Majority Vote and Other Problems when using Computational Tools

Computational tools are essential for most of our research. To use these tools, one needs to know how they work. Problems in application of computational methods to variation analysis can appear at several stages and affect, for example, the interpretation of results. Such cases are discussed along with suggestions how to avoid them. The applications include incomplete reporting of methods, especially about the use of prediction tools; method selection on unscientific grounds and without consulting independent method performance assessments; extending application area of methods outside their intended purpose; use of the same data several times for obtaining majority vote; and filtering of datasets so that variants of interest are excluded. All these issues can be avoided by discontinuing the use software tools as black boxes.     

VIPdb,a genetic Variant Impact Predictor Database

Genome sequencing identifies vast number of genetic variants. Predicting these variants’ molecular and clinical effects is one of the preeminent challenges in human genetics. Accurate prediction of the impact of genetic variants improves our understanding of how genetic information is conveyed to molecular and cellular functions, and is an essential step towards precision medicine. Over one hundred tools/resources have been developed specifically for this purpose. We summarize these tools as well as their characteristics, in the genetic Variant Impact Predictor Database (VIPdb). This database will help researchers and clinicians explore appropriate tools, and inform the development of improved methods. VIPdb can be browsed and downloaded at https://genomeinterpretation.org/vipdb.     

Commentary on strategies for switching antipsychotics

Inadequate reporting is problematic for several reasons. If authors do not provide sufficient details concerning the conduct of their study, readers are left with an incomplete picture of what was done. As such, they are not able to judge the merits of the results and interpret them. The EQUATOR Network is a new initiative aimed at improving the clarity and transparency of reporting health research.     

Major histocompatibility complex linked databases and prediction tools for designing vaccines

Presently, the major histocompatibility complex (MHC) is receiving considerable interest owing to its remarkable role in antigen presentation and vaccine design. The specific databases and prediction approaches related to MHC sequences, structures and binding/nonbinding peptides have been aggressively developed in the past two decades with their own benchmarks and standards. Before using these databases and prediction tools, it is important to analyze why and how the tools are constructed along with their strengths and limitations. The current review presents insights into web-based immunological bioinformatics resources that include searchable databases of MHC sequences, epitopes and prediction tools that are linked to MHC based vaccine design, including population coverage analysis. In T cell epitope forecasts, MHC class I binding predictions are very accurate for most of the identified MHC alleles. However, these predictions could be further improved by integrating proteasome cleavage (in conjugation with transporter associated with antigen processing (TAP) binding) prediction, as well as T cell receptor binding prediction. On the other hand, MHC class II restricted epitope predictions display relatively low accuracy compared to MHC class I. To date, pan-specific tools have been developed, which not only deliver significantly improved predictions in terms of accuracy, but also in terms of the coverage of MHC alleles and supertypes. In addition, structural modeling and simulation systems for peptide–MHC complexes enable the molecular-level investigation of immune processes. Finally, epitope prediction tools, and their assessments and guidelines, have been presented to immunologist for the design of novel vaccine and diagnostics.     

Gene mapping in cancer

Observation of genetic alterations that appear consistently in specific types and stages of cancer provides a strong impetus to cancer geneticists to focus their investigations on the exploration of such volatile regions of the human genome. Introduction of powerful molecular cytogenetic and molecular genetic methods in recent years permits more detailed analysis, which will help researchers in their efforts to determine if such areas of the human genome have a functional role in the initiation and progressive development of leukemias and solid tumors. This discussion will focus on several provocative molecular cytogenetic tools that are currently available to localize potential cancer-associated genes and on how these methods are being used in conjunction with the current modes of analysis, including cytogenetics and somatic cell genetics. In addition, we will explore how these methods will help to isolate and dissect recently discovered cancer-associated genes within the human genome. All of these methods used in combination with each other will provide essential DNA markers for future diagnostic and prognostic evaluation of cancer.     

Reporting guidelines: doing better for readers

There is clear guidance on the responsibilities of editors to ensure that the research they publish is of the highest possible quality. Poor reporting is unethical and directly impacts patient care. Reporting guidelines are a relatively recent development to help improve the accuracy, clarity, and transparency of biomedical publications. They have caught on, with hundreds of reporting guidelines now available. Some journals endorse reporting guidelines while a smaller number have used various approaches to implement them. Yet challenges remain – biomedical research is still not optimally reported despite the abundance of reporting guidelines. Electronic algorithms are now being developed to facilitate the choice of correct reporting guideline(s), while other tools are being integrated into journal editorial management processes. Universities need to consider whether it is responsible to advance careers of faculty based on poorly reported research which is of little societal value. If journals embraced auditing of the quality of articles they publish this would give them and their readers essential feedback from which to improve their product.     

