Operational research techniques in medical treatment and Diagnosis: A Review
---
paper_title: A Variational Inequality Formulation of the Dynamic Network User Equilibrium Problem

paper_content:

In the present paper we are concerned with developing more realistic dynamic models of route choice and departure time decisions of transportation network users than have been proposed in the literature heretofore. We briefly review one class of models that is a dynamic generalization of the static Wardropian user equilibrium, the so-called Boston traffic equilibrium. In contrast, we then propose a new class of models that is also a dynamic generalization of the static Wardropian user equilibrium. In particular, we show for the first time that there is a variational inequality formulation of dynamic user equilibrium with simultaneous route choice and departure time decisions which, when appropriate regularity conditions hold, preserves the first in, first out queue discipline.
---
paper_title: Theory of optimal control and mathematical programming

paper_content:

An electrical testing device for indicating resistance when testing insulation under high voltage conditions by supplying a high voltage which is monitored and controlled to prevent excessive power consumption when the insulation being tested is faulty. The device may be operated in an alternative mode to test continuity at low voltage.
---
paper_title: Dynamic programming and the calculus of variations

paper_content:

Abstract Problems in the Calculus of Variations can be viewed as multistage decision problems of a continuous type. It follows that their solutions can be characterized by the functional equation technique of dynamic programming [1]. In this paper, it will be shown that the functional equation approach yields, in simple and intuitive fashion, formal derivations of such classical necessary conditions of the Calculus of Variations as the Euler-Lagrange equations, the Weierstrass and Legendre conditions, natural boundary conditions, a transversality condition and the Erdmann corner conditions. The more general “problem of Bolza” in which the final time is defined implicitly and in which the expression to be extremized is the sum of an integral and a function evaluated at the end point is also considered. The principal necessary condition, usually called the “multiplier rule,” is deduced. We shall also derive necessary conditions for the case where the decision variables are restricted by inequality constraints. Finally, it is shown that the functional equation characterization readily yields the Hamilton-Jacobi partial differential equation of classical mechanics.
---
paper_title: Principles Of Optimal Control Theory

paper_content:

In the late 1950's, the group of Soviet mathematicians consisting of L. S. Pontryagin, V. G. Boltyanskii, R. V. Gamkrelidze, and E. F. Mishchenko made fundamental contributions to optimal control theory. Much of their work was collected in their monograph, The Mathematical Theory of Optimal Processes. Subsequently, Professor Gamkrelidze made further important contributions to the theory of necessary conditions for problems of optimal control and general optimization problems. In the present monograph, Professor Gamkrelidze presents his current view of the fundamentals of optimal control theory. It is intended for use in a one-semester graduate course or advanced undergraduate course. We are now making these ideas available in English to all those interested in optimal control theory. West Lafayette, Indiana, USA Leonard D. Berkovitz Translation Editor Vll Preface This book is based on lectures I gave at the Tbilisi State University during the fall of 1974. It contains, in essence, the principles of general control theory and proofs of the maximum principle and basic existence theorems of optimal control theory. Although the proofs of the basic theorems presented here are far from being the shortest, I think they are fully justified from the conceptual view point. In any case, the notions we introduce and the methods developed have one unquestionable advantage -they are constantly used throughout control theory, and not only for the proofs of the theorems presented in this book.
---
paper_title: Theory of optimal control and mathematical programming

paper_content:

An electrical testing device for indicating resistance when testing insulation under high voltage conditions by supplying a high voltage which is monitored and controlled to prevent excessive power consumption when the insulation being tested is faulty. The device may be operated in an alternative mode to test continuity at low voltage.
---
paper_title: The Nature of Statistical Learning Theory

paper_content:

Setting of the learning problem consistency of learning processes bounds on the rate of convergence of learning processes controlling the generalization ability of learning processes constructing learning algorithms what is important in learning theory?.
---
paper_title: COMPUTERIZED BREAST CANCER DIAGNOSIS AND PROGNOSIS FROM FINE NEEDLE ASPIRATES

paper_content:

Objective: To use digital image analysis and machine learning to (1) improve breast mass diagnosis based on fine-needle aspirates and (2) improve breast cancer prognostic estimations. Design: An interactive computer system evaluates, diagnoses, and determines prognosis based on cytologic features derived from a digital scan of fine-needle aspirate slides. Setting: The University of Wisconsin (Madison) Departments of Computer Science and Surgery and the University of Wisconsin Hospital and Clinics. Patients: Five hundred sixty-nine consecutive patients (212 with cancer and 357 with benign masses) provided the data for the diagnostic algorithm, and an additional 118 (31 with malignant masses and 87 with benign masses) consecutive, new patients tested the algorithm. One hundred ninety of these patients with invasive cancer and without distant metastases were used for prognosis. Interventions: Surgical biopsy specimens were taken from all cancers and some benign masses. The remaining cytologically benign masses were followed up for a year and surgical biopsy specimens were taken if they changed in size or character. Patients with cancer received standard treatment. Outcome Measures: Cross validation was used to project the accuracy of the diagnostic algorithm and to determine the importance of prognostic features. In addition, the mean errors were calculated between the actual times of distant disease occurrence and the times predicted using various prognostic features. Statistical analyses were also done. Results: The predicted diagnostic accuracy was 97% and the actual diagnostic accuracy on 118 new samples was 100%. Tumor size and lymph node status were weak prognosticators compared with nuclear features, in particular those measuring nuclear size. Compared with the actual time for recurrence, the mean error of predicted times for recurrence with the nuclear features was 17.9 months and was 20.1 months with tumor size and lymph node status (P=.11). Conclusion: Computer technology will improve breast fine-needle aspirate accuracy and prognostic estimations. (Arch Surg. 1995;130:511-516)
---
paper_title: Optimum excitation of phases and amplitudes in a phased array hyperthermia system

paper_content:

In order to achieve a desired temperature distribution inside and outside of malignant tissues, optimization techniques could be used in phased array hyperthermia systems to control effectively the amplitude and phase of the radiating elements. The optimization of a four-element phased array hyperthermia system operating at 432 MHz is examined theoretically. The proposed technique is based on a detailed physical model of the tissue medium to be heated in terms of both electromagnetic and thermal properties. A penalty function technique using a Newton method is applied to determine the optimum phases and amplitudes of the array. Several array geometrics have been studied and numerical results are presented.
---
paper_title: Determination of Insulin Sensitivity: Methodological Considerations

paper_content:

During the past decade, it became obvious that in contrast to defective insulin secretion in type I diabetes, defective insulin action (insulin resistance) is the most pertinent feature of type II diabetes. In addition, it has been known for a long time that obesity and insulin resistance are closely linked. Recently, hypertension also has been shown to often coincide with insulin resistance, although any causal relationships are still hypothetical. Last, several widely used pharmacological drugs such as diuretics, adrenergic blockers, and angiotensin-converting enzyme inhibitors may influence insulin sensitivity. Therefore, growing interest has emerged to most accurately measure insulin sensitivity. Although considerable knowledge has accumulated as to the actual mechanisms of insulin-dependent glucose transport, the signal transduction pathway of insulin remains poorly understood. When insulin sensitivity is measured, it is the overall glucose uptake that is quantified under controlled conditions. Other actions of insulin, such as the transport of ions, (e.g., sodium and potassium), synthesis of insulin-like growth factor-binding proteins, translocation of transporter proteins, and regulation of enzyme activities, are much more difficult to quantify. Of the many approaches used to quantify insulin action, the euglycemic hyperinsulinemic clamp technique has emerged as the most reliable tool, fulfilling clinical and scientific demands equally. In combination with tracer methodology and calorimetry, a detailed view into the quantitative aspects of insulin action at different target cells is possible. Whether insulin resistance extends to other known actions of insulin in addition to those on glucose metabolism remains open to debate.
---
paper_title: Insulin secretion, insulin sensitivity and hepatic insulin extraction in primary hyperparathyroidism before and after surgery

paper_content:

OBJECTIVE Primary hyperparathyroidism (pHPT) is associated with hypertension, hyperinsulinaemia, and insulin resistance. The present study investigated the causes of these metabolic disturbances by quantifying insulin sensitivity and glucose effectiveness, and by assessing the time course of β-cell insulin secretion and hepatic insulin extraction, during a dynamic condition such as after an intravenous glucose load. In addition, we evaluated the possible link between metabolic disorders and high blood pressure. ::: ::: SUBJECTS We studied 16 patients with pHPT, before and 12 weeks after parathyroldectomy; eight of these patients were re-evaluated one year after surgery. The control group consisted of 18 healthy volunteers. ::: ::: DESIGN AND MEASUREMENTS All subjects underwent an oral and a frequently sampled intravenous glucose tolerance test. The data from the intravenous glucose tolerance test were analysed by means of the minimal model technique which yields relevant parameters to comprehend the metabolic status of the single individual. ::: ::: RESULTS The glucose intolerance condition was characterized by a severely impaired insulin sensitivity in pHPT (3.2 ± 0.5 vs 9.5 ± 1.5 x 104/min/(μU/ml) of control subjects; P < 0.001), as well as by a reduced glucose effectiveness, (0.02 ± 0.002 vs 0.03 ± 0.003/min of control subjects; P < 0.04). Total insulin secretion during the 4 hours of the test was almost twofold elevated in comparison to the control subjects (32795 ± 4769 vs 16864 ± 1850 pM, P < 0.004) and its basal component significantly correlated with the high blood pressure. Hepatic extraction of insulin was significantly increased in pHPT (85.2 vs 76.2%, P < 0.03), possibly as a compensatory mechanism of hypersecretion, which however did not prevent peripheral hyperinsulinaemia in pHPT. Patients with pHPT were divided into two subgroups with normal and impaired glucose tolerance. The patients with impaired glucose tolerance had a significant reduction of first phase insulin response, although their basal and stimulated insulin levels were higher. Tissue insulin sensitivity and glucose effectiveness did not significantly differ between the two subgroups. After surgery, all the biochemical parameters (former hypercalcaemia, hypophosphataemia, elevated parathormone levels) were normalized, insulin sensitivity significantly improved (6.1 x 104/min/(μU/ml), P < 0.001), whereas glucose effectiveness remained completely unchanged. Basal and stimulated insulin responses were insignificantly lowered after surgery, and hepatic extraction did not change either. ::: ::: CONCLUSIONS Patients with pHPT exhibited decreased insulin sensitivity and insulin hypersecretion. The latter is only partially amellorated by increased hepatic insulin extraction. After surgery, although the biochemical abnormalities were fully reversible, the metabolic changes improved only partially.
---
paper_title: β-Cell Function and Insulin Sensitivity in Nondiabetic HLA-identical Siblings of Insulin-Dependent Diabetics

paper_content:

Insulin secretion and insulin sensitivity were compared in 12 HLA-identical siblings of insulin-dependent diabetics and nondiabetic controls. Only the maximum acute insulin response to intravenous arginine was lower in the siblings than in the matched controls ( P P
---
paper_title: Deterioration in carbohydrate metabolism and lipoprotein changes induced by modern, high fat diet in Pima Indians and Caucasians.

paper_content:

The transition from a high carbohydrate to a high fat diet may explain in part the dramatic increase in the prevalence of noninsulin-dependent diabetes mellitus among Pima Indians over the last century. In this study, 12 Pimas and 12 caucasians, all nondiabetic, were admitted to a metabolic ward and, in random order, fed 2 14-day weight-maintaining diets: a traditional Pima diet (percentage of calories: carbohydrate, 70% fat, 15%; protein, 15%) and a high fat modern diet (carbohydrate, 30%; fat, 50%; protein, 20%). Carbohydrate metabolism was characterized using the modified iv glucose tolerance test (minimal model), the acute insulin responses to arginine during a 3-step glycemic clamp, and the oral glucose tolerance test. Compared with the traditional diet, the modern diet was associated with a decrease in oral glucose tolerance (P less than 0.01) and higher plasma cholesterol concentrations (P less than 0.02). The decline in glucose tolerance was associated with similar insulin-mediated, but 23% lower glucose-mediated (P less than 0.001), glucose disposal, a 17% lower acute insulin response to glucose (P less than 0.03), a 9% lower beta-cell sensitivity to glucose (P less than 0.02), and similar beta-cell capacities. Pimas and caucasians responded similarly, except for larger changes in plasma lipids among the Pimas. Since glucose-mediated glucose disposal, beta-cell function, and glucose tolerance deteriorated on the modern diet, it is likely that diet composition affects the prevalence of noninsulin-dependent diabetes mellitus in both Pimas and caucasians.
---
paper_title: Pathogenesis of age-related glucose intolerance in man: insulin resistance and decreased beta-cell function.

paper_content:

To identify the pathogenic factors responsible for glucose intolerance of aging, we measured a variety of metabolic parameters, including insulin sensitivity and islet cell function, in 10 young (18-36 yr old) and 10 older (57-82 yr old) men of normal body weight. Subject groups had equivalent fasting plasma glucose and fat cell size values. Frequently sampled iv glucose tolerance tests were performed, and the data were analyzed by computer using the minimal model approach. This technique yields the following measures: SI, the insulin sensitivity index; phi 1 and phi 2, indices of first and second phase beta-cell responsiveness to glucose; n, fractional insulin clearance, and SG, a measure of dynamic glucose disappearance dependent on glucose per se. We also evaluated beta-cell responsiveness independently by measuring the plasma insulin response to arginine injections at three levels of glycemia and calculated potentiation slope from the relationship between the acute insulin response to arginine and the prestimulus glucose level. The older men were glucose intolerant (glucose disappearance rate, 1.32% min-1) compared to the younger men (glucose disappearance rate, 2.21% min-1; P less than 0.01). This intolerance was the result of both a beta-cell defect and insulin resistance. The potentiation slope (r = -0.67; P less than 0.02) and phi 2 (r = -0.47; P less than 0.05) both decreased with age. In addition, SI in the older group was diminished 63% (2.4 vs. 6.5; 10(-4) min-1/microU/ml; P less than 0.001) and was unrelated to differences in body fat. No differences were found in either n or SG. These studies suggest that the diminished glucose tolerance of aging in normal weight men has multifactorial causality. Both beta-cell dysfunction and insulin resistance are important. In contrast, we found little evidence for changes in insulin clearance or insulin-independent glucose disappearance contributing to age-related glucose intolerance.
---
paper_title: Using the ADAP Learning Algorithm to Forecast the Onset of Diabetes Mellitus

paper_content:

Abstract ::: Neural networks or connectionist models for parallel processing are not new. However, a resurgence of interest in the past half decade has occurred. In part, this is related to a better understanding of what are now referred to as hidden nodes. These algorithms are considered to be of marked value in pattern recognition problems. Because of that, we tested the ability of an early neural network model, ADAP, to forecast the onset of diabetes mellitus in a high risk population of Pima Indians. The algorithm's performance was analyzed using standard measures for clinical tests: sensitivity, specificity, and a receiver operating characteristic curve. The crossover point for sensitivity and specificity is 0.76. We are currently further examining these methods by comparing the ADAP results with those obtained from logistic regression and linear perceptron models using precisely the same training and forecasting sets. A description of the algorithm is included.
---
paper_title: Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects.

paper_content:

Although minimal model analysis of frequently sampled iv glucose tolerance tests (FSIGTs) to measure insulin sensitivity is well recognized, application has been limited by the need for endogenous insulin secretion. In the present study we determined whether use of exogenous insulin could permit minimal model assessment of insulin sensitivity (SI) to be extended to diabetic subjects. Normal volunteers had separate FSIGT assessments supplemented with both tolbutamide and insulin to accelerate glucose disappearance, while diabetics had a FSIGT supplemented only with insulin. There was a strong and highly significant correlation between the two assessments in normal subjects (r = 0.87; P less than 0.001), and the rank order of SI generally was maintained with the two assessments over a 3-fold range of SI; however, insulin-determined SI was 16% lower (3.4 +/- 0.4 vs. 4.1 +/- 0.4 x 10(-4) min/microU.microL; P less than 0.01). Diabetic subjects had markedly lower insulin sensitivity than controls (SI = 0.61 +/- 0.16; P less than 0.0001). Across all subjects, the level of fasting serum glucose was correlated inversely with both insulin sensitivity (r = -0.62; P less than 0.05) and acute insulin responses (r = -0.72; P less than 0.02); however, insulin sensitivity in diabetic subjects with little insulin secretion (0.6 +/- 0.2) was comparable to insulin sensitivity in diabetic subjects with near-normal responses (0.6 +/- 0.3). In subjects with fasting hyperglycemia, there were significant correlations between insulin sensitivity and body mass index, percent fat mass, and waist/hip ratio (all P less than 0.03). Among all female subjects, there was also a strong correlation between insulin sensitivity and upper body obesity, as measured by waist/hip ratio (r = -0.68; P less than 0.02). Model parameters also permitted glucose uptake to be estimated in diabetic vs. normal subjects at comparable hyperglycemia (11.1 mmol/L). Total glucose uptake was decreased in diabetic subjects (5.2 +/- 0.8 vs. 12.7 +/- 1.7 mg/min.kg in normals; P less than 0.001), insulin-dependent glucose uptake was diminished to a greater extent (1.3 +/- 0.4 vs. 6.2 +/- 1.2) than noninsulin-independent glucose uptake (3.9 +/- 0.5 vs. 6.4 +/- 0.9; both P less than 0.02). Administration of insulin permits minimal model FSIGT analysis to be applied to diabetic as well as normal subjects, yielding information about both insulin- and noninsulin-mediated glucose uptake as well as insulin sensitivity and insulin secretion.
---
paper_title: Insulin sensitivity, binding, and kinetics in pancreatogenic and type I diabetes

paper_content:

Pancreatogenic diabetes (PD), secondary either to chronic calcific pancreatitis or to pancreatectomy, is characterized by higher frequency of hypoglycemic events during insulin therapy in comparison with type I insulin-dependent diabetes (IDD). Not only glucagon deficiency, but an enhanced peripheral tissue sensitivity to insulin could account for this metabolic behavior. We investigated several facets of insulin action, e.g., tissue sensitivity to insulin, insulin binding to red cells, and insulin kinetics in seven patients with PD in comparison with type I. Tissue sensitivity to insulin was evaluated by means of the glucose-insulin clamp technique as M/I x 100 ratio (mg . kg .-1 min-1/muU . ml-1), where M is the amount of glucose infused by Biostator GCIIS to clamp BG at basal level and I is the free insulin plateau concentration achieved by a primed-constant insulin infusion. At high BG 15 h after the last injection of regular insulin M/I x 100 was 7.79 (range 4.25-9.75) in PD and 4.20 (range 1.20-6.91) in D (P less than 0.05). At low and equal BG M/I x 100 was 8.55 (range 6.35-9.72) in PD and 3.42 (range 1.19-6.75) in D (P less than 0.01). The rate of endogenous glucose production was nearly totally suppressed in both groups of patients. Just before the two clamps, 125I-insulin specific binding to red cells was studied. The maximum specific binding was significantly higher in PD than in D at high BG (10.7 +/- 1.7 vs. 7.4 +/- 0.8/10(9) red cells) and at low and equal BG (12.4 +/- 1.2 vs. 6.8 +/- 0.8). Receptor concentration also was significantly higher in PD thant in D (P less than 0.02) while no significant differences were found in high affinity (Ke). Insulin kinetic data were analysed by using both "Model independent" (or noncompartmental) method and compartmental modeling. Patients with PD had significantly higher (P less than 0.05) plasma clearance of insulin.
---
paper_title: Relationship of insulin clearance and secretion to insulin sensitivity in non-diabetic Mexican Americans.

paper_content:

The antecedents of type II diabetes, while still controversial, are thought to involve decreased insulin sensitivity and compensatory hypersecretion of insulin. Mexican Americans have a three-fold excess risk of type II diabetes and non-diabetic Mexican Americans are characterized by hyperinsulinaemia and insulin resistance. Few data exist, however, on whether there are defects in insulin secretion and/or clearance in this population. We examined insulin sensitivity, secretion and clearance using combined insulin and C-peptide measurements analysed by the minimal model technique of Bergman and colleagues in 10 non-obese, normoglycaemic Mexican Americans and 11 age, sex and obesity-matched non-Hispanic whites. Mexican Americans had significantly decreased insulin sensitivity (SI 4.06 s. 7.56, P = 0.017), higher first phase insulin secretion (1.03 nM vs. 0.72 nM) and decreased insulin clearance (0.099 vs. 0.161) than non-Hispanic whites. Thus, normal Mexican Americans have higher rather than lower insulin secretion suggesting that lower insulin sensitivity may be an early defect in this ethnic group. In addition, they have reduced insulin clearance. Moreover, insulin sensitivity and insulin clearance were positively correlated. We thus speculate that decreased insulin clearance may represent a further autoregulatory mechanism in addition to increased insulin secretion to compensate for decreased insulin sensitivity.
---
paper_title: Insulin resistance in myotonic dystrophy.

paper_content:

The aim of the present study was to obtain a comprehensive picture of the rate of insulin secretion and of tissue sensitivity to the endogenous hormone in myotonic dystrophy patients (MyD). The minimal model approach was utilized for the analysis of frequently sampled intravenous glucose tolerance test data (FSIGT). This method provided the characteristic parameters: SI, insulin sensitivity index; SG fractional glucose disappearance independent of dynamic insulin; n, fractional insulin clearance; phi 1 and phi 2 first and second phase insulin delivery sensitivities to glucose stimulation. In MyD patients SI was reduced (p less than 0.01) by 71% to 1.4 +/- 0.3 x 10(-4) min-1/(microU/ml), whereas in controls it was 4.85 +/- 0.77; SG was within the normal range: 0.044 +/- 0.012 min-1 in MyD patients and 0.036 +/- 0.017 min-1 in controls; phi 1 increased in MyD patients (7.4 +/- 1.3 min (microU/ml)/(mg/dl) versus 4.1 +/- 1.2 in controls); phi 2 increased in MyD patients (126 +/- 47 x 10(4) min-2/(microU/ml)/(mg/dl) versus 17 +/- 6 in controls; p less than 0.05). MyD patients showed a normal tolerance with the glucose disappearance constant, KG within the normal range: 2.75 versus 2.62% min-1 in controls. In MyD patients insulin resistance was associated with a higher than normal insulin delivery for both secretory phases, although the second phase was responsible for releasing a greater amount of hormone. In conclusion MyD patients try to compensate for overall insulin resistance by a more marked pancreatic response.
---
paper_title: Insulin sensitivity, insulin secretion and glucose effectiveness in diabetic and non-diabetic cirrhotic patients

paper_content:

In cirrhotic patients with normal fasting glucose levels both insulin insensitivity and a blunted early insulin response to oral glucose are important determinants of the degree of intolerance to oral glucose. It is not known whether the ability of hyperglycaemia per se to enhance glucose disposal (glucose effectiveness) is also impaired. It is also unclear whether overt diabetes is due to: (1) more marked insulin insensitivity; (2) impaired insulin secretion; (3) reduced glucose effectiveness; or (4) a combination of these mechanisms. We used the "minimal model" to analyse the results of a 3-h intravenous glucose tolerance test to assess glucose effectiveness, insulin sensitivity and insulin responses in 12 non-diabetic cirrhotic patients, 8 diabetic cirrhotic patients and 10 normal control subjects. Fasting blood glucose levels were 4.8 +/- 0.2, 7.5 +/- 0.6 and 4.7 +/- 0.1 mmol/l, respectively. Fasting insulin and C-peptide levels were higher in both cirrhotic patient groups compared with control subjects. The glucose clearance between 6 and 19 min after i.v. glucose was lower in both cirrhotic groups (non-diabetic, 1.56 +/- 0.14, diabetic, 0.76 +/- 0.06, control subjects, 2.49 +/- 0.16 min-1%, both p < 0.001 vs control subjects). Serum insulin peaked at 3 and 23 min in the non-diabetic cirrhotic patients and control subjects; both peaks were higher in the non-diabetic cirrhotic patients and showed a delayed return to basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)
---
paper_title: Glucose tolerance and insulin action in rats with renovascular hypertension.

paper_content:

To test whether hypertension can cause hyperinsulinemia or insulin resistance, we performed intravenous glucose tolerance tests at 1 month and euglycemic clamps at 3 months after induction of two-kidney, one clip renovascular hypertension in rats. At 1 month, systolic pressure was higher in 21 clipped than in 12 control animals (161 +/- 5 mm Hg, range 134-187 mm Hg versus 119 +/- 3 mm Hg, range 108-146 mm Hg; p less than 0.001). Glucose tolerance, assessed as the glucose fractional disappearance rate between 3 and 11 minutes after the glucose injection, was similar in the clipped and sham groups (0.059 +/- 0.002 versus 0.056 +/- 0.002 min-1, respectively; p greater than 0.4). The total area under the insulin curve during glucose tolerance tests was also similar in the clipped and sham groups (926 +/- 95 versus 869 +/- 126 microunits/ml x min; p greater than 0.4). There was no significant relation between systolic blood pressure and insulin area during glucose tolerance tests in the clipped group, but there was a positive rectilinear relation in the control group (r = 0.66; p = 0.01). Fourteen animals had euglycemic clamps 2 months after glucose tolerance tests. At that time, systolic pressure (direct femoral measurement) was higher in the seven clipped animals (189 +/- 13 mm Hg versus 122 +/- 5 mm Hg in controls; p less than 0.001). Insulin infusions of 1 and 4 milliunits/min/kg body wt effected similar plasma insulin levels in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
---
paper_title: Reduced insulin sensitivity in nondiabetic, HLA-identical siblings of insulin-dependent diabetic subjects.

paper_content:

Nondiabetic, HLA-identical siblings of insulin-dependent diabetic subjects have an increased risk of developing diabetes. Since insulin resistance is present in newly diagnosed diabetic subjects, we studied 12 HLA-identical siblings to determine whether they have impaired insulin sensitivity. Each sibling was carefully matched for age, sex, and body weight to a control from a nondiabetic family. The insulin sensitivity index (SI) was determined after an intravenous glucose tolerance test (IVGTT) using the minimal model of insulin kinetics. The insulin sensitivity index was significantly lower in the HLA-identical siblings compared with their matched controls.
---
paper_title: Glucose disposal, β-cell secretion, and hepatic insulin extraction in cirrhosis: A minimal model assessment

paper_content:

Abstract Factors controlling glucose metabolism after IV load were studied in nine patients with compensated cirrhosis and in six age-matched controls. The time courses of glucose, insulin, and C peptide were analyzed by means of the minimal model technique. In cirrhosis, insulin sensitivity was reduced by approximately 70% and glucose-dependent glucose uptake (glucose effectiveness) by 45%. Decreased glucose effectiveness explained 65% of the variance of glucose disappearance and correlated with the ratio of urinary creatinine to height, an independent measure of muscle mass ( r = 0.839). β-cell responsiveness to glucose, measured on C-peptide kinetics, was variable and increased on average by 170% and 107% (first-phase and second-phase, respectively). The total amount of insulin secreted by β-cells in the course of the study was nearly doubled, whereas the basal insulin secretion rate was in the normal range. The time courses of hepatic extraction of insulin did not differ between groups, and basal extraction was on average 58% in controls and 56% in patients with cirrhosis. It was reduced to 30% in a single patient who had severe hepatocellular failure and large spontaneous portosystemic shunting. We conclude that the alterations in glucose metabolism of cirrhosis include a decreased insulin sensitivity, a reduced glucose effectiveness, and an increased pancreatic responsiveness to glucose, leading to hyperinsulinemia. The hepatic extraction of insulin is reduced only in the very advanced stages of the disease, possibly because of a large reserve capacity of the hepatic parenchyma.
---
paper_title: Simultaneous parameter estimation and segmentation of Gibbs random fields using simulated annealing

paper_content:

An adaptive segmentation algorithm is developed which simultaneously estimates the parameters of the underlying Gibbs random field (GRF)and segments the noisy image corrupted by additive independent Gaussian noise. The algorithm, which aims at obtaining the maximum a posteriori (MAP) segmentation is a simulated annealing algorithm that is interrupted at regular intervals for estimating the GRF parameters. Maximum-likelihood (ML) estimates of the parameters based on the current segmentation are used to obtain the next segmentation. It is proven that the parameter estimates and the segmentations converge in distribution to the ML estimate of the parameters and the MAP segmentation with those parameter estimates, respectively. Due to computational difficulties, however, only an approximate version of the algorithm is implemented. The approximate algorithm is applied on several two- and four-region images with different noise levels and with first-order and second-order neighborhoods. >
---
paper_title: Stochastic relaxation, Gibbs distributions and the Bayesian restoration of images*

paper_content:

We make an analogy between images and statistical mechanics systems. Pixel gray levels and the presence and orientation of edges are viewed as states of atoms or molecules in a lattice-like physical system. The assignment of an energy function in the physical system determines its Gibbs distribution. Because of the Gibbs distribution, Markov random field (MRF) equivalence, this assignment also determines an MRF image model. The energy function is a more convenient and natural mechanism for embodying picture attributes than are the local characteristics of the MRF. For a range of degradation mechanisms, including blurring, non-linear deformations, and multiplicative or additive noise, the posterior distribution is an MRF with a structure akin to the image model. By the analogy, the posterior distribution defines another (imaginary) physical system. Gradual temperature reduction in the physical system isolates low-energy states (‘annealing’), or what is the same thing, the most probable states under the Gib...
---
paper_title: An adaptive clustering algorithm for image segmentation

paper_content:

The problem of segmenting images of objects with smooth surfaces is considered. The algorithm that is presented is a generalization of the K-means clustering algorithm to include spatial constraints and to account for local intensity variations in the image. Spatial constraints are included by the use of a Gibbs random field model. Local intensity variations are accounted for in an iterative procedure involving averaging over a sliding window whose size decreases as the algorithm progresses. Results with an 8-neighbor Gibbs random field model applied to pictures of industrial objects, buildings, aerial photographs, optical characters, and faces show that the algorithm performs better than the K-means algorithm and its nonadaptive extensions that incorporate spatial constraints by the use of Gibbs random fields. A hierarchical implementation is also presented that results in better performance and faster speed of execution. The segmented images are caricatures of the originals which preserve the most significant features, while removing unimportant details. They can be used in image recognition and as crude representations of the image. >
---
paper_title: Continuous voxel classification by stochastic relaxation: theory and application to MR imaging and MR angiography

paper_content:

Abstract In this paper we present a stochastic relaxation method for voxel classification in magnetic resonance (MR) images. This method is based on Bayesian decision theory. In this framework, the optimal classification corresponds to the minimum of an objective function, which is here defined as the expected number of misclassified voxels. The objective function encodes constraints according to two a priori models: the scene model and the camera model. The scene model reflects a priori knowledge of anatomy and morphology; the camera model relates observed MR-image intensities to anatomical objects. Both models are described using the concept of Markov random fields (MRF). This allows continuity and local contextual constraints to be easily modelled via the associated Gibbs Potential Functions. The minimum of the objective function is approximated asymptotically by stochastically sampling the associated Gibbs posterior joint probability distribution. The method is applied to brain tissue classification in MRI and blood vessel classification in MR angiograms. Each application contains a novel aspect: in the former, we introduce topological constraints on neighbouring tissues; in the latter, we incorporate shape constraints on cylindrical structures.
---
paper_title: 3D reconstruction of the brain from magnetic resonance images using a connectivity algorithm.

paper_content:

We present high resolution three dimensional (3D) connectivity, surface construction and display algorithms that detect, extract, and display the surface of a brain from contiguous magnetic resonance (MR) images. The algorithms identify the external brain surface and create a 3D image, showing the fissures and surface convolutions of the cerebral hemispheres, cerebellum, and brain stem. Images produced by these algorithms also show the morphology of other soft tissue boundaries such as the cerebral ventricular system and the skin of the patient. For the purposes of 3D reconstruction, our experiments show that T1 weighted images give better contrast between the surface of the brain and the cerebral spinal fluid than T2 weighted images. 3D reconstruction of MR data provides a non-invasive procedure for examination of the brain surface and other anatomical features.
---
paper_title: Multiresolution Adaptive K-means Algorithm for Segmentation of Brain MRI

paper_content:

Segmentation of MR brain scans has received an enormous amount of attention in the medical imaging community over the past several years. In this paper we propose a new and general segmentation algorithm involving 3D adaptive K-Means clustering in a multiresolution wavelet basis. The voxel image of the brain is segmented into five classes namely, cerebrospinal fluid, gray matter, white matter, bone and background (remaining pixels). The segmentation problem is formulated as a maximum a posteriori (MAP) estimation problem wherein, the prior is assumed to be a Markov Random Field (MRF). The MAP estimation is achieved using an iterated conditional modes technique (ICM) in wavelet basis. Performance of the segmentation algorithm is demonstrated via application to phantom images as well as MR brain scans.
---
paper_title: Three-dimensional segmentation and interpolation of magnetic resonance brain images.

paper_content:

The authors propose a method for the 3-D reconstruction of the brain from anisotropic magnetic resonance imaging (MRI) brain data. The method essentially consists in two original algorithms both for segmentation and for interpolation of the MRI data. The segmentation process is performed in three steps. A gray level thresholding of the white and gray matter tissue is performed on the brain MR raw data. A global white matter segmentation is automatically performed with a global 3-D connectivity algorithm which takes into account the anisotropy of the MRI voxel. The gray matter is segmented with a local 3-D connectivity algorithm. Mathematical morphology tools are used to interpolate slices. The whole process gives an isotropic binary representation of both gray and white matter which are available for 3-D surface rendering. The power and practicality of this method have been tested on four brain datasets. The segmentation algorithm favorably compares to a manual one. The interpolation algorithm was compared to the shaped-based method both quantitatively and qualitatively.
---
paper_title: Statistical analysis of dirty pictures

paper_content:

A continuous two-dimensional region is partitioned into a fine rectangular array of sites, or ‘pixels', each pixel having a particular '‘colour’ belonging to a prescribed finite set. The true colouring of the region is unknown but, associated with each pixel, there is a possibly multivariate record which conveys imperfect information about its colour according to a known statistical model. The aim is to reconstruct the true scene, with the additional knowledge that pixels close together tend to have the same or similar colours. In this paper, it is assumed that the local characteristics of the true scene can be represented by a non-degenerate Markov random field. Such information can be combined with the records by Bayes' theorem and the true scene can be estimated according to standard criteria. However, the computational burden is enormous and the reconstruction may reflect undesirable large-scale properties of the random field. Thus, a simple, iterative method of reconstruction is proposed, which does ...
---
paper_title: Multi-Resolution Stochastic 3D Shape Models for Image Segmentation

paper_content:

3D Shape modeling has been a very prominent part of Computer Vision over the past decade. Several shape modeling techniques have been proposed in literature, some are local (distributed parameter) while others are global (lumped parameter) in terms of the parameters required to describe the shape. Hybrid models that combine both ends of this parameter spectrum have been in vogue only recently. However, they do not allow a smooth transition between the two extremes of this parameter spectrum.
---
paper_title: Pinta: a system for visualizing the anatomical structures of the brain from MR imaging

paper_content:

Pinta is a system for segmentation and visualization of anatomical structures obtained from serial sections reconstructed from magnetic resonance imaging. The system approaches the segmentation problem by assigning each volumetric region to an anatomical structure. This is accomplished by satisfying constraints at the pixel level, slice level, and volumetric level. Each slice is represented by an attributed graph, where nodes correspond to regions and links correspond to the relations between regions. These regions are obtained by grouping pixels based on similarity and proximity. The slice level attributed graphs are then coerced to form a volumetric attributed graph, where volumetric consistency can be verified. The volumetric graph is used to ensure consistency from symbolic representations obtained from individual slices. The system allows errors to be made at the slice level, yet removes them when the volumetric consistency cannot be verified. Once the segmentation is complete, the 3D surfaces of the brain can be constructed and visualized. >
---
paper_title: Assessment of autonomic function in humans by heart rate spectral analysis.

paper_content:

Spectral analysis of spontaneous heart rate fluctuations were assessed by use of autonomic blocking agents and changes in posture. Low-frequency fluctuations (below 0.12 Hz) in the supine position are mediated entirely by the parasympathetic nervous system. On standing, the low-frequency fluctuations increase and are jointly mediated by the sympathetic and parasympathetic nervous systems. High-frequency fluctuations, at the respiratory frequency, are decreased by standing and are mediated solely by the parasympathetic system. Heart rate spectral analysis is a powerful noninvasive tool for quantifying autonomic nervous system activity.
---
paper_title: Spectral and cross-spectral analysis of heart rate and arterial blood pressure variability signals

paper_content:

Abstract A parametric method for autoregressive (AR) auto- and cross-spectral analysis is presented for the contemporaneous processing of heart rate and arterial blood pressure variability signals. In particular, the introduced bivariate spectral analysis (phase and coherence spectra) provides quantitative and objective means which are useful to measure the role played by the neural controlling systems (sympathetic and parasympathetic systems) on the cardiovascular signals under different pathophysiological conditions. Algorithmic aspects, connected to the way of processing discrete numerical series synchronized to single cardiac beats, are particularly stressed. Important applications are foreseen both in physiological studies and in clinical practice as an aid to the detection of various relevant cardiovascular pathologies such as hypertension and diabetes.
---
paper_title: Estimation of parameters for a linear difference equation with application to EEG analysis

paper_content:

Abstract A linear difference equation is used as a model to generate a stationary discrete sequence of random variables. From the experimental data the parameters are estimated by first computing the first 100 correlation coefficients and then applying one of two available algorithms. The first algorithm gives a maximum likelihood estimate by replacing the original equation with an autoregressive scheme and a moving average scheme. The parameters of the latter are estimated by numerical optimization, while the others are obtained in closed form. For a system of order p it is sufficient to optimize in q ⩽ p variables. The second algorithm is based on a linear recursive relation for the correlation coefficients. It is considerably faster than the first one but gives about the same accuracy expressed in terms of maximum or mean square error for the reconstructed correlation coefficients. The estimation procedures are tried on a few recorded EEG signals and it is found that typically a fifth-order system suffices to give an accuracy of about 5% for the correlation coefficients. The sampling interval is found to be of considerable importance. It is argued that our model may be used with advantage to define suitable parameters to described the stationary parts of EEG signals; two sets of parameters are actually discussed.
---
paper_title: OPTIMIZATION OF THE ABSORBED POWER DISTRIBUTION FOR AN ANNULAR PHASED ARRAY HYPERTHERMIA SYSTEM

paper_content:

Abstract One of the systems under investigation for producing hyperthermia noninvasively for treating deep-seated tumors is the annular phased array. This device consists of two rings of eight electromagnetic apertures that are placed concentrically about the long axis of the patient and radiate energy toward the center. Previous theoretical and clinical studies have concentrated primarily on systems where the amplitude and phase of the signal applied to each aperture were the same, and these studies have shown that the system is capable of depositing power deep within the patient. Nevertheless, in many situations the system was not capable of producing desirable temperature distributions in the tumor and normal tissue. In this paper we report on a 2-dimensional theoretical investigation where an optimization routine was used to select the amplitude and phases of each of eight apertures. The optimization procedure and resulting calculations were based on CT scans of patients with tumors. The electrical and thermal properties of the different organs and tissues were taken into account. The optimization routine tried to achieve uniform absorbed power in the tumor region with zero absorbed power outside. Using the optimized amplitudes and phases, the SAR (specific absorption rate, W/kg) was calculated for the array. The results show that in general the optimization procedure was successful in that the power deposited within the tumor volume was increased with less power deposited into normal tissue when compared to the equal amplitude and phase case. This SAR data was then used as the input to a program based on the bioheat transfer equation, which calculated the temperature distribution in the patient model for an assumed set of blood perfusion rates. Depending on the location, size of the tumor, and blood perfusion rates, the improvement in the percentage of the tumor brought to therapeutic temperature varied from 0% to as much as 80%.
---
paper_title: Strategies for optimized application of annular-phased-array systems in clinical hyperthermia

paper_content:

A theoretical framework is presented for optimized heating of deep-seated tumours by phase and amplitude steering. The optimization problem for a specific tumour and perfusion case results in a functional dependency between power-level and maximum obtainable therapeutic efficiency. Different optimization criteria and strategies are outlined, which cause an increase of power or thermal dose in the tumour. Three tumour models (central pelvic tumour, eccentric abdominal tumour with or without necrosis) are analysed in detail. The simulation studies predict that appreciable parts of these tumours (50–100%) can be heated efficiently (42.5–43°C) within the range of available and clinically tolerated power levels (1–5 kW/m), if tumour perfusion is less than 20–25 ml/100 g min. Some improvements are obtained by increasing the number of independent channels (from four to eight) and by the application of time-dependent (complementary) power-deposition patterns.
---
paper_title: Optimum excitation of phases and amplitudes in a phased array hyperthermia system

paper_content:

In order to achieve a desired temperature distribution inside and outside of malignant tissues, optimization techniques could be used in phased array hyperthermia systems to control effectively the amplitude and phase of the radiating elements. The optimization of a four-element phased array hyperthermia system operating at 432 MHz is examined theoretically. The proposed technique is based on a detailed physical model of the tissue medium to be heated in terms of both electromagnetic and thermal properties. A penalty function technique using a Newton method is applied to determine the optimum phases and amplitudes of the array. Several array geometrics have been studied and numerical results are presented.
---
paper_title: SAR optimization in a phased array radiofrequency hyperthermia system

paper_content:

RF deep hyperthermia systems make use of phased arrays of applicators in order to heat tumors selectively while maintaining healthy tissue at normal temperatures. A new method for the array synthesis is proposed based on the identification of targets to be heated (tumors) and targets to be prevented from excess electromagnetic radiation. The best array feed for each target is found from the solution of the eigenvector problem for a positive definite Hermitian matrix defined for that target. The optimal feed in a global sense then results from a trade-off of the best feeds of individual targets enforced through minimization of an objective function aimed at weighting the distances of the globally optimal feed from the feed vectors optimized for each target separately. An application to the heating of a pelvis is provided as an example.
---
paper_title: Optimization of Simulated Two-Dimensional Temperature Distributions Induced by Multiple Electromagnetic Applicators

paper_content:

A computer simulation to calculate transient temperature distributions in realistic cross sections of the human body is described. In the simulation, the therapeutic effect of hyperthermia administration is maximized by optimum use of the electromagnetic applicators. The time-dependent mathematical optimum for the levels of energy going to the applicators as well as for the waterbolus separating the applicators from the patients is computed. Among other applications, this modeling is useful for predicting limitations to certain types of hypertherrnia systems, and has the potential for realistic computer-aided therapy planning. As an example, the treatment planning for a tumor in the lower limb is given in the case of incoherent sources.
---
paper_title: Important prognostic factors influencing outcome of combined radiation and hyperthermia

paper_content:

Abstract Clinical experience with combined local-regional hyperthermia and radiation therapy has been rapidly accumulating over the past few decades. Its superior efficacy to the use of radiation alone has been demonstrated in several retrospective and prospective reports in the literature. It is evident now that there are several important factors that will influence the final outcome of the treated patients. The parameters that will be discussed in this paper include: I. Pretreatments factors: 1. tumor dimension 2. tumor histology 3. tumor site. II. Treatment factors: 1. radiation therapy dose 2. hyperthermia parameters: (a) thermal variables (b) number of heat treatments (c) sequence of hyperthermia and radiation treatments (d) hyperthermic device. Finally, evaluation of response and complications will also be discussed. The importance of abiding by an accepted reporting system will be emphasized, and clarification of times at which response assessments were made will also be discussed. With the availability of longer term follow-up, use of an actuarial method of reporting becomes more important. The future of hyperthermia and radiation remains very promising but a lot of questions still need to be answered by well-conducted and reported clinical trials.
---

Title: Operational Research Techniques in Medical Treatment and Diagnosis: A Review

Section 1: Introduction
Description 1: This section discusses the background and motivation for the review, outlining the main objectives and the framework of the paper, including an overview of operational research techniques in medical treatment and diagnosis.

Section 2: Dynamic System Modelling
Description 2: This section provides a brief description of nonlinear system models, including available identification and control methods, and introduces new suggested methods.

Section 2.1: Dynamical Systems and their Properties
Description 2.1: This subsection reviews the main properties of dynamical systems and their fundamental definitions, including stability, controllability, and observability.

Section 2.2: Dynamic System Identification
Description 2.2: This subsection discusses identification techniques for dynamic systems, including traditional and advanced methods for system estimation.

Section 2.3: Nonlinear Estimation with Constraints
Description 2.3: This subsection explores nonlinear estimation methods involving constrained optimization for achieving statistically correct estimates.

Section 2.4: Simultaneous Estimation and Optimisation
Description 2.4: This subsection presents methods for simultaneous estimation and optimization in nonlinear dynamic models.

Section 3: Dynamic Modelling in Medicine
Description 3: This section discusses how dynamic system theory applies to medical diagnosis and treatment, emphasizing its importance and potential benefits.

Section 4: Applications of Dynamical Modelling
Description 4: This section illustrates practical applications of dynamic modelling in various medical problems, including specific examples.

Section 4.1: Glucose-Insulin Kinetics
Description 4.1: This subsection discusses dynamic models for glucose and insulin kinetics, particularly in the diagnosis and treatment of diabetes.

Section 4.2: Magnetic Resonance Imaging Segmentation
Description 4.2: This subsection addresses the application of operational research techniques to segmenting brain MRI images for medical analysis.

Section 4.3: Analysis of Heart Dynamics
Description 4.3: This subsection explores models for heart dynamics, focusing on how heart rate and blood pressures can be analysed and controlled using dynamic systems.

Section 4.4: Optimisation in Hyperthermic Treatment
Description 4.4: This subsection examines the use of dynamic models to optimize hyperthermic treatments for cancer by controlling heat delivery to tumors.

Section 5: Conclusions
Description 5: This section summarizes the findings of the review, emphasizing key points and future directions for research in dynamic modelling of medical phenomena.