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Design of lambda Cro fold: solution structure of a monomeric variant of the de novo protein.

One of the classical DNA-binding proteins, bacteriophage lambda Cro, forms a homodimer with a unique fold of alpha-helices and beta-sheets. We have computationally designed an artificial sequence of 60 amino acid residues to stabilize the backbone tertiary structure of the lambda Cro dimer by simulated annealing using knowledge-based structure-sequence compatibility functions. The designed amino acid sequence has 25% identity with that of natural lambda Cro and preserves Phe58, which is important for formation of the stably folded structure of lambda Cro. The designed dimer protein and its monomeric variant, which was redesigned by the insertion of a beta-hairpin sequence at the C-terminal region to prevent dimerization, were synthesized and biochemically characterized to be well folded. The designed protein was monomeric under a wide range of protein concentrations and its solution structure was determined by NMR spectroscopy. The solved structure is similar to that of a monomeric variant of natural lambda Cro with a root-mean-square deviation of the polypeptide backbones at 2.1A and has a well-packed protein core. Thus, our knowledge-based functions provide approximate but essential relationships between amino acid sequences and protein structures, and are useful for finding novel sequences that are foldable into a given target structure.

Amino Acid Sequence↗

Analysis of DNA microarrays using algorithms that employ rule-based expert knowledge.

The ability to investigate the transcription of thousands of genes concurrently by using DNA microarrays offers both major scientific opportunities and significant analytical challenges. Here we describe GABRIEL, a rule-based system of computer programs designed to apply domain-specific and procedural knowledge systematically and uniformly for the analysis and interpretation of data from DNA microarrays. GABRIEL'S problem-solving rules direct stereotypical tasks, whereas domain-specific knowledge pertains to gene functions and relationships or to experimental conditions. Additionally, GABRIEL can learn novel rules through genetic algorithms, which define patterns that best match the data being analyzed and can identify groupings in gene expression profiles preordered by chromosomal position or by a nonsupervised algorithm such as hierarchical clustering. GABRIEL subsystems explain the logic that underlies conclusions and provide a graphical interface and interactive platform for the acquisition of new knowledge. The present report compares GABRIEL'S output with published findings in which expert knowledge has been applied post hoc to microarray groupings generated by hierarchical clustering.

Algorithms↗

Automated human frontal lobe identification in MR images based on fuzzy-logic encoded expert anatomic knowledge.

Identification of human brain structures in MR images comprises an area of increasing interest, which also presents numerous methodological challenges. Here we describe a new knowledge-based automated method designed to identify several major brain sulci and then to define the frontal lobes by using the identified sulci as landmarks. To identify brain sulci, sulcal images were generated by morphologic operations and then separated into different components based on connectivity analysis. Subsequently, the individual anatomic features were evaluated by using fuzzy membership functions. The crisp decisions, i.e., the identification of sulci, were made by taking the maximum of the summation of all the membership functions. The identification was designed in a hierarchical order. The longitudinal fissure was extracted first. The left and right central sulci were then identified based on the left and right hemispheres. Next, the lateral sulci were identified based on the central sulci and hemispheres. Finally, the left and right frontal lobes were defined from the two hemispheres. The method was evaluated by visual inspection, comparison with manual segmentation, and comparison with manually volumetric results in references. The average Jaccard similarities of left and right frontal lobes between the automated and manual segmentation were 0.89 and 0.91, respectively. The average Kappa indices of left and right frontal lobes between the automated and manual segmentation were 0.94 and 0.95, respectively. These results show relatively high accuracy of using this novel method for human frontal lobe identification and segmentation.

Algorithms↗

Management of hepatitis C patients by primary care physicians in the USA: results of a national survey.

Hepatitis C is a major health problem worldwide, yet very little research has been performed to assess the knowledge base and practice patterns of primary care physicians (PCPs) regarding hepatitis C. The aim of this study is to determine the knowledge base and practice patterns of a nationwide cohort of PCPs. A survey was developed to assess the knowledge of PCPs regarding risk factors for hepatitis C, management of hepatitis C patients and attitude regarding testing for hepatitis C. The survey was mailed to 4000 PCPs in the USA. A total of 1412 (39%) PCPs completed the survey. The vast majority, > 90%, of PCPs correctly identified the most common risk factors for hepatitis C. However, only 59% indicated they ask all patients about hepatitis C risk factors, 70% reported they test all patients with hepatitis C risk factors and 78% test all patients with elevated liver enzymes for hepatitis C. Most (72%) PCPs would refer an HCV-positive patient with elevated aminotransferase but only 28% would refer an HCV-positive patient with normal aminotransferase to a specialist. One-fourth of the PCPs did not know what treatment to recommend for hepatitis C patients. Our data suggest that hepatitis C patients may be underdiagnosed and under-referred. Specific educational initiatives and practice guidelines for PCPs are needed to optimize the recognition of patients at risk for hepatitis C and to ensure appropriate testing and referral.

