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Contains fulltext : 174792.pdf (Publisher’s version ) (Closed access) Glucose plasma measurements for diabetes patients are generally presented as a glucose concentration-time profile with 15-60min time scale intervals. This limited resolution obscures detailed dynamic events of glucose appearance and metabolism. Measurement intervals of 15min or more could contribute to imperfections in present diabetes treatment. High resolution data from mixed meal tolerance tests (MMTT) for 24 type 1 and type 2 diabetes patients were used in our present modeling. We introduce a model based on the physiological properties of transport, storage and utilization. This logistic approach follows the principles of electrical network analysis and signal processing theory. The method mimics the physiological equivalent of the glucose homeostasis comprising the meal ingestion, absorption via the gastrointestinal tract (GIT) to the endocrine nexus between the liver, pancreatic alpha and beta cells. This model demystifies the metabolic 'black box' by enabling in silico simulations and fitting of individual responses to clinical data. Five-minute intervals MMTT data measured from diabetic subjects result in two independent model parameters that characterize the complete glucose system response at a personalized level. From the individual data measurements, we obtain a model which can be analyzed with a standard electrical network simulator for diagnostics and treatment optimization. The insulin dosing time scale can be accurately adjusted to match the individual requirements of characterized diabetic patients without the physical burden of treatment.

textabstractIn the province-wide colorectal cancer (CRC) screening program in Ontario, Canada, individuals with a family history of CRC are offered colonoscopy screening and those without are offered guaiac fecal occult blood testing (gFOBT, Hemoccult II). We used microsimulation modeling to estimate the cumulative number of CRC deaths prevented and colonoscopies performed between 2008 and 2038 with this family history-based screening program, compared to a regular gFOBT program. In both programs, we assumed screening uptake increased from 30% (participation level in 2008 before the program was launched) to 60%. We assumed that 11% of the population had a family history, defined as having at least one first-degree relative diagnosed with CRC. The programs offered screening between age 50 and 74 years, every two years for gFOBT, and every ten years for colonoscopy. Compared to opportunistic screening (2008 participation level kept constant at 30%), the gFOBT program cumulatively prevented 6,700 more CRC deaths and required 570,000 additional colonoscopies by 2038. The family history-based screening program increased these numbers to 9,300 and 1,100,000, a 40% and 93% increase, respectively. If biennial gFOBT was replaced with biennial fecal immunochemical test (FIT), annual Hemoccult Sensa or five-yearly sigmoidoscopy screening, both the added benefits and colonoscopies required would decrease. A biennial gFOBT screening program that identifies individuals with a family history of CRC and recommends them to undergo colonoscopy screening would prevent 40% (range in sensitivity analyses: 20-51%) additional deaths while requiring 93% (range: 43-116%) additional colonoscopies, compared to a regular gFOBT screening program. What's new? One of the first population-based screening programs for colorectal cancer (CRC) to offer colonoscopy for individuals with a family history of the disease is Canada's ColonCancerCheck. The present study estimated the long-term effects of the program, to 2038, via microsimulation modeling. Compared with a program based on guaiac fecal occult blood testing (gFOBT) alone, the family history-based program was projected to prevent 40% more deaths. The incorporation of family history-based colonoscopy into CRC screening was estimated to increase demand for the procedure by 93%.

Background:Many individuals have not received recommended colorectal cancer (CRC) screening before they become Medicare eligible at the age of 65. We aimed to estimate the long-term implications of increased CRC screening in the pre-Medicare population (50-64 y) on costs in the pre-Medicare and Medicare populations (65+ y).Methods:We used 2 independently developed microsimulation models [Microsimulation Screening Analysis Colon (MISCAN) and Simulation Model of CRC (SimCRC)] to project CRC screening and treatment costs under 2 scenarios, starting in 2010: current trends (60% of the population up-to-date with screening recommendations) and enhanced participation (70% up-to-date). The population was scaled to the projected US population for each year between 2010 and 2060. Costs per year were derived by age group (50-64 and 65+ y).Results:By 2060, the discounted cumulative total costs in the pre-Medicare population were $35.7 and $28.1 billion higher with enhanced screening participation, than in the current trends scenario ($252.1 billion with MISCAN and $239.5 billion with SimCRC, respectively). Because of CRC treatment savings with enhanced participation, cumulative costs in the Medicare population were $18.3 and $32.7 billion lower (current trends: $423.5 billion with MISCAN and $372.8 billion with SimCRC). Over the 50-year time horizon an estimated 60% (MISCAN) and 89% (SimCRC) of the increased screening costs could be offset by savings in Medicare CRC treatment costs.Conclusion:Increased CRC screening participation in the pre-Medicare population could reduce CRC incidence and mortality, whereas the additional screening costs can be largely offset by long-term Medicare treatment savings.

