Prognostic models in medicine. AI and statistical approaches.
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Artificial Intelligence↗
Biomedical subjects
P J Lucas
Publications and source records attributed to P J Lucas.
Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor.
The immune system, despite its complexity, is maintained at a relative steady state. Mechanisms involved in maintaining lymphocyte homeostasis are poorly understood; however, recent availability of transgenic (Tg) and knockout mouse models with altered balance of lymphocyte cell populations suggest that cytokines play a major role in maintaining lymphocyte homeostasis. We show here that transforming growth factor (TGF)-beta plays a critical role in maintaining CD8(+) T cell homeostasis in a Tg mouse model that specifically overexpresses a dominant negative TGF-beta II receptor (DNRII) on T cells. DNRII T cell Tg mice develop a CD8(+) T cell lymphoproliferative disorder resulting in the massive expansion of the lymphoid organs. These CD8(+) T cells are phenotypically "naive" except for the upregulation of the cell surface molecule CD44, a molecule usually associated with memory T cells. Despite their dominance in the peripheral lymphoid organs, CD8(+) T cells appear to develop normally in the thymus, suggesting that TGF-beta exerts its homeostatic control in the peripheral immune system.
Animals↗
A probabilistic and decision-theoretic approach to the management of infectious disease at the ICU.
The medical community is presently in a state of transition from a situation dominated by the paper medical record to a future situation where all patient data will be available on-line by an electronic clinical information system. In data-intensive clinical environments, such as intensive care units (ICUs), clinical patient data are already fully managed by such systems in a number of hospitals. However, providing facilities for storing and retrieving patient data to clinicians is not enough; clinical information systems should also offer facilities to assist clinicians in dealing with hard clinical problems. Extending an information system's capabilities by integrating it with a decision-support system may be a solution. In this paper, we describe the development of a probabilistic and decision-theoretic system that aims to assist clinicians in diagnosing and treating patients with pneumonia in the intensive-care unit. Its underlying probabilistic-network model includes temporal knowledge to diagnose pneumonia on the basis of the likelihood of laryngotracheobronchial-tree colonisation by pathogens, and symptoms and signs actually present in the patient. Optimal antimicrobial therapy is selected by balancing the expected efficacy of treatment, which is related to the likelihood of particular pathogens causing the infection, against the spectrum of antimicrobial treatment. The models were built on the basis of expert knowledge. The patient data that were available were of limited value in the initial construction of the models because of problems of incompleteness. In particular, detailed temporal information was missing. By means of a number of different techniques, among others from the theory of linear programming, these data have been used to check the probabilistic information elicited from infectious-disease experts. The results of an evaluation of a number of slightly different models using retrospective patient data are discussed as well.
Anti-Bacterial Agents↗
Prognostic methods in medicine.
Prognosis--the prediction of the course and outcome of disease processes--plays an important role in patient management tasks like diagnosis and treatment planning. As a result, prognostic models form an integral part of a number of systems supporting these tasks. Furthermore, prognostic models constitute instruments to evaluate the quality of health care and the consequences of health care policies by comparing predictions according to care norms with actual results. Approaches to developing prognostic models vary from using traditional probabilistic techniques, originating from the field of statistics, to more qualitative and model-based techniques, originating from the field of artificial intelligence (AI). In this paper, various approaches to constructing prognostic models, with emphasis on methods from the field of AI, are described and compared.
Artificial Intelligence↗
An intelligent system for pacemaker reprogramming.
The process of reprogramming a cardiac pacemaker can be described in terms similar to those used for describing diagnostic problem solving. In this paper, the process of reprogramming a pacemaker is formalized as a special form of abductive diagnostic reasoning, where observable findings are interpreted with respect to results obtained from diagnostic tests. The dynamics of this process is cast as a diagnostic strategy, where information is gathered in a structured fashion. This abductive theory of pacemaker reprogramming has been used as the basis for an actual system that in its present form is capable of assisting cardiologists in dealing with problems in atrial sensing and pacing. The performance of the system has been evaluated using data from actual patients.
Algorithms↗
Computer-based decision support in the management of primary gastric non-Hodgkin lymphoma.