Adult↗

Modern office design in the "information age".

This article reviews the process of reaching the goal of modernizing a new or existing endodontic office. Incorporating computer-based technologies in the office requires significant planning, best achieved by forming a technology goal that addresses budget, knowledge base, and infrastructure issues. Making the transition to the modern dental practice is expensive and time-consuming but also profitable and exciting. Soon, all dental offices will be using digital radiographic systems, video systems, and patient charting programs that use no paper documentation. As the computer familiarity and staff knowledge based increases with the growing use of computers in society overall, finding the office personnel able to harness the efficiency and power of the technology in the dental office will be easier. Through careful planning and formation of a reasonable technology goal, updating an old office or creating a new modern endodontic practice with the technologies and their patients can benefit.

Computer Systems↗

Epilepsy genes and the genetics of epilepsy syndromes: the promise of new therapies based on genetic knowledge.

Treatment strategies based on the molecular biology of the epilepsies may soon become a reality. Critical steps in this process are identifying molecular genetic defects in specific epilepsies, understanding of the neurobiologic consequences of those defects, and developing methods to correct the molecular defects or their downstream consequences. Identification of molecular defects is easier in single-gene epilepsies than in those with complex inheritance, although the latter are more common. A number of epilepsies have been mapped and, in two cases, specific genes have been identified. Unverricht-Lundborg disease is caused by defects in the cystatin B gene, with absence of the gene product. Autosomal dominant nocturnal frontal lobe epilepsy in some families is caused by mutations in the alpha4-subunit of the nicotinic acetylcholine receptor gene. In vitro studies suggest that the mutations lead to impaired function of the acetylcholine receptor, raising the possibility of cholinergic therapy for this condition. Advances in the molecular biology of the epilepsies are likely to change our understanding radically and to allow opportunities to develop innovative new treatments for epilepsy.

Animals↗

Complementary herbal and alternative drugs in clinical practice.

TOPIC: Complementary and alternative medicine agents (CAMs). PURPOSE: To summarize the current empirical data about the major CAMs purporting to have psychotherapeutic value. SOURCES OF INFORMATION: Extant literature. CONCLUSIONS: Available evidence indicates that CAMs, while generally safe, are not risk free. While CAM use grows, nurses and other health professionals have a limited knowledge base about the action, side effects, and interactions of common CAM agents. Nurses need to increase their knowledge base about CAMs in order to help patients in decision making regarding the use of these agents to treat common psychiatric symptoms.

Dietary Supplements↗

An intelligent interactive system for delivering individualized information to patients.

This paper is a report on the first phase of a long-term, interdisciplinary project whose goal is to increase the overall effectiveness of physicians' time, and thus the quality of health care, by improving the information exchange between physicians and patients in clinical settings. We are focusing on patients with long-term and chronic conditions, initially on migraine patients, who require periodic interaction with their physicians for effective management of their condition. We are using medical informatics to focus on the information needs of patients, as well as of physicians, and to address problems of information exchange. This requires understanding patients' concerns to design an appropriate system, and using state-of-the-art artificial intelligence techniques to build an interactive explanation system. In contrast to many other knowledge-based systems, our system's design is based on empirical data on actual information needs. We used ethnographic techniques to observe explanations actually given in clinic settings, and to conduct interviews with migraine sufferers and physicians. Our system has an extensive knowledge base that contains both general medical terminology and specific knowledge about migraine, such as common trigger factors and symptoms of migraine, the common therapies, and the most common effects and side effects of those therapies. The system consists of two main components: (a) an interactive history-taking module that collects information from patients prior to each visit, builds a patient model, and summarizes the patients' status for their physicians; and (b) an intelligent explanation module that produces an interactive information sheet containing explanations in everyday language that are tailored to individual patients, and responds intelligently to follow-up questions about topics covered in the information sheet.