The effects of a single oral dose of liothyronine (L-T3) on thyroid stimulating hormone (TSH) and other related thyroid system parameters are partly understood despite therapeutic use of this hormone over many decades. We characterize individualized responses of the hypothalamus-pituitary-thyroid (HPT) axis and its related temporal hormonal profile using an electrical network model. Based on thyroid hormone responses from blood samples using a single 50[Formula: see text][Formula: see text]g oral dose of liothyronine in healthy persons with a normal operating euthyroid feedback HPT system, we derived an equivalent electrical circuit model for the system’s responses. The mathematical model was tested with a circuit simulator and validated with individualized clinical data. This signal processing technique makes the evaluation of bioequivalence and bioavailability of various preparations of liothyronine at an individualized level a feasible endeavor for clinical application.

Item does not contain fulltext The components of thyrotropic feedback control are well established in mainstream physiology and endocrinology, but their relation to the whole system's integrated behavior remains only partly understood. Most modeling research seeks to derive a generalized model for universal application across all individuals. We show how parameterizable models, based on the principles of control theory, tailored to the individual, can fill these gaps. We develop a system network describing the closed-loop behavior of the hypothalamus-pituitary (HP)-thyroid interaction and the set point targeted by the control system at equilibrium. The stability of this system is defined by using loop gain conditions. Defined points of homeostasis of the hypothalamus-pituitary-thyroid (HPT) feedback loop found at the intersections of the HP and thyroid transfer functions at the boundaries of normal reference ranges were evaluated by loop gain calculations. At equilibrium, the feedback control approaches a point defined in both dimensions by a [TSH]-[FT4] coordinate for which the loop gain is greater than unity. This model describes the emergence of homeostasis of the HPT axis from characteristic curves of HP and thyroid, thus supporting the validity of the translation between physiological knowledge and clinical reference ranges.

Item does not contain fulltext The hypothalamus-pituitary-thyroid (HPT) axis represents a complex, non-linear thyroid hormone system in vertebrates governed by numerous variables. The common modeling approach until now aims at a comprehensive inclusion of all known physiological influences. In contrast, we develop a parsimonious mathematical model that integrates the hypothalamus-pituitary (HP) complex as an endocrinologic unit based on a parameterized negative exponential function between free thyroxine (FT4) as stimulus and thyrotropin (thyroid stimulating hormone, TSH) as response. Model validation with clinical data obtained from geographically different hospitals revealed a goodness-of-fit largely ranging between 90%

Background Despite rendering serum free thyroxine (FT4) and thyrotropin (TSH) within the normal population ranges broadly defined as euthyroidism, many patients being treated for hyperthyroidism and hypothyroidism persistently experience subnormal well-being discordant from their pre-disease healthy euthyroid state. This suggests that intra-individual physiological optimal ranges are narrower than laboratory-quoted normal ranges and implies the existence of a homeostatic set point encoded in the hypothalamic-pituitary-thyroid (HPT) axis that is unique to every individual. Methods We have previously shown that the dose–response characteristic of the hypothalamic-pituitary (HP) unit to circulating thyroid hormone levels follows a negative exponential curve. This led to the discovery that the normal reference intervals of TSH and FT4 fall within the ‘knee’ region of this curve where the maximum curvature of the exponential HP characteristic occurs. Based on this observation, we develop the theoretical framework localizing the position of euthyroid homeostasis over the point of maximum curvature of the HP characteristic. Results The euthyroid set points of patients with primary hypothyroidism and hyperthyroidism can be readily derived from their calculated HP curve parameters using the parsimonious mathematical model above. It can be shown that every individual has a euthyroid set point that is unique and often different from other individuals. Conclusions In this treatise, we provide evidence supporting a set point-based approach in tailoring euthyroid targets. Rendering FT4 and TSH within the laboratory normal ranges can be clinically suboptimal if these hormone levels are distant from the individualized euthyroid homeostatic set point. This mathematical technique permits the euthyroid set point to be realistically computed using an algorithm readily implementable for computer-aided calculations to facilitate precise targeted dosing of patients in this modern era of personalized medicine.