Primary non-Hodgkin lymphoma of the stomach is a rare disorder for which clinical management has not yet been settled completely. Faced with the many uncertainties associated with the selection of a treatment for a patient with this disorder, it is difficult to determine the treatment that is optimal for the patient, as well as the prognosis to be expected. The development of a decision-theoretic model of non-Hodgkin lymphoma of the stomach is described. The model aims to assist the clinician in exploring various clinical questions, among others questions concerning prognosis and optimal treatment. Central to the model is a probabilistic network that offers an explicit representation of the uncertainties underlying the decision-making process. The model has been incorporated in a decision-support system. Preliminary evaluation results indicate that the performance of the model in its present form matches the performance of experienced clinicians.
Combined Modality Therapy↗
Model-based diagnosis in medicine.
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Artificial Intelligence↗
Randomised controlled trial of a synthetic triglyceride milk formula for preterm infants.
AIMS: To test whether use of infant formula containing synthetic structured triglycerides results in: (i) increased palmitate absorption; (ii) increased total fat absorption; (iii) reduction in calcium soap formation in the gut; and hence (iv) increased calcium absorption. METHODS: A randomised study was made of 24 infants comparing three formulas, one containing the synthetic fat Betapol with 74% of palmitate in the 2-position, which was substantially higher than in the two comparison diets (8.4% and 28%). The hypothesised outcomes were tested using balance studies, detailed chemical analysis of stool specimens and dual calcium isotope tracers (44calcium orally and 46calcium intravenously). RESULTS: Three of the four hypotheses were confirmed: use of a formula rich in 2-position palmitate (i) improved palmitate (16:0) and also (18:0) absorption; (ii) reduced the formation of insoluble calcium soaps in the stool; and (iii) improved calcium absorption, determined by the dual tracer technique from 42 (SE 3)% to 57 (7)%. CONCLUSION: Synthetic triglycerides that mimic the stereoisometric structure of those in breast milk may have a valuable role in the design of formulas used for preterm infants in neonatal intensive care units.
Animals↗
Randomized outcome trial of human milk fortification and developmental outcome in preterm infants.
Despite potential benefits, human milk may fail to meet preterm infants' nutrient requirements. We tested the hypothesis that fortified breast milk, fed alone or with preterm formula, would improve neurodevelopment and growth at 18-mo follow-up without adverse short-term clinical or biochemical consequences. Two hundred seventy-five preterm infants from two medical centers (birth weight < 1850 g; mean gestation 29.8 +/- 2.7 wk) whose mothers chose to provide breast milk were randomly assigned to receive for a mean of 39 d a multinutrient fortifier or control supplement containing phosphate and vitamins. Breast milk comprised 47.6% and 46.4% of enteral intake in fortified and control groups, respectively; preterm formula supplements were used when insufficient breast milk was available. Overall, there were no significant growth advantages with fortification; although, when breast milk exceeded 50% of intake, fortification promoted faster weight gain (an advantage of 1.6 g.kg-1.d-1; 95% CI: 0.1, 3.1; P < 0.05). Compared with control infants, the fortified group showed 1) higher plasma urea from week 2 (P = 0.04), 2) higher plasma calcium (mean 2.34 +/- 0.01 compared with 2.27 +/- 0.02 mmol/L; P = 0.003), 3) a greater rise in alkaline phosphatase by week 6 (P = 0.04), 4) more clinical infections (suspected plus proven; 43% compared with 31%, P = 0.04), 5) a nonsignificantly increased incidence of necrotizing enterocolitis (5.8% compared with 2.2%, P = 0.12), and 6) higher white cell and platelet counts. Developmental scores at 18 mo were slightly but not significantly higher in the fortified group. This study confirmed that breast milk fortifiers can improve short-term growth (when breast milk intakes are high); but beneficial effects on long-term development remained unproven. Future research is required to evaluate potential adverse consequences and explore more optimal fortification strategies.
Acid-Base Equilibrium↗
Functional significance of the Fas molecule in naive lymphocytes.