Anthropology, Cultural↗

Survey to assess dental practitioner's knowledge of infectious disease.

The prerequisite to understanding the need for infection control practices in dentistry is a sound knowledge of infectious disease and the potential for its transmission in the dental setting. To assess the infectious disease knowledge-base of dental practitioners, a questionnaire was developed and distributed to dentists in British Columbia. The survey results showed that many of the mechanisms, routes and risks for the transmission of viral pathogens in the dental setting are not clearly understood by dentists. Continuing education is needed to ensure that compliance with current infection control recommendations, and the provision of appropriate patient care, continues to be based on a clear understanding by dentists of the mechanisms of infection. By identifying the current infectious disease knowledge-base of dentists, this survey may permit more specifically-directed continuing education programs to be offered.

Adult↗

[An expert system for the diagnosis of risk of ischemic heart disease].

The RIBS expert system was created by using the means and tools of the OBSES software complex (an expert system shell). RIBS is designed for determining the risk level in the occurrence of ischemic heart disease. The knowledge base is structured and is broken down into 13 hierarchical clusters. Three types of attributes are used for knowledge base cluster representation. To calculate the significance of facts and rules, the methods of polar and score ratings and others are used. A consultation fragment report with delivery of ischemic heart disease risk integral value is provided.

Coronary Disease↗

Knowledge management: evaluating the organizational requirements and culture for an emerging technology.

The purpose of this paper is to explore the application of knowledge management concepts to an information systems (IS) knowledge base, as opposed to a clinical one. The field of Medical Informatics is committed to helping others manage medical information and knowledge through the application of information technology. At Partners HealthCare, a wide variety of clinical information management systems have been built and implemented in complex environments, creating an extensive applied informatics knowledge base. How should healthcare IS departments manage this intellectual capital? That's the question that Partners HealthCare is asking its senior and middle IS managers. This paper reports on an internal survey addressing Knowledge Management (KM) requirements, the potential application of this technology in our organization, and discusses where we are today and where to go from here.

Data Collection↗

SMR (simulating medical reasoning): an expert shell for non-AI experts.

SMR is an expert system shell designed to put the tools for knowledge acquisition directly into the hands of the domain expert. Since the knowledge base is represented as free text within a simplified syntactic structure, it is intelligible to anyone familiar with medical terminology. The knowledge base includes the rules for inference making as well as data groupings and protocols to facilitate case recording. In this paper, SMR is presented from the expert's point of view, describing the rule syntax and procedures for formulating the required diagnostic or therapeutic knowledge in the chosen domain. Similarly, the end-user's application of the system to patient data and the provisions for exploring and explaining the system's conclusions and reasoning processes are detailed. Avoiding tedious and often inane dialog, the user enters all that is known about the patient and receives a report of the system's conclusions and recommendations followed by a list of observations to be made in patient follow-up. An expert system for evaluating the diabetic patient is used to illustrate system operations.

Computer Simulation↗

Distance-scaled, finite ideal-gas reference state improves structure-derived potentials of mean force for structure selection and stability prediction.

The distance-dependent structure-derived potentials developed so far all employed a reference state that can be characterized as a residue (atom)-averaged state. Here, we establish a new reference state called the distance-scaled, finite ideal-gas reference (DFIRE) state. The reference state is used to construct a residue-specific all-atom potential of mean force from a database of 1011 nonhomologous (less than 30% homology) protein structures with resolution less than 2 A. The new all-atom potential recognizes more native proteins from 32 multiple decoy sets, and raises an average Z-score by 1.4 units more than two previously developed, residue-specific, all-atom knowledge-based potentials. When only backbone and C(beta) atoms are used in scoring, the performance of the DFIRE-based potential, although is worse than that of the all-atom version, is comparable to those of the previously developed potentials on the all-atom level. In addition, the DFIRE-based all-atom potential provides the most accurate prediction of the stabilities of 895 mutants among three knowledge-based all-atom potentials. Comparison with several physical-based potentials is made.

Computational Biology↗

Multipurpose practice guideline modules for clinical decision analysis and quality improvement.

This study aimed to measure the loss of information in communication between clinical researchers and information system developers, to design a tool for sharing clinical practice guidelines, and to test the feasibility of this tool in knowledge base development. The analysis of a sample of 101 randomized controlled clinical trials indicated that exact numeric results were published in only 64 percent of the trials. While structured abstracts were associated with improved total quality scores (p0.001), there was no significant improvement in reporting numeric results (p=0.31). Based on the documented loss of information and the needs of various parties involved, the concept of a multipurpose knowledge module was developed for sharing clinical practice recommendations. Such clinical practice guideline modules were applied in developing the knowledge base of a quality feedback expert system (QFES).