A critical appraisal of 'evidence-based medicine' in allergy and asthma

 Clinical guidelines are 'systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances'. They may offer concise instructions on which diagnostic or screening tests to order, stipulate how medical services should be provided, how long patients should stay in hospital, or many other details relevant to clinical practice. This paper argues that guidelines should be simple, adapted to the clinical setting they inform and to treatment availability in their respective geographic context and that they should not be viewed as a yardstick but as support for physicians. The benefits of evidence-based-medicine (EBM), which defines the value of medical interventions in terms of empiric evidence from clinical trials, are growing in many contexts and are well described. Not sufficiently acknowledged, however, are the limits of EBM. A gap still exists between clinical research and clinical practice which should be better recognized and assessed.     

Predictive data mining in clinical medicine: current issues and guidelines

BACKGROUND: The widespread availability of new computational methods and tools for data analysis and predictive modeling requires medical informatics researchers and practitioners to systematically select the most appropriate strategy to cope with clinical prediction problems. In particular, the collection of methods known as 'data mining' offers methodological and technical solutions to deal with the analysis of medical data and construction of prediction models. A large variety of these methods requires general and simple guidelines that may help practitioners in the appropriate selection of data mining tools, construction and validation of predictive models, along with the dissemination of predictive models within clinical environments. PURPOSE: The goal of this review is to discuss the extent and role of the research area of predictive data mining and to propose a framework to cope with the problems of constructing, assessing and exploiting data mining models in clinical medicine. METHODS: We review the recent relevant work published in the area of predictive data mining in clinical medicine, highlighting critical issues and summarizing the approaches in a set of learned lessons. RESULTS: The paper provides a comprehensive review of the state of the art of predictive data mining in clinical medicine and gives guidelines to carry out data mining studies in this field. CONCLUSIONS: Predictive data mining is becoming an essential instrument for researchers and clinical practitioners in medicine. Understanding the main issues underlying these methods and the application of agreed and standardized procedures is mandatory for their deployment and the dissemination of results. Thanks to the integration of molecular and clinical data taking place within genomic medicine, the area has recently not only gained a fresh impulse but also a new set of complex problems it needs to address.     

Differential Use of Image Enhancement Techniques by Experienced and Inexperienced Observers

Full-field digital mammography (FFDM) systems are currently being used to acquire mammograms in digital format, but digital displays are less than ideal compared to traditional film-screen display. Certain physical properties of softcopy displays [e.g., modulation transfer function (MTF)] are less than optimal compared to film. We developed methods to compensate for some of these softcopy display deficiencies, based on careful physical characterization of the displays and image-processing software. A series of 100 FFDM and 60 digitized images was shown to six observers—half experienced (mammographers) and half inexperienced (radiology residents). The observers had to decide if a mass or microcalcification cluster was present and classify it as benign or malignant. A window could be activated that brought the image detail within the window to full resolution and corrected for the nonisotropic MTF of the Cathode Ray Tube (CRT) display. Experienced readers had better diagnostic performance and took less time to view the images. Experienced readers used window/level more than inexperienced readers, but inexperienced readers used magnification and the MTF compensation tool more often. Use of the magnification and the MTF tool increased reader decision confidence. Experienced and inexperienced readers use image-processing tools differently, with certain tools increasing reader confidence. Understanding how observers use image-processing tools may help in the development of better and more automated user interfaces.     

Tufts Health Sciences Database: lessons, issues, and opportunities.

The authors present their seven-year experience with developing the Tufts Health Sciences Database (Tufts HSDB), a database-driven information management system that combines the strengths of a digital library, content delivery tools, and curriculum management. They describe a future where online tools will provide a health sciences learning infrastructure that fosters the work of an increasingly interdisciplinary community of learners and allows content to be shared across institutions as well as with academic and commercial information repositories. The authors note the key partners in Tufts HSDB's success--the close collaboration of the health sciences library, educational affairs, and information technology staff. Tufts HSDB moved quickly from serving the medical curriculum to supporting Tufts' veterinary, dental, biomedical sciences, and nutrition schools, thus leveraging Tufts HSDB research and development with university-wide efforts including Internet2 middleware, wireless access, information security, and digital libraries. The authors identify major effects on teaching and learning, e.g., what is better taught with multimedia, how faculty preparation and student learning time can be more efficient and effective, how content integration for interdisciplinary teaching and learning is promoted, and how continuous improvement methods can be integrated. Also addressed are issues of faculty development, copyright and intellectual property, budgetary concerns, and coordinating IT across schools and hospitals. The authors describe Tufts' recent experience with sharing its infrastructure with other schools, and welcome inquiries from those wishing to explore national and international partnerships to create a truly open and integrated infrastructure for education across the health sciences.     

Outcomes, Guidelines, and Manuals: On Leading Horses to Water

Addis, Wade, and Hatgis (this issue) identify practitioner concerns about manual-based psychotherapies. Their conclusions are consistent with literature and experience regarding the use of outcome measurement and practice guidelines. it is not surprising, therefore, to find practitioners as unwilling and unable to use manual-based psychotherapies as they are to use outcomes and guidelines. Increased attention to the reasons for this reluctance will improve practitioner receptivity to these clinical resources. Careful attention to the names and labels given to these tools and avoidance of their promotion to appease the managed care industry are essential. Those developing manual-based psychotherapies must also heed the advice of Addis et al. regarding the need to take practitioner concerns seriously.     

