with a thumb- and a palm-binding polymerase inhibitor had a dramatic impact on the number of replicon colonies able to replicate in the presence of both inhibitors. A more exact characterization through molecular cloning showed that 97.7% of replicons contained amino acid substitutions that conferred resistance to either of the inhibitors. Of those, 65% contained simultaneously multiple amino acid substitutions that conferred resistance to both inhibitors. Double-mutant replicons Met414Leu and Met423Thr were predominantly selected, which showed reduced replication capacity compared to the WT replicon. These findings demonstrate the selection of replicon variants dually resistant to two NS5B polymerase inhibitors binding to different sites of the enzyme. Additionally, these findings provide initial insights into the in vitro mutational threshold of the HCV NS5B polymerase and the potential impact of viral fitness on the selection of multiple-resistant mutants.