The Fas molecule mediates apoptotic signal in many cell types. Mouse mutations (lpr, lprcg, gld), which impair the function of Fas, cause spontaneous autoimmune disease. We generated Fas-deficient (Fas-/-) mice by homologous recombination. In embryonic stem cells Fas-/- mice developed lpr-like disease, confirming that the abnormality of Fas is causal in the lpr phenotype. We also made Fas-/- chimeric mice composed of a mixture of Fas+/+ and Fas-/- cells. The chimeric mice also showed the lpr phenotype. In Fas-/-, chimeric mice, the Fas-deficient population expanded progressively among mature T and B lymphocytes. The expansion of Fas-deficient lymphocytes occurred at the naive, pre-primed, lymphocyte stage. These results suggest that the Fas molecule functions not only after antigenic stimulation, as previously hypothesized, but also at the naive lymphocyte stage.
Animals↗
Naive CD28-deficient T cells can initiate but not sustain an in vitro antigen-specific immune response.
Naive T cells require an Ag-specific signal, as well as a costimulatory signal to mount a primary Ag-specific response. Because of their low precursor frequency, it has been difficult to study costimulatory requirements of these Ag-specific T cells. We have generated a CD28-deficient mouse that has been bred to a TCR transgenic (Tg) mouse to better study the function of CD28 during CD4+ T cell responses to Ag. In the absence of CD28, naive TCR Tg T cells responded vigorously to peptide, but responded poorly to mitogen activation. Comparison of activation-induced cell-surface molecules, including CD25, CD44, CD69, and CD71, showed no significant differences between CD28+ and CD28- TCR Tg T cells during the first 24 to 48 h after Ag stimulation. Despite relatively normal surface phenotype and normal proliferative response to Ag, CD28- T cells produced little IL-2, had a decreased sensitivity to lower Ag concentrations, and were unable to maintain their proliferative response. These results suggest that naive T cells are able to utilize other costimulatory signals to initiate a primary Ag-specific response, but require CD28 for optimal, sustained proliferation.
Abatacept↗
The human anti-murine xenogeneic cytotoxic response. II. Activated murine antigen-presenting cells directly stimulate human T helper cells.
Generation of a human T cell anti-murine xenogeneic response has previously been shown to be dependent on presentation of murine Ag by human APC. We have undertaken a series of experiments to better delineate the cellular defects that prevent effective production of IL-2 by human T cells upon direct exposure to murine stimulator populations. It was found that although resting human T cells cannot respond effectively to resting murine APC, they can respond to activated murine stimulator populations. Such APC activation could be mediated by murine granulocyte-macrophage-CSF or LPS that were associated with increased expression of B7-2 on the xenogeneic stimulating cell populations. Blocking studies with Ab provided further evidence that costimulation through CD28 played a critical role in the stimulation of human T cells by activated murine-stimulator cells in the production of IL-2. These results demonstrate the usefulness of this xenogeneic system in understanding human T cell-APC interactions and defining minimally sufficient T cell activation requirements. They further delineate the cellular level of deficient activation in the xenogeneic stimulation of human T cells by murine cell populations, and identify the potential importance of CD28/CTLA4 and its ligands in xenogeneic responses. These observations and concepts have implications for clinical efforts in xenografting.
Animals↗
Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice.
The bcl-2 proto-oncogene can prevent the death of many cell types. Mice were generated that were chimeric for the homozygous inactivation of bcl-2. Lymphocytes without Bcl-2 differentiated into phenotypically mature cells. However, in vitro, the mature T cells that lacked Bcl-2 had shorter life-spans and increased sensitivity to glucocorticoids and gamma-irradiation. In contrast, stimulation of CD3 inhibited the death of these cells. T and B cells with no Bcl-2 disappeared from the bone marrow, thymus, and periphery by 4 weeks of age. Thus, Bcl-2 was dispensable for lymphocyte maturation, but was required for a stable immune system after birth.
Animals↗
Human CD8+ xenoreactive T cells mediate tissue injury in vivo.
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Animals↗
Sick building syndrome--know your ventilation rates.
To summarise, although the occurrence of sick building syndrome could be due to a range of causal factors, research shows that it is probable that low outside air intake volume and pollution generated by the ventilation system and the building contents play a role in producing its effects. This being so, it is important that the flow of outside air into the building and the distribution of fresh or mixed air around the interior are known and controlled. However it is difficult to control the flow rate by conventional means and the use of fixed minimum position dampers is not likely to maintain a minimum fresh air flow rate under most wind velocities. What is needed is a control system which relies on direct measurement of air flow rate connected to a modulated minimum outside air intake damper to provide a constant and verifiable volume of fresh air flow. Flow sensors also open up the possibility of direct measurement and control of return and mixed air volumes and of course the flow of air anywhere else in the system.
Air Pollution, Indoor↗
T-lymphocyte interleukin 2-dependent tyrosine protein kinase signal transduction involves the activation of p56lck.
Addition of interleukin 2 (IL-2) to IL-2-dependent T cells results in tyrosine protein kinase signal transduction events even though the IL-2 receptor alpha and beta chains lack intrinsic enzymatic activity. Here we report that addition of IL-2 to IL-2-dependent human T cells transiently stimulates the specific activity of p56lck, a member of the src family of nonreceptor tyrosine protein kinases expressed at high levels in T lymphocytes. The ability of IL-2 to induce p56lck activation was found to be independent of the capacity of p56lck to associate with either CD4 or CD8. Following IL-2 treatment, p56lck was found to undergo serine/threonine phosphorylation modifications that resulted in altered mobility of the lck gene product on polyacrylamide gels. These observations raise the possibility that p56lck participates in IL-2-mediated signal transduction events in T cells.
CD4 Antigens↗
Second evaluation of HEPAR, an expert system for the diagnosis of disorders of the liver and biliary tract.
HEPAR is an expert system which can be used as a supportive tool in the diagnosis of disorders of the liver and biliary tract. When consulted for a particular patient, the system assesses the patient's disorder in two stages. In the first stage, data of medical history, physical examination and routine laboratory tests are used to determine whether the disorder is hepatocellular or biliary obstructive, and whether benign or malignant features are present. In the second stage, the system produces a differential diagnosis out of a set of 80 disease categories, using the conclusions of the first stage of the assessment and the results of a restricted number of supplementary investigations, i.e. serological tests and ultrasonography. The conclusions of the two stages are ordered by the amount of evidence computed by HEPAR. The system is not yet suitable for clinical use. The system has been evaluated using data of 181 patients selected from a population of 214 consecutively admitted patients with jaundice. The patients were classified by the system as having a hepatocellular or biliary obstructive, and a benign or malignant disorder in 96% and 100% of the cases, respectively. When comparing the conclusions with strongest evidence with the final clinical diagnoses, the patients were classified correctly in 86% and 83% of the classified cases, respectively. A differential diagnosis was produced in 87% of the patients. A correspondence between the diagnosis with strongest evidence and the final clinical diagnosis was found in 78% of the classified patients.
Adolescent↗
No T-cell tyrosine protein kinase signalling or calcium mobilization after CD4 association with HIV-1 or HIV-1 gp120.
The T lymphocyte surface protein CD4 is an integral membrane glycoprotein noncovalently associated with the tyrosine protein kinase p56lck. In normal T cells, surface association of CD4 molecules with other CD4 molecules or other T-cell surface proteins, such as the T-cell antigen receptor, stimulates the activity of the p56lck tyrosine kinase, resulting in the phosphorylation of various cellular proteins at tyrosine residues. Thus, the signal transduction in T cells generated through the surface engagement of CD4 is similar to that observed for the class of growth factor receptors possessing endogenous tyrosine kinase activity. As CD4 is also the cellular receptor for the human immunodeficiency virus (HIV), binding of the virus or gp120 (the virus surface protein responsible for specific CD4+ T-cell association) could mimic the types of immunological interactions that have previously been found to stimulate p56lck and trigger T-cell activation pathways. We have evaluated this possibility and report here that binding of HIV-1 or the virus glycoprotein gp120 to CD4+ human T cells fails to elicit detectable p56lck-dependent tyrosine kinase activation and signalling, alterations in the composition of cellular phosphotyrosine-containing proteins, or changes in intracellular Ca2+ concentration.
Antibodies, Monoclonal↗