Verification of Antimicrobial Susceptibility Testing Methods: a Practical Approach

The process of verifying an antimicrobial susceptibility testing (AST) system can be very confusing. There are different AST methods, such as MIC methods and disk diffusion testing. In addition, there are several different reasons why verification might be necessary, such as implementing a new method in the laboratory or implementing non-FDA interpretive criteria or breakpoints on an FDA-cleared AST system. The Clinical Laboratory Improvement Amendment (CLIA) provides some general guidance, but ultimately, it is the responsibility of a laboratory director to decide the composition of a verification study protocol. Variables to consider are what methods should be compared, what and how many isolates should be tested, how the results will be compared, and what study results will result in an acceptable study outcome. This article provides some general guidelines for developing and conducting a verification study of an AST system.     

Toward mapping the biology of the genome

This issue of Genome Research presents new results, methods, and tools from The ENCODE Project (ENCyclopedia of DNA Elements), which collectively represents an important step in moving beyond a parts list of the genome and promises to shape the future of genomic research. This collection sheds light on basic biological questions and frames the current debate over the optimization of tools and methodological challenges necessary to compare and interpret large complex data sets focused on how the genome is organized and regulated. In a number of instances, the authors have highlighted the strengths and limitations of current computational and technical approaches, providing the community with useful standards, which should stimulate development of new tools. In many ways, these papers will ripple through the scientific community, as those in pursuit of understanding the "regulatory genome" will heavily traverse the maps and tools. Similarly, the work should have a substantive impact on how genetic variation contributes to specific diseases and traits by providing a compendium of functional elements for follow-up study. The success of these papers should not only be measured by the scope of the scientific insights and tools but also by their ability to attract new talent to mine existing and future data.     

Guidelines for cognitively efficient multimedia learning tools: educational strategies, cognitive load, and interface design.

The field of medical education has consistently embraced new technologies in an attempt to improve the training process of our nation's doctors. There are thousands of available multimedia learning tools (MMLTs), but no quantitative scale exists to assess their efficiency and overall educational value. The authors review existing literature and suggest guidelines for creating cognitively efficient medical MMLTs. In 2004, the authors searched PubMed to identify articles regarding mutimedia learning, including educational strategies and existing MMLTs. The primary search terms included "multimedia learning," "cognitive load," and "surgical education." The resulting articles were evaluated and reviewed for educational and interface design techniques, and a list of common features was generated. The authors cross-referenced these features with extensive theories of cognitive load to create a list of methods that demonstrated improved learning. Techniques common to existing MMLTs often neglect to account for theories of cognitive load and may be detrimental to the learning process. The authors outlined important educational considerations and guidelines for the design of effective MMLTs. With large resources being spent to produce MMLTs, more research is necessary to establish successful design techniques. The authors summarized existing research, outlined educational issues in multimedia design, and proposed future directions for study.     

The impact of different criteria for selecting information to be provided to women undergoing diagnostic breast tests

OBJECTIVE: To determine if the content of written information for women undergoing diagnostic breast tests would change depending on the criteria used to decide what information should be included. METHODS: Questionnaire study eliciting the views of advocates, breast physicians, breast surgeons, general practitioners, people with an interest in ethics, and women who had undergone breast tests on information that should be provided to women undergoing diagnostic breast tests. Different criteria were used to determine what information should be included in the written information. RESULTS: Advocates, breast physicians, breast surgeons, general practitioners, people with an interest in ethics, and women who had undergone breast tests held significantly different views about the importance of specific information items for women undergoing tests. Different methods of resolving these differences in views lead to the inclusion of different information in patient information material. CONCLUSION: This study highlights the practical necessity for guidelines for developing written information to include details about how to resolve differences in opinions about what information should be included in patient material. PRACTICE IMPLICATIONS: Further research is needed to determine the most appropriate way to decide the content of written information. In the meantime, developers of written patient information need to be cognizant of the effects of their decisions on the content of patient information.     

Smoking cessation: progress,priorities, and prospectus

The authors review developments in understanding smoking cessation interventions over the past decade. Noteworthy is the unprecedented growth of research and knowledge that has left a deeper understanding of how best to use new and existing behavioral and pharmacologic tools and strategies to help smokers quit. The status of public-health-level interventions is evaluated, questions are raised concerning their efficacy, and suggestions are offered for further refinement of these intervention strategies. Development of cessation guidelines is reviewed, and the state of knowledge concerning behavioral and pharmacologic interventions is summarized. The authors also present agendas for behavioral and pharmacologic research related to smoking cessation and discuss individual difference factors among smokers that may prove to be important in designing new and refining existing treatments.