Background. This treatise investigates error sources in measurements applicable to the hypothalamus-pituitary-thyroid (HPT) system of analysis for homeostatic set point computation. The hypothalamus-pituitary transfer characteristic (HP curve) describes the relationship between plasma free thyroxine [FT4] and thyrotropin [TSH].Objective. We define the origin, types, causes, and effects of errors that are commonly encountered in TFT measurements and examine how we can interpret these to construct a reliable HP function for set point establishment.Design and Methods. The error sources in the clinical measurement procedures are identified and analyzed in relation to the constructed HP model.Results. The main sources of measurement and interpretation uncertainties are (1) diurnal variations in [TSH], (2) TFT measurement variations influenced by timing of thyroid medications, (3) error sensitivity in ranges of [TSH] and [FT4] (laboratory assay dependent), (4) rounding/truncation of decimals in [FT4] which in turn amplify curve fitting errors in the [TSH] domain in the lower [FT4] range, (5) memory effects (rate-independent hysteresis effect).Conclusions. When the main uncertainties in thyroid function tests (TFT) are identified and analyzed, we can find the most acceptable model space with which we can construct the best HP function and the related set point area.

The analysis was limited to patients who survived at least 5 years and patients were censored at the time of the next colonoscopy or five years after the index procedure. Factors predictive of repeat colonoscopy were examined with univariate analysis and a multivariable logistic model was used to determine predictors of repeat colonoscopy within five years. Results: A total of 7,507 patients were included in the study. Through the end of the five year follow up, 33.3% received another colonoscopy and 24.2% underwent repeat polypectomy. FOBT, flexible sigmoidoscopy and barium enema were performed in 34.8%, 3.9% and 3.1%, respectively. We observed a marked decrease in repeat colonoscopy at 1, 3 and 5 years with more recent years of index procedures (Table). Other predictors of undergoing repeat colonoscopy were younger age, lower comorbidity score, colonoscopy within 5 years prior to the index procedure, and a previous diagnosis of IBD or carcinoma in situ. There was no clinically significant association with physician specialty, geographic location or small area socioeconomic variables. The decreasing use of colonoscopy with time was maintained in a multivariable analysis (multivariable odds ratio (OR) 2002: 0.81, 95% CI 0.74-0.90; OR 2003: 0.72, 95% CI 0.65-0.80; OR 0.59, 95% CI 0.53-0.66). Conclusions: In this population-based sample, we have documented underuse of follow up colonoscopy at 5 years after polypectomy. In particular, the use of this procedure has decreased over the four-year study period. Coupled with other data showing overuse of follow up colonoscopy in patients without resected polyps, the findings suggest significant discordance between guidelines and actual practice.

Introduction: Fecal immunochemical tests (FIT) have suboptimal sensitivity for advanced neoplasia and require successive screening rounds for an optimal preventive effect. However, data about the influence of screening interval length on attendance and diagnostic yield are lacking, nor is it known whether the increased sensitivity of FIT compared to the conventional guaiac-based FOBT allows for longer screening intervals. We therefore performed repeated FIT screening in a population-based trial comparing 1, 2, and 3 year intervals. Methods: Three representative samples of the Dutch population (total=7,500) aged 50-75 years were randomly selected prior to invitation. Individuals were invited for two 1-sample FIT screening rounds (cut-off ≥ 50 ng Hb/mL) with intervals of respectively 1 (group A), 2 (B), or 3 years (C). Subjects with a positive FIT in the 1st screening round, and those who had moved away/died were not invited for the 2nd round. Results: In group A, attendance was 64.6% (1,544/2,391) in the 1st and 62.7% (n=1,302/2,077) in the 2nd screening round. Of the 1st round participants, 89.8% also attended the 2nd screening round. Of the non-participants in the 1st screening round, 16.3% did participate in the 2nd round. We refer to Table 1 for group B and C. Corrected for 1st round attendance, a longer screening interval improved participation in the 2nd FIT-based screening round (group A (reference) 89.8% vs. group B 90.9%, and vs. group C 91.4%; p