Abstracting and Indexing↗

Determining protein topology from skeletons of secondary structures.

We report a novel computational procedure for determining protein native topology, or fold, by defining loop connectivity based on skeletons of secondary structures that can usually be obtained from low to intermediate-resolution density maps. The procedure primarily involves a knowledge-based geometry filter followed by an energetics-based evaluation. It was tested on a large set of skeletons covering a wide range of protein architecture, including one modeled from an experimentally determined 7.6A cryo-electron microscopy (cryo-EM) density map. The results showed that the new procedure could effectively deduce protein folds without high-resolution structural data, a feature that could also be used to recognize native fold in structure prediction and to interpret data in fields like structure genomics. Most importantly, in the energetics-based evaluation, it was revealed that, despite the inevitable errors in the artificially constructed structures and limited accuracy of knowledge-based potential functions, the average energy of an ensemble of structures with slightly different configurations around the native skeleton is a much more robust parameter for marking native topology than the energy of individual structures in the ensemble. This result implies that, among all the possible topology candidates for a given skeleton, evolution has selected the native topology as the one that can accommodate the largest structural variations, not the one rigidly trapped in a deep, but narrow, conformational energy well.

Algorithms↗

MD Concept: a model for integrating medical knowledge.

Many integrated clinical information systems depend on large knowledge bases containing dictionary of terms as well as specific information about each term and the relationships between terms. We propose a knowledge base model called MD Concept which is based on a semantic network and uses an object-oriented paradigm and relational tables. A prototype has been developed which integrates the Unified Medical Language System (UMLS) with other databases including the Systematized Nomenclature of Medicine (SNOMED II), the Diagnostic and Statistical Manual of Mental Disorders (DSM-IIIR) and a pharmaceutical database. We demonstrate how a user can easily navigate in this knowledge world using a browser.

Artificial Intelligence↗

New computer-based tools for empiric antibiotic decision support.

Since 1995 we have been developing a decision-support model, called Q-ID, which uses a series of infectious disease knowledge bases to make recommendations for empirical treatment or to check the appropriateness of current antibiotic therapy. From disease manifestations and risk factors, a differential diagnosis for the patient is generated by a diagnostic medical expert system. The resulting probability of each: disease is multiplied by the expected benefit in improved mortality and morbidity from optimal antibiotic treatment of each disease. To generate empirical treatment recommendations, site-specific data on sensitivity to antibiotics of each organism is used as an estimate of the likelihood of achieving maximum benefit for each disease on the patient's differential. Combining this data with drug and patient specific factors, the model recommends the antibiotic(s) most likely to produce the optimal benefit in this patient with the least risk and expense. In this paper the model is described, excerpts from each of the knowledge bases are presented, and performance of the model in a real case is shown for illustration.

Aged↗

Clinical experience as evidence in evidence-based practice.

BACKGROUND: This paper's starting point is the recognition (descriptive not normative) that, for the vast majority of day-to-day clinical decision-making situations, the 'evidence' for decision-making is experiential knowledge. Moreover, reliance on this knowledge base means that nurses must use cognitive shortcuts or heuristics for handling information when making decisions. These heuristics encourage systematic biases in decision-makers and deviations from the normative rules of 'good' decision-making. AIMS: The aim of the paper is to explore three common heuristics and the biases that arise when handling complex information in clinical decision-making (overconfidence, hindsight and base rate neglect) and, in response to these biases, to illustrate some simple techniques for reducing the negative influence of heuristics. DISCUSSION: Nurses face a limited range of types of uncertainty in their clinical decisions and draw primarily on experiential knowledge to handle these uncertainties. This paper argues that experiential knowledge is a necessary but not sufficient basis for clinical decision-making. It illustrates how overconfidence in one's knowledge base, being correct 'after the event' or with the benefit of hindsight, and ignoring the base rates associated with events, conditions or health states, can impact on professional judgements and decisions. The paper illustrates some simple strategies for minimizing the impact of heuristics on the real-life clinical decisions of nurses. CONCLUSION: The paper concludes that more research knowledge of the impact of heuristics and techniques to combat them in nursing decisions is needed.

Clinical Competence↗