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Current attempts to implement and apply automated control systems for the management of glucose homeostasis in individuals with diabetes are partly successful. In most semi and closed loop control systems to mimic the action of a normal pancreas in diabetes patients, insulin is administered subcutaneously. However, the parameters for insulin diffusion and transport time constants are relatively large and have wide individual variations. Therefore, deviation from a normal meal can result in suboptimal euglycemic control. Stable and reliable closed loop feedback control using continuous glucose monitoring under these conditions is difficult and needs regular interventions from the user. This article describes the translation of the endocrine physiology of a normal pancreas to an electronic equivalent. With this translation, the complex effects of a direct intravenous pulsatile method of insulin and glucagon administration can be simulated in accordance with physiological observations in a healthy subject and has been built with standard electronic components. This device is applicable for any individual and under any condition to automatically maintain the desired optimal euglycemic condition. The insulin and glucagon response control is presented in the same physiological pulsatile manner as is observed in healthy individuals., (© 2024. The Author(s).)

In clinical endocrinology, it is often assumed that the results of thyroid hormone function tests (TFTs) before total thyroidectomy are considered euthyroid when the circulating concentrations of thyrotropin [TSH] and free thyroxine [FT4] are within the normal reference ranges. Postoperative thyroid replacement therapy with levothyroxine. The aim of L-T4 is to reproduce the preoperative euthyroid condition. Currently, intra-individual changes in the euthyroid set point before and after total thyroidectomy are only partly understood. After total thyroidectomy, a greater postoperative [FT4] than preoperative [FT4] for equivalent euthyroid [TSH] was found, with differences ranging from 3 to 8 pmol/L. This unexplained difference can be explained by the use of a mathematical model of the hypothalamus-pituitary-thyroid (HPT) axis set point theory. In this article, the postoperative HPT euthyroid set point was calculated using a dataset of total thyroidectomized patients with at least three distinguishable postoperative TFTs. The postoperative [TSH] set point was used as a homeostatic reference for the comparison of preoperative TFTs. The preoperative [FT4] value was equal to the postoperative [FT4] value in 50% of the patients, divided by a factor of ~ 1.25 (within +/- 10%). The factor of 1.25 stems from the lack of postoperative use of thyroidal triiodothyronine (T3). Furthermore, approximately 25% of the patients presented a greater preoperative [FT4] difference than postoperative [FT4]/1.25 combined with a normal [TSH] difference. Based on these observations, the effect of T3 on the value of the [FT4] set point was analyzed and explained from a control theory perspective., (© 2024. Prof. Dr. Jan van der Hoeven stichting voor theoretische biologie.)

With the current clinical method for the treatment of hypothyroidism the target for the optimum individual values for free thyroxine concentrations [FT4] and thyrotropine concentrations [TSH] of the specific patient are unknown. This situation leads to unnecessary long experimental medication administration that can take a period of sometimes one year. In this article a method will be described where hypothyroid patients are characterized with weekly measured FT4 and TSH concentrations during the first three weeks of synthetic thyroxine or levothyroxine (L-T4) treatment to predict their optimum [FT4] and belonging [TSH] endpoint for a euthyroid homeostatic state. The treatment with levothyroxine will start for all patients with a reference dose of 100 µg, which can be adjusted by the treating physician to a more safe and appropriate dose for the individual which is monitored with weekly thyroid function tests to observe the progress. After three weeks all characteristics of the patient can be inferred from the measured data. The final titration target together with the individual thyroxine half life can be calculated. With the known characteristics and the L-T4 titration target the clinician or treating physician has an instrument to reduce the experimental treatment burden for the patient from one year to a maximum of four weeks., (© 2023. Prof. Dr. Jan van der Hoeven stichting voor theoretische biologie.)

Purpose To compare the cost-effectiveness of computed tomographic (CT) colonography and colonoscopy screening by using data on unit costs and participation rates from a randomized controlled screening trial in a dedicated screening setting. Materials and Methods Observed participation rates and screening costs from the Colonoscopy or Colonography for Screening, or COCOS, trial were used in a microsimulation model to estimate costs and quality-adjusted life-years (QALYs) gained with colonoscopy and CT colonography screening. For both tests, the authors determined optimal age range and screening interval combinations assuming a 100% participation rate. Assuming observed participation for these combinations, the cost-effectiveness of both tests was compared. Extracolonic findings were not included because long-term follow-up data are lacking. Results The participation rates for colonoscopy and CT colonography were 21.5% (1276 of 5924 invitees) and 33.6% (982 of 2920 invitees), respectively. Colonoscopy was more cost-effective in the screening strategies with one or two lifetime screenings, whereas CT colonography was more cost-effective in strategies with more lifetime screenings. CT colonography was the preferred test for willingness-to-pay-thresholds of €3200 per QALY gained and higher, which is lower than the Dutch willingness-to-pay threshold of €20 000. With equal participation, colonoscopy was the preferred test independent of willingness-to-pay thresholds. The findings were robust for most of the sensitivity analyses, except with regard to relative screening costs and subsequent participation. Conclusion Because of the higher participation rates, CT colonography screening for colorectal cancer is more cost-effective than colonoscopy screening. The implementation of CT colonography screening requires previous satisfactory resolution to the question as to how best to deal with extracolonic findings. © RSNA, 2018 Online supplemental material is available for this article.

Background & Aims: Biomarker assays could increase the accuracy of noninvasive detection of colorectal cancer (CRC); fecal immunochemical tests (FITs) are estimated to miss 27%-47% of CRCs and 70%-80% of advanced adenomas per round of screening. We investigated the conditions under which biomarker screens would be cost-effective compared with FIT screens of average-risk individuals., Methods: We used the MISCAN-Colon microsimulation model to estimate the effects of various CRC screening test characteristics on life-years gained (LYG) and; age-specific all-cause mortality was based on the 2010 Dutch life tables. Simulated CRC incidence rate and CRC stage distribution were calibrated to observed data in The Netherlands from 1999 through 2003 (before opportunities for screening). Survival rates after diagnosis of CRC at an age younger than 75 years were based on CRC relative survival data from 1985 through 2004; survival for individuals diagnosed at an age of 75 years or older was adjusted to fit the observed age-increasing mortality/incidence ratio. We modeled FIT along with hypothetical biomarker tests with different test performance levels. For each biomarker test we calculated the maximum unit cost for the test to be cost-effective compared with FIT, assuming a willingness-to-pay threshold of €50,000 ($56,000) per LYG., Results: Biennial FIT screening of subjects 55-75 years old provided 84.9 LYG at a cost of €122,000 ($137,000) per 1000 participants. Considering a unit cost of €7 ($8) for FIT (including kit and analysis only, excluding organizational costs), a biomarker test that detects CRC with higher levels of specificity and sensitivity (100%) and advanced adenomas at a proportionally higher level of sensitivity (53%) should never exceed a cost of €51 ($57). The threshold cost could increase to more than €200 ($224) for high-performing biomarker tests in cases of limited colonoscopy capacity or higher uptake of this test., Conclusions: By using the MISCAN-Colon microsimulation model to estimate effects of CRC screening tests, we found that for a biomarker test with increased overall performance to be cost-effective, it should not exceed 7-fold the unit cost of FIT. This maximum would increase substantially if colonoscopy becomes more expensive or scarce, or if the new test has higher screening uptake. These values could be used to estimate the added value of new biomarkers compared with current FIT screening., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The ColonCancerCheck screening program for colorectal cancer (CRC) in Ontario, Canada, is considering switching from biennial guaiac fecal occult blood test (gFOBT) screening between age 50-74 years to the more sensitive, but also less specific fecal immunochemical test (FIT). The aim of this study is to estimate whether the additional benefits of FIT screening compared to gFOBT outweigh the additional costs and harms., Methods: We used microsimulation modeling to estimate quality adjusted life years (QALYs) gained and costs of gFOBT and FIT, compared to no screening, in a cohort of screening participants. We compared strategies with various age ranges, screening intervals, and cut-off levels for FIT. Cost-efficient strategies were determined for various levels of available colonoscopy capacity., Results: Compared to no screening, biennial gFOBT screening between age 50-74 years provided 20 QALYs at a cost of CAN$200,900 per 1,000 participants, and required 17 colonoscopies per 1,000 participants per year. FIT screening was more effective and less costly. For the same level of colonoscopy requirement, biennial FIT (with a high cut-off level of 200 ng Hb/ml) between age 50-74 years provided 11 extra QALYs gained while saving CAN$333,300 per 1000 participants, compared to gFOBT. Without restrictions in colonoscopy capacity, FIT (with a low cut-off level of 50 ng Hb/ml) every year between age 45-80 years was the most cost-effective strategy providing 27 extra QALYs gained per 1000 participants, while saving CAN$448,300., Interpretation: Compared to gFOBT screening, switching to FIT at a high cut-off level could increase the health benefits of a CRC screening program without considerably increasing colonoscopy demand.

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 μ 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.

Background: Northeastern states of the United States have shown more progress in reducing colorectal cancer (CRC) incidence and mortality rates than Southern states, and this has resulted in considerable disparities. This study quantified how the disparities in CRC rates between Louisiana (a Southern state) and New Jersey (a Northeastern state) would be affected if differences in risk factors, screening, and stage-specific CRC relative survival between the states were eliminated., Methods: This study used the Microsimulation Screening Analysis Colon microsimulation model to estimate age-adjusted CRC incidence and mortality rates in Louisiana from 1995 to 2009 under the assumption that 1) Louisiana had the same smoking and obesity prevalence observed in New Jersey, 2) Louisiana had the same CRC screening uptake observed in New Jersey, 3) Louisiana had the same stage-specific CRC relative survival observed in New Jersey, or 4) all the preceding were true., Results: In 2009, the observed CRC incidence and mortality rates in Louisiana were 141.4 cases and 61.9 deaths per 100,000 individuals, respectively. With the same risk factors and screening observed in New Jersey, the CRC incidence rate in Louisiana was reduced by 3.5% and 15.2%, respectively. New Jersey's risk factors, screening, and survival reduced the CRC mortality rate in Louisiana by 3.0%, 10.8%, and 17.4%, respectively. With all trends combined, the modeled rates per 100,000 individuals in Louisiana became lower than the observed rates in New Jersey for both incidence (116.4 vs 130.0) and mortality (44.7 vs 55.8)., Conclusions: The disparities in CRC incidence and mortality rates between Louisiana and New Jersey could be eliminated if Louisiana could attain New Jersey's levels of risk factors, screening, and survival. Priority should be given to enabling Southern states to improve screening and survival rates., (© 2015 American Cancer Society.)

Objective: To determine adherence to recommended surveillance intervals in clinical practice., Design: 2997 successive patients with a first adenoma diagnosis (57% male, mean age 59 years) from 10 hospitals, who underwent colonoscopy between 1998 and 2002, were identified via Pathologisch Anatomisch Landelijk Geautomatiseerd Archief: Dutch Pathology Registry. Their medical records were reviewed until 1 December 2008. Time to and findings at first surveillance colonoscopy were assessed. A surveillance colonoscopy occurring within ± 3 months of a 1-year recommended interval and ± 6 months of a recommended interval of 2 years or longer was considered appropriate. The analysis was stratified by period per change in guideline (before 2002: 2-3 years for patients with 1 adenoma, annually otherwise; in 2002: 6 years for 1-2 adenomas, 3 years otherwise). We also assessed differences in adenoma and colorectal cancer recurrence rates by surveillance timing., Results: Surveillance was inappropriate in 76% and 89% of patients diagnosed before 2002 and in 2002, respectively. Patients eligible under the pre-2002 guideline mainly received surveillance too late or were absent (57% of cases). For patients eligible under the 2002 guideline surveillance occurred mainly too early (48%). The rate of advanced neoplasia at surveillance was higher in patients with delayed surveillance compared with those with too early or appropriate timed surveillance (8% vs 4-5%, p<0.01)., Conclusions: There is much room for improving surveillance practice. Less than 25% of patients with adenoma receive appropriate surveillance. Such practice seriously hampers the effectiveness and efficiency of surveillance, as too early surveillance poses a considerable burden on available resources while delayed surveillance is associated with an increased rate of advanced adenoma and especially colorectal cancer., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

In 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., (© 2015 UICC.)

Background: The National Colorectal Cancer Roundtable, a national coalition of public, private, and voluntary organizations, has recently announced an initiative to increase colorectal cancer (CRC) screening rates in the United States to 80% by 2018. The authors evaluated the potential public health benefits of achieving this goal., Methods: The authors simulated the 1980 through 2030 United States population of individuals aged 50 to 100 years using microsimulation modeling. Test-specific historical screening rates were based on National Health Interview Survey data for 1987 through 2013. The effects of increasing screening rates from approximately 58% in 2013 to 80% in 2018 were compared to a scenario in which the screening rate remained approximately constant. The outcomes were cancer incidence and mortality rates and numbers of CRC cases and deaths during short-term follow-up (2013-2020) and extended follow-up (2013-2030)., Results: Increasing CRC screening rates to 80% by 2018 would reduce CRC incidence rates by 17% and mortality rates by 19% during short-term follow-up and by 22% and 33%, respectively, during extended follow-up. These reductions would amount to a total of 277,000 averted new cancers and 203,000 averted CRC deaths from 2013 through 2030., Conclusions: Achieving the goal of increasing the uptake of CRC screening in the United States to 80% by 2018 may have a considerable public health impact by averting approximately 280,000 new cancer cases and 200,000 cancer deaths within <20 years. Cancer 2015;121:2281-2285. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., (© 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

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.

Purpose: Screening is a major contributor to colorectal cancer (CRC) mortality reductions in the United States but is underused. We estimated the fraction of CRC deaths attributable to nonuse of screening to demonstrate the potential benefits from targeted interventions., Methods: The established microsimulation screening analysis colon model was used to estimate the population attributable fraction (PAF) in people aged ≥50 years. The model incorporates long-term patterns and effects of screening by age and type of screening test. PAF for 2010 was estimated using currently available data on screening uptake. PAF was also projected assuming constant future screening rates to incorporate lagged effects from past increases in screening uptake. We also computed PAF using Levin's formula to gauge how this simpler approach differs from the model-based approach., Results: There were an estimated 51,500 CRC deaths in 2010, about 63% (N ∼ 32,200) of which were attributable to nonscreening. The PAF decreases slightly to 58% in 2020. Levin's approach yielded a considerably more conservative PAF of 46% (N ∼ 23,600) for 2010., Conclusions: Most of the current United States CRC deaths are attributable to nonscreening. This underscores the potential benefits of increasing screening uptake in the population. Traditional methods of estimating PAF underestimated screening effects compared with model-based approaches., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Importance: Many Medicare beneficiaries undergo more intensive colonoscopy screening than recommended. Whether this is favorable for beneficiaries and efficient from a societal perspective is uncertain., Objective: To determine whether more intensive colonoscopy screening than recommended is favorable for Medicare beneficiaries (ie, whether it results in a net health benefit) and whether it is efficient from a societal perspective (ie, whether the net health benefit justifies the additional resources required)., Design, Setting, and Participants: Microsimulation modeling study of 65-year-old Medicare beneficiaries at average risk for colorectal cancer (CRC) and with an average life expectancy who underwent a screening colonoscopy at 55 years with negative results., Interventions: Colonoscopy screening as recommended by guidelines (ie, at 65 and 75 years) vs scenarios with a shorter screening interval (5 or 3 instead of 10 years) or in which screening was continued to 85 or 95 years., Main Outcomes and Measures: Quality-adjusted life-years (QALYs) gained (measure of net health benefit); additional colonoscopies required per additional QALY gained and additional costs per additional QALY gained (measures of efficiency)., Results: Screening previously screened Medicare beneficiaries more intensively than recommended resulted in only small increases in CRC deaths prevented and life-years gained. In comparison, the increases in colonoscopies performed and colonoscopy-related complications experienced were large. As a result, all scenarios of more intensive screening than recommended resulted in a loss of QALYs, rather than a gain (ie, a net harm). The only exception was shortening the screening interval from 10 to 5 years, which resulted in 0.7 QALYs gained per 1000 beneficiaries. However, this scenario was inefficient because it required no less than 909 additional colonoscopies and an additional $711 000 per additional QALY gained. Results in previously unscreened beneficiaries were slightly less unfavorable, but conclusions were identical., Conclusions and Relevance: Screening Medicare beneficiaries more intensively than recommended is not only inefficient from a societal perspective; often it is also unfavorable for those being screened. This study provides evidence and a clear rationale for clinicians and policy makers to actively discourage this practice.

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.

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.

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% < R² < 99%, each HP characteristic curve being uniquely defined for each individual akin to a fingerprint. Specifically, the HP model represents the afferent feedback limb of the HPT axis while the efferent limb is mathematically depicted by TSH input to the thyroid gland which responds by secreting T4 as its chief output. The complete HPT axis thus forms a closed loop system with negative feedback resulting in an equilibrium state or homeostasis under defined conditions illustrated by the intersection of the HP and thyroid response characteristics. In this treatise, we demonstrate how this mathematical approach facilitates homeostatic set points computation for personalized dosing of thyroid medications of patients to individualized euthyroid states., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The sensitivity and specificity of a single faecal immunochemical test (FIT) are limited. The performance of FIT screening can be improved by increasing the screening frequency or by providing more than one sample in each screening round. This study aimed to evaluate if two-sample FIT screening is cost-effective compared with one-sample FIT., Design: The MISCAN-colon microsimulation model was used to estimate costs and benefits of strategies with either one or two-sample FIT screening. The FIT cut-off level varied between 50 and 200 ng haemoglobin/ml, and the screening schedule was varied with respect to age range and interval. In addition, different definitions for positivity of the two-sample FIT were considered: at least one positive sample, two positive samples, or the mean of both samples being positive., Results: Within an exemplary screening strategy, biennial FIT from the age of 55-75 years, one-sample FIT provided 76.0-97.0 life-years gained (LYG) per 1000 individuals, at a cost of € 259,000-264,000 (range reflects different FIT cut-off levels). Two-sample FIT screening with at least one sample being positive provided 7.3-12.4 additional LYG compared with one-sample FIT at an extra cost of € 50,000-59,000. However, when all screening intervals and age ranges were considered, intensifying screening with one-sample FIT provided equal or more LYG at lower costs compared with two-sample FIT., Conclusion: If attendance to screening does not differ between strategies it is recommended to increase the number of screening rounds with one-sample FIT screening, before considering increasing the number of FIT samples provided per screening round.

Objective: Colorectal cancer screening by means of faecal immunochemical tests (FITs) requires successive screening rounds for an optimal preventive effect. However, data on the influence of the length of the screening interval on participation and diagnostic yield are lacking. Repeated FIT screening was therefore performed in a population-based trial comparing various repeat intervals., Design: 7501 Dutch individuals aged 50-74 years were randomly selected and invited for two 1-sample FIT screening rounds (haemoglobin (Hb) concentration ≥ 50 ng/ml, corresponding to 10 μg Hb/g faeces) with intervals of 1 (group I), 2 (group II) or 3 years (group III)., Results: In group I, participation was 64.7% in the first screening round and 63.2% in the second. The corresponding percentages for groups II and III were 61.0% vs 62.5% and 62.0% vs 64.0%. Triennial screening resulted in a higher participation rate in the second screening round compared with annual screening (p=0.04). The overall positivity rate in the second screening round was significantly lower compared with the first round (6.0% vs 8.4%; OR 0.69, 95% CI 0.58 to 0.82) and did not depend on interval length (p=0.23). Similarly, the overall detection rate of advanced neoplasia was significantly lower in the second round compared with the first screening round (1.9% vs 3.3%; OR 0.57, 95% CI 0.43 to 0.76) and also did not depend on interval length (p=0.62). The positive predictive value of the FIT did not significantly change over time (41% vs 33%; p=0.07)., Conclusion: The total number of advanced neoplasia found at repeat FIT screening is not influenced by the interval length within a range of 1-3 years. Furthermore, there is a stable and acceptably high participation in the second screening round. This implies that screening intervals can be tailored to local resources.

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.

Background: The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information regarding cancer occurrence and trends in the United States. This year's report includes trends in colorectal cancer (CRC) incidence and death rates and highlights the use of microsimulation modeling as a tool for interpreting past trends and projecting future trends to assist in cancer control planning and policy decisions., Methods: Information regarding invasive cancers was obtained from the NCI, CDC, and NAACCR; and information on deaths was obtained from the CDC's National Center for Health Statistics. Annual percentage changes in the age-standardized incidence and death rates (based on the year 2000 US population standard) for all cancers combined and for the top 15 cancers were estimated by joinpoint analysis of long-term trends (1975-2006) and for short-term fixed-interval trends (1997-2006). All statistical tests were 2-sided., Results: Both incidence and death rates from all cancers combined significantly declined (P < .05) in the most recent time period for men and women overall and for most racial and ethnic populations. These decreases were driven largely by declines in both incidence and death rates for the 3 most common cancers in men (ie, lung and prostate cancers and CRC) and for 2 of the 3 leading cancers in women (ie, breast cancer and CRC). The long-term trends for lung cancer mortality in women had smaller and smaller increases until 2003, when there was a change to a nonsignificant decline. Microsimulation modeling demonstrates that declines in CRC death rates are consistent with a relatively large contribution from screening and with a smaller but demonstrable impact of risk factor reductions and improved treatments. These declines are projected to continue if risk factor modification, screening, and treatment remain at current rates, but they could be accelerated further with favorable trends in risk factors and higher utilization of screening and optimal treatment., Conclusions: Although the decrease in overall cancer incidence and death rates is encouraging, rising incidence and mortality for some cancers are of concern., (Copyright 2009 American Cancer Society.)