Gene-based approach to human gene-phenotype correlations

Elucidating the genetic basis of human phenotypes is a major goal of contemporary geneticists. Logically, two fundamental and contrasting approaches are available, one that begins with a phenotype and concludes with the identification of a responsible gene or genes; the other that begins with a gene and works toward identifying one or more phenotypes resulting from allelic variation of it. This paper provides a conceptual overview of phenotype-based vs. gene-based procedures with emphasis on gene-based methods. A key feature of a gene-based approach is that laboratory effort first is devoted to developing an assay for mutations in the gene under regard; the assay then is applied to the evaluation of large numbers of unrelated individuals with a variety of phenotypes that are deemed potentially resulting from alleles at the gene. No effort is directed toward chromosomally mapping the loci responsible for the phenotypes scanned. Example is made of my laboratory’s successful use of a gene-based approach to identify genes causing hereditary diseases of the retina such as retinitis pigmentosa. Reductions in the cost and improvements in the speed of scanning individuals for DNA sequence anomalies may make a gene-based approach an efficient alternative to phenotype-based approaches to correlating genes with phenotypes.

A model-based approach for assessing in vivo combination therapy interactions

We present an approach for evaluating the efficacy of combination antitumor agent schedules that accounts for order and timing of drug administration. Our model-based approach compares in vivo tumor volume data over a time course and offers a quantitative definition for additivity of drug effects, relative to which synergism and antagonism are interpreted. We begin by fitting data from individual mice receiving at most one drug to a differential equation tumor growth/drug effect model and combine individual parameter estimates to obtain population statistics. Using two null hypotheses: (i) combination therapy is consistent with additivity or (ii) combination therapy is equivalent to treating with the more effective single agent alone, we compute predicted tumor growth trajectories and their distribution for combination treated animals. We illustrate this approach by comparing entire observed and expected tumor volume trajectories for a data set in which HER-2/neu-overexpressing MCF-7 human breast cancer xenografts are treated with a humanized, anti-HER-2 monoclonal antibody (rhuMAb HER-2), doxorubicin, or one of five proposed combination therapy schedules.

Creating local bibliographic databases: new tools for evidence-based health care*

The Internet has created new opportunities for librarians to present literature search results to clinicians. In order to take full advantage of these opportunities, libraries need to create locally maintained bibliographic databases. A simple method of creating a local bibliographic database and publishing it on the Web is described. The method uses off-the-shelf software and requires minimal programming. A hedge search strategy for outcome studies of clinical process interventions is created, and Ovid is used to search MEDLINE. The search results are saved and imported into EndNote libraries. The citations are modified, exported to a Microsoft Access database, and published on the Web. Clinicians can use a Web browser to search the database. The bibliographic database contains 13,803 MEDLINE citations of outcome studies. Most searches take between four and ten seconds and retrieve between ten and 100 citations. The entire cost of the software is under $900. Locally maintained bibliographic databases can be created easily and inexpensively. They significantly extend the evidence-based health care services that libraries can offer to clinicians.

Evidence-based librarianship: an overview

Objective: To demonstrate how the core characteristics of both evidence-based medicine (EBM) and evidence-based health care (EBHC) can be adapted to health sciences librarianship.