Torgny Groth

Turnover in humans of β2‐microglobulin: the constant chain of HLA‐antigens

Abstract. The turnover of β2‐microglobulin, the common subunit of the HLA antigens, has been examined in normal subjects and in some patients with kidney disorders, multiple myeloma and rheumatoid arthritis. All patients displayed elevated serum levels of β2‐microglobulin. The plasma disappearance curve of 125I‐β2‐microglobulin demonstrated that the protein has a rapid turnover (11/2 = 21 h; range 1 1–2‐8 h) in normal persons and in patients with a normal glomerular filtration rate. In patients with kidney disorders the impaired renal filtration prolonged the turnover time and led to elevated serum levels of β2‐microglobulin.

Optimal Discrimination of Mild Hyperparathyroidism with Total Serum Calcium, Ionized Calcium and Parathyroid Hormone Measurements

The serum concentrations of calcium, albumin and parathyroid hormone (PTH) and the plasma levels of ionized calcium were determined in 124 healthy subjects, 89 patients with primary hyperparathyroidism (HPT), 23 of whom had the syndrome of multiple endocrine neoplasia type 1 (MEN-1) and 43 patients who had hypercalcaemia of other causes than HPT (non-HPT), in most cases due to widespread malignancies. The total serum calcium was corrected for the serum albumin concentration (CaM). Healthy females over the age of 50 had higher CaM, than younger females and the women of all ages also had, higher serum PTH levels than males. For all study groups both the intra- and inter-diurnal variations were small for all the studied variables. Discriminant function and optimal discriminatory limits were calculated with the help of computer programs. A consideration of all the individuals in the discriminant analysis, revealed that measurements of CaM alone separated most HPT patients both from the healthy subjects and from the non-HPT patients. However, when only those who had borderline values (defined as CaM between 2.45 and 2.75 mmol/l) were included it turned out that measurements of ionized calcium markedly improved the delineation of mild HPT from the healthy subjects and that, in addition, PTH measurements helped to exclude those with non-HPT hypercalcaemia. The optimal discriminatory levels of serum calcium were calculated as the levels which caused the minimum loss in terms of misclassification when attention was paid to the relative importance of false positive to false negative classifications and to the prevalence of HPT. The optimal discriminatory level for serum calcium for a weighting ratio between false positive to false negative of 1:1, and a prevalence of HPT of 1%, was calculated to be 2.68 mmol/l and for a prevalence of 50% 2.56 mmol/l. In the latter situation a weighting ratio of 10:1 for false positive to false negative gave a level of 2.63 mmol/l while a weighting ratio of 1:10 corresponded to an optimal discriminatory level of 2.47 mmol/l.

The development of a multicenter database for reference values in clinical neurophysiology--principles and examples.

This paper describes the work undertaken to establish principles for the development of multicenter databases for reference values in clinical neurophysiology. The study was initiated because of interest of the involved laboratories in knowledge-based systems in electromyographic diagnosis, for which it was necessary to formalize the key concepts in the diagnostic process: diseases, pathophysiology and test results. The paper deals specifically with the structuring of results of motor and sensory nerve conduction studies.

Plasma concentration and renal excretion of adenine and 2,8-dihydroxyadenine after administration of adenine in man

A new method of high performance liquid chromatography (HPLC) which makes it possible to analyse 2,8-dihydroxyadenine (DOA) in plasma in concentrations exceeding 0.25 mumol/l is described. The method was used to study the renal elimination of DOA. For comparison, the renal handling of adenine was also investigated. The results from an analysis of the experimental data support the assumption that more than one concentration-dependent mechanism exists in the renal tubuli for each of the two purines, adenine and DOA. In general the clearance values are higher for DOA than for adenine and indicate net secretion for both substances.

Transferability of neural network-based decision support algorithms for early assessment of chest-pain patients.

The present investigation concerns methodological and epidemiological aspects of the transferability of artificial neural network-based algorithms, as key-components for classification in decision support systems (DSS). The prevalence of pathological conditions to be detected must be known in order to tune an artificial neural networks (ANN)-decision algorithm so that the predictive values of the outcome fulfil medical requirements. Another aspect of transferability, when clinical laboratory results are used, concerns differences in analytical performance of measuring instruments. The relative bias between two instruments is not known exactly, but must be estimated and corrected for. A general method, based on original measured data sets and statistical modeling, was developed for simulating the impact of various correction procedures when using different analytical instruments. The simulation methodology was applied to a real clinical problem of ruling-in/ruling-out of patients with suspected acute myocardial infarction (AMI) by biochemical monitoring. The recommended correction procedure was based on method comparison with use of five duplicate measurements on a common set of patient samples covering the relevant measuring interval. Transferability of laboratory data over time was also studied. The design of quality assurance procedures should be based on analytical quality requirement specifications related to medical needs. Limits of critically sized systematic errors were assessed by calculating the decrease in diagnostic performance of the ANN-algorithm as a result of temporary analytical disturbances. The consequences for the design of QA procedures was illustrated. It is concluded that the actual ANN-decision algorithm for early assessment of chest-pain patients should be possible to transfer to new sites under realistic conditions.

A hyaluronan-loading test applied to patients with liver and joint diseases.

The serum hyaluronan disappearance data, after an intravenous bolus injection of hyaluronan, were evaluated in terms of model-based parameters. The loading test was performed in 10 healthy persons (basal serum hyaluronan concentration, C0, 24.9 +/- 8.9 micrograms/l [mean +/- S.D.]), 6 patients with joint disease (62.3 +/- 41.1 micrograms/l) and 19 patients with liver disease (206 +/- 214 micrograms/l). The highest maximum Michaelis-Menten elimination rate (Vmax = 287 +/- 86 micrograms/min) was found in patients with joint disease, significantly higher than in healthy persons (Vmax = 179 +/- 16, P = 0.0015) and in patients with liver disease (Vmax = 149 +/- 59, P = 0.0002). C0 and Vmax were evaluated as discriminants for assessment of residual liver function. In patients with liver disease C0 correlated with liver function score (r = 0.875, P < 0.0001) and serum albumin concentration (r = -0.813, P < 0.0001). The Vmax parameter did not correlate with conventional liver function tests or with the liver score but a significantly negative correlation of Vmax with C0 was found in patients with liver disease. A combination of the C0 level and the Vmax parameter was found to discriminate between healthy persons, patients with joint disease and patients with liver disease and should be of benefit in separating patients, with or without elevated serum hyaluronan levels, into groups having increased influx or reduced elimination, respectively, of circulating hyaluronan.

INFORM: development of information management and decision support systems for High Dependency Environments.

The long-term aim in the INFORM Project is to develop, evaluate and implement a new generation of Information Systems for hospital High Dependency Environments (HDE — Intensive Care Units, Neonatal Units, Burns Units, Operating and Recovery Rooms, and other specialised areas). The distinguishing feature of the HDE is the very large amount of data that is collected through monitors and paper records about the state of critically ill patients; this has made the role of the staff a technical one in addition to a caring one. The INFORM System will integrate Decision Support with on-line, off-line and observed patient data and, in addition, will incorporate and integrate unit management features.In the Exploratory Phase of the Project, functional requirements have been set out. These are based on four components: conceptual model of the HDE; evaluation of existing HDE Information Systems; development of a novel software architecture using a Knowledge-Based Systems (KBS) methodology, and based on a critical review of KBS applied to the HDE; monitoring of appropriate leading-edge technological developments.The conceptual model has two components: a patient-related information model, and a department-related cost model. The patient-related model is identifying key and difficult areas of decision making. A key aspect of INFORM is integration of clinical Decision Support for these areas into the Information System through a layered software architecture. The lower layers are concerned with monitoring and alarming and the higher levels with patient assessment and therapy planning. The functionality and interconnection of these layers are being determined.

Methods for selection of adequate neural network structures with application to early assessment of chest pain patients by biochemical monitoring

A methodology for selecting, training and estimating the performance of adequate artificial neural network (ANN) structures and incorporating them with algorithms that are optimized for clinical decision making is presented. The methodology was applied to the problem of early ruling-in/ruling-out of patients with suspected acute myocardial infarction using frequent biochemical monitoring. The selection of adequate ANN structures from a set of candidates was based on criteria for model compatibility, parameter identifiability and diagnostic performance. The candidate ANN structures evaluated were the single-layer perceptron (SLP), the fuzzified SLP, the multiple SLP, the gated multiple SLP, the multi-layer perceptron (MLP) and the discrete-time recursive neural network. The identifiability of the ANNs was assessed in terms of the conditioning of the Hessian of the objective function, and variability of parameter estimates and decision boundaries in the trials of leave-one-out cross-validation. The commonly used MLP was shown to be non-identifiable for the present problem and available amount of data, despite artificially reducing the model complexity with use of regularization methods. The investigation is concluded by recommending a number of guidelines in order to obtain an adequate ANN model.

Myoglobin kinetics in patients suffering from acute myocardial infarction in its early phase —as studied by the single injection method

The turnover of myoglobin has been examined with the single injection technique in eight patients suffering from acute myocardial infarction during its early phase. All patients had elevated serum levels of myoglobin and creatine kinase-MB. The serum disappearance curve of [125I]myoglobin could be fitted adequately by a two-compartment model. The kinetic parameters did not differ form those estimated for six healthy old volunteers, previously studied with the same technique. The average elimination rate constant was 0.80 +/- 0.37 h-1 and the average turnover was 5.5 +/- 3.2 h (SD). The values are in good agreement with corresponding estimates for the retinol-binding protein, with a molecule weight (21,000) close to that for myoglobin (mol. wt 17,800). In comparison with beta 2-microglobulin, another low molecular weight protein (mol. wt 11,800), the elimination rate constant for myoglobin is significantly smaller and the turnover time is longer, as could be expected form the difference in molecular weight. Plasma protein binding of myoglobin could not be excluded, however.

2.7. Methods and approaches to determine “optimal” quality for clinical chemical data

Although clinical reasoning and decision-making may be very complex, there are methods to perform both piecemeal and more complete optimizations with regard to the use of clinical chemical data and for assessing quality specification. Some methods and approaches are described and illustrated with examples: (i) rules for propagation of errors in simple algebraic/statistical transformations; (ii) systems and sensitivity analysis using biochemical/pathophysiological simulation models; (iii) systems and sensitivity analysis of simulated clinical classification and decision processes. It is concluded that the possible gain of useful information by improving analytical and pre-analytical quality should be related to the often more important aspects of test selection test and test combination, period and frequency of observation, and the use of correct conceptual models for transformation of data.