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PubMed1994

Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987.

This paper presents an analysis of data on the incidence of leukemia, lymphoma and myeloma in the Life Span Study cohort of atomic bomb survivors during the period from late 1950 through the end of 1987 (93,696 survivors accounting for 2,778,000 person-years). These analyses add 9 additional years of follow-up for leukemia and 12 for myeloma to that in the last comprehensive reports on these diseases. This is the first analysis of the lymphoma incidence data in the cohort. Using both the Leukemia Registry and the Hiroshima and Nagasaki tumor registries, a total of 290 leukemia, 229 lymphoma and 73 myeloma cases were identified. The primary analyses were restricted to first primary tumors diagnosed among residents of the cities or surrounding areas with Dosimetry System 1986 dose estimates between 0 and 4 Gy kerma (231 leukemias, 208 lymphomas and 62 myelomas). Analyses focused on time-dependent models for the excess absolute risk. Separate analyses were carried out for acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelocytic leukemia (CML) and adult T-cell leukemia (ATL). There were few cases of chronic lymphocytic leukemia in this population. There was strong evidence of radiation-induced risks for all subtypes except ATL, and there were significant subtype differences with respect to the effects of age at exposure and sex and in the temporal pattern of risk. The AML dose-response function was nonlinear, whereas there was no evidence against linearity for the other subtypes. When averaged over the follow-up period, the excess absolute risk (EAR) estimates (in cases per 10(4) PY Sv) for the leukemia subtypes were 0.6, 1.1 and 0.9 for ALL, AML and CML, respectively. The corresponding estimated average excess relative risks at 1 Sv are 9.1, 3.3 and 6.2 respectively. There was some evidence of an increased risk of lymphoma in males (EAR = 0.6 cases per 10(4) PY Sv) but no evidence of any excess in females. There was no evidence of an excess risk for multiple myeloma in our standard analyses.

Adolescent↗

PubMed2004

Nest architecture, activity pattern, worker density and the dynamics of disease transmission in social insects.

The role of disease in the organization of insect colonies has become an important focus of research in evolutionary pathobiology, in which the relationship of sociality and disease transmission can be comparatively and experimentally analysed. In this paper we use an individual-based model of disease transmission to assess how an epidemic is influenced by worker density and activity level, the probability of disease transmission, and the structural organization of the nest. First, we observed in our model a nonlinear interaction between worker density and the probability of disease transmission: high levels of both factors interact to enhance the likelihood of an epidemic. Additionally, when we incorporated in our model the empirical observation that only a fraction of the worker population in social insect colonies is active at any given point in time, results suggested that relatively low levels of worker movement can have a significant impact on the spread of disease, slowing its transmission through the colony. Finally, we found that nests having even a simple spatial separation of chambers could delay the spread of infection and diminish the severity of an outbreak. The effect of nest structure in delaying infection spread became more pronounced as nest architecture became increasingly unidimensional, as in the case of simple gallery nests. Therefore, nest architecture and worker activity patterns might indeed exert considerable influence on the dynamics of epidemics in social insects and should be incorporated into models of disease transmission.

Animals↗

PubMed2001

Quantitative modeling of category learning in amnesic patients.

Category rule learning was examined in two amnesic patients using the perceptual categorization task (e.g., Ashby & Gott, 1988; Filoteo & Maddox, 1999). Traditional accuracy-based analyses as well as quantitative model-based analyses were performed. Unlike accuracy-based analyses, the model-based approach allowed us to examine both categorization rule learning and variability in the trial-by-trial application of the participant's categorization rule. The results indicated that the amnesic patients were as accurate as the controls in learning a complex, nonlinear rule over a large number of trials. The model-based analysis indicated that, in general, the amnesic patients learned the categorization rule as well as controls and applied their rule as consistently as controls. Categorization performance on a second day of testing revealed that amnesic patients can retain the categorization rule over a 24-h period. These results suggest that the brain regions damaged in amnesia are not involved in category learning or memory for the category structures.

Adult↗

PubMed2025

APNet, an explainable sparse deep learning model to discover differentially active drivers of severe COVID-19.

MOTIVATION: Computational analyses of bulk and single-cell omics provide translational insights into complex diseases, such as COVID-19, by revealing molecules, cellular phenotypes, and signalling patterns that contribute to unfavourable clinical outcomes. Current in silico approaches dovetail differential abundance, biostatistics, and machine learning, but often overlook nonlinear proteomic dynamics, like post-translational modifications, and provide limited biological interpretability beyond feature ranking. RESULTS: We introduce APNet, a novel computational pipeline that combines differential activity analysis based on SJARACNe co-expression networks with PASNet, a biologically informed sparse deep learning model, to perform explainable predictions for COVID-19 severity. The APNet driver-pathway network ingests SJARACNe co-regulation and classification weights to aid result interpretation and hypothesis generation. APNet outperforms alternative models in patient classification across three COVID-19 proteomic datasets, identifying predictive drivers and pathways, including some confirmed in single-cell omics and highlighting under-explored biomarker circuitries in COVID-19. AVAILABILITY AND IMPLEMENTATION: APNet's R, Python scripts, and Cytoscape methodologies are available at https://github.com/BiodataAnalysisGroup/APNet.

COVID-19↗

PubMed1996

Evaluation of inductively heated ferromagnetic alloy implants for therapeutic interstitial hyperthermia.

Ferromagnetic alloys heated by magnetic induction have been investigated as interstitial hyperthermia delivery implants for over a decade, utilizing low Curie temperatures to provide thermal self-regulation. The minimally invasive method is attractive for fractionated thermal treatment of tumors which are not easily heated by focused microwave or ultrasound techniques. Past analyses of ferromagnetic seeds by other authors depict poor experimental correlation with theoretical heating predictions. Improvements in computer hardware and commercially available finite element analysis software have simplified the analysis of inductively heated thermal seeds considerably. This manuscript examines end effects of finite length implants and nonlinear magnetic material properties to account for previous inconsistencies. Two alloys, Ni-28 wt% Cu (NiCu) and Pd-6.15 wt% Co (PdCo), were used for comparison of theoretical and experimental calorimetric results. Length to diameter (L/d) ratios of over 20 for cylindrical seeds are necessary for minimization of end effects. Magnetic properties tested for alloys of NiCu and PdCo illustrate considerable nonlinearity of these materials in field strength ranges used for induction heating. Field strength dependent magnetic permeabilities and calorimetric data illustrate that more detailed material information must be included to accurately estimate induction power loss for these implants.

Alloys↗

PubMed2001

Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations.

PURPOSE: To conduct a phase I study of ZD9331, a potent, nonpolyglutamatable thymidylate synthase inhibitor using a short daily infusion for 5 consecutive days every 21 days. PATIENTS AND METHODS: Patients with refractory cancer or cancer for which no standard therapy was available were treated in escalating doses using an accelerated titration design. Plasma and urine samples were collected at timed intervals in the first cycle for pharmacokinetic analysis. RESULTS: Seventy-four patients were enrolled at 12 dose levels from a starting dose of 0.4 mg/m(2)/d to 16 mg/m(2)/d and 25 mg/d fixed dosing, of which 67 were assessable for toxicity. Maximum-tolerated dose was reached at 16 mg/m(2)/d. Myelosuppression was dose-limiting, consisting of thrombocytopenia associated with neutropenic fever. Body-surface area did not correlate with drug clearance; therefore, fixed daily dosing of 25 mg/d was studied and found to be tolerable, with two of 12 dose-limiting events. Dose-limiting nonhematologic toxicity consisted of grade 3 erythematous maculopapular rash observed in one patient at 12 mg/m(2)/d and one patient at 25 mg/d. Pharmacokinetic analysis showed nonlinearity, with clearance increasing with dose. The mean clearance and terminal half-life of the drug were 6.6 +/- 2.0 mL/min and 71.3 +/- 27.0 hours, respectively. Area-under-the concentration-time curve was a better predictor of toxicity than dose, using multiple linear regression analyses. Minor response (40% shrinkage of tumor) was observed in one patient with colorectal cancer treated at 12 mg/m(2)/d. CONCLUSION: The recommended dose for ZD9331 on this schedule is 25 mg/d. Neutropenia, thrombocytopenia, and rash were dose-limiting, and efficacy studies in colorectal cancer are indicated.

Adult↗

PubMed2006

Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia.

OBJECTIVE: To develop and a priori validate a methotrexate population pharmacokinetic model in children with acute lymphoblastic leukaemia (ALL), receiving high-dose methotrexate followed by folinic acid rescue, identifying the covariates that could explain part of the pharmacokinetic variability of methotrexate. METHODS: The study was carried out in 49 children (aged 6 months to 17 years) who received high-dose methotrexate (3 g/m(2) per course) in long-term treatment. In an index group (37 individuals; 1236 methotrexate plasma concentrations), a population pharmacokinetic model was developed using a nonlinear mixed-effects model. The remaining patients' data (12 individuals; 278 methotrexate plasma concentrations) were used for model validation. Age, sex, total bodyweight (TBW), height, body surface area, lowest urine pH during infusion, serum creatinine, ALT, AST, folinic acid dose and length of rescue were analysed as possible covariates. The final predictive performance of the pharmacokinetic model was tested using standardised mean prediction errors. RESULTS: The final population pharmacokinetic model (two-compartmental) included only age and total bodyweight as influencing clearance (CL) and volume of distribution of central compartment (V(1)). For children aged < or =10 years: CL (L/h) = 0.287 . TBW(0.876); V(1) (L) = 0.465 . TBW, and for children aged >10 years: CL (L/h) = 0.149 . TBW; V(1) (L) = 0.437 . TBW. From the base to the final model, the inter-individual variabilities for CL and V(1) were significantly reduced in both age groups (30-50%). The coefficients of variation of the pharmacokinetic parameters were <30%, while residual and inter-occasional coefficients maintained values close to 40%. Validation of the proposed model revealed the suitability of the model. CONCLUSION: A methotrexate population pharmacokinetic model has been developed for ALL children. The proposed model