Training Synergies Between Medical Informatics and Health Services Research: Successes and Challenges

Stanford''s two decades of success in linking medical informatics and health services research in both training and investigational activities reflects advantageous geography and history as well as natural synergies in the two areas. Health services research and medical informatics at Stanford have long shared a quantitative, analytic orientation, along with linked administration, curriculum, and clinical activities. Both the medical informatics and the health services research curricula draw on diverse course offerings throughout the university, and both the training and research overlap in such areas as outcomes research, large database analysis, and decision analysis/decision support. The Stanford experience suggests that successful integration of programs in medical informatics and health services research requires areas of overlapping or synergistic interest and activity among the involved faculty and, hence, in time, among the students. This is enhanced by a mixture of casual and structured contact among students from both disciplines, including social interactions. The challenges to integration are how to overcome any geographic separation that may exist in a given institution; the proper management of relationships with those sub-areas of medical informatics that have less overlap with health services research; and the need to determine how best to exploit opportunities for collaboration that naturally occur.Training in medical informatics and health services research has been closely linked at Stanford University for almost two decades. Although the close linkage was deliberate, it was facilitated by historical circumstances, in particular the common academic structures in which both programs arose. In this paper, we describe some of that rationale and history, identifying the areas of overlap that we have pursued in coordinating the training opportunities for graduate students and fellows in both areas of study. As we shall note, the synergies have been great, and in some cases trainees have collaborated closely on research while also taking some of the same courses. We believe that these interactions can be a model for the design of training programs that encourage scholarly interactions between medical informatics and health services research. Although our initial charge was to describe both the successes and failures in integrating the programs, we found that we could not identify any outright failures and that it would be better to delineate the complexities and challenges that we have faced in bringing together these two disciplines.     

T2 hyperintense foci on magnetic resonance images of schizophrenic patients and controls.

High resolution magnetic resonance imaging (MRI) of the brain was performed on 18 male schizophrenic patients and 15 male normal control subjects using an identical imaging protocol. The number and size of T2 hyperintense foci were clinically quantified by an academic radiologist. Large foci (greater than or equal to 3 mm in diameter) were observed more frequently on patient images (7/18) than on control images (1/15). The imaging protocol detected high rates of focal hyperintensities, but no differences between patients and controls were noted in the total affected brain area (sum of focal areas) or in the presence or absence of foci.     

A multivariate analysis of mortality and hospital admissions with high-flux dialysis.

The use of high-flux dialysis in clinical practice increased rapidly despite an absence of reports on the clinical effectiveness of the technique. Mortality and hospital admission rates of patients treated with high-flux dialysis were evaluated and compared with those of patients treated with conventional dialysis in a hospital-based renal dialysis unit in northern California. By use of a retrospective, cross-over design, 253 patients enrolled in the dialysis unit from January 1987 to January 1991 were studied. During this period, 107 patients were treated with high-flux dialysis for at least 1 month, and all but 17 of them had received conventional dialysis before switching to high-flux dialysis. The remaining 146 patients were treated with only conventional dialysis. Of the 80 patients who died during the study period, 69 were receiving conventional dialysis and 11 were receiving high-flux dialysis. The multivariate analyses, adjusted for age, gender, ethnic background, type of renal failure, comorbid conditions, and duration of ESRD, showed that annual mortality was substantially less for patients treated with high-flux dialysis compared with that for patients treated with conventional dialysis (7 versus 20%; P < 0.001). The difference in the rate of hospital admissions was not statistically significant. In this nonexperimental study, methods were applied to control for selectivity bias and other factors that might confound the apparent treatment effect. The findings suggest that the potential benefits of high-flux dialysis are sufficient to justify further confirmation in a randomized, controlled trial.     

Immunogenic proteins of Trichomonas vaginalis as demonstrated by the immunoblot technique.

Fifteen clinical isolates of Trichomonas vaginalis were evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with transfer to nitrocellulose and by immunoblots probed with human sera. All T. vaginalis isolates showed similar banding patterns by Coomassie brilliant blue and silver staining of the electrophoresis gels and by amido black staining of the nitrocellulose. However, by the immunoblot technique, differences in banding patterns were noted, particularly in the high-molecular-weight zone (greater than 1.5 X 10(5], which were consistent in numerous experiments. A common immunogenic band was noted at a molecular weight of approximately 100,000 in all T. vaginalis isolates probed with six sera reactive in an enzyme-linked immunosorbent assay but was not seen or was only faintly visible when isolates were probed with sera considered to be nonreactive by the assay. Many other bands were identified, some of which appeared common to all isolates, but were not recognized by all sera tested. These studies demonstrate the antigenic heterogeneity of T. vaginalis and show that different individuals appear to respond immunologically to different T. vaginalis antigens.     

Temperature-sensitive membrane association of pp60src in tsNY68-infected cells correlates with increased tyrosine phosphorylation of membrane-associated proteins

Incubation of membrane vesicles from normal and Rous sarcoma virus-transformed chick embryo fibroblasts (CEF) with [gamma-32P]ATP resulted in the phosphorylation of a large number of proteins. The major differences observed between the membrane vesicles of untransformed and transformed cells were: (1) a 5- to 10-fold increase in the proportion of labeled phosphotyrosine in transformed vesicles and (2) the phosphorylation of pp60src in vesicles from transformed cells. Of the many proteins labeled in vitro, only pp60src was immunoprecipitated by TBR serum. Phosphorylation of the immunoprecipitated pp60src occurred on tyrosine in the 26-kDa carboxy-terminal Staphylococcus aureus V8 protease fragment. pp60src was not phosphorylated in vitro in membrane vesicles prepared from tsNY68-infected cells grown at the nonpermissive temperature. The proportion of labeled phosphotyrosine in membrane proteins from tsNY68-infected cells grown at the nonpermissive temperature was only slightly increased relative to that observed in membranes prepared from normal cells. Subcellular fractionation indicated that while pp60src was membrane associated in tsNY68-infected cells grown at the permissive temperature, pp60src was chiefly soluble in tsNY68-infected cells grown at the nonpermissive temperature. Temperature-sensitive membrane association of pp60src in tsNY68-infected cells was also observed by indirect immunofluorescence microscopy. When membranes were prepared from tsNY68-infected cells that had been downshifted from the nonpermissive to the permissive temperature, the reappearance of in vitro phosphorylated pp60src and the increase in the proportion of labeled phosphotyrosine in membrane vesicles correlated with the kinetics of src immune complex kinase reactivation and membrane association of pp60src.     

AIDS vaccine development: the long and winding road

Development of a vaccine that provides sterilizing immunity against HIV infection remains an elusive goal, due primarily to the difficulty in generating neutralizing antibodies to primary HIV isolates. In lieu of a present solution to this problem, recent approaches to develop vaccines against HIV/AIDS have focused not on preventing infection outright, but on eliciting potent antiviral CD8+ T-cell responses to limit HIV replication in individuals who become infected after vaccination. Successful control of HIV replication in vivo, enabled by vaccine-elicited immune responses should, in turn, attenuate an individual's rate of progression to AIDS while reducing their likelihood of subsequently transmitting HIV. Recent pre-clinical evaluation of CTL-based vaccines in non-human primate models of AIDS has shown several different vaccine modalities (e.g. heterologous 'prime/boost' strategies such as DNA + recombinant viral vectors) to be capable of eliciting high-level cellular immune responses that are associated with limitation of virus replication and protection against disease following challenge with select pathogenic virus isolates. However, it is not currently known to what extent these protective effects, observed under optimal experimental conditions in select animal models, can be translated into relevant protection of humans against AIDS. In this article we discuss the promise, potential limitations, and scientific challenges that currently provide the context for efforts to develop and successfully employ a safe and effective AIDS vaccine.     

HLA-B alleles of the Navajo: no evidence for rapid evolution in the Nadene

New HLA-B locus alleles have been found in South American Amerindian populations but were largely absent in North American Amerindian tribes also descended from this first Paleo-Indian migration. We have now extended these studies to the Navajo, descendants of the second Nadene migration. No new functional alleles were found at the B locus of this tribe. This limited study supports the notion that while new B locus variants are common in South American Amerindians, it is more difficult to find new B locus alleles in North American native peoples. Whether this dichotomy is due to differences in pathogen environment and/or population structures between North and South America remains a subject of speculation.     

Efficacy and safety of recombinant human activated protein C for severe sepsis

BACKGROUND: Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. RESULTS: A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). CONCLUSIONS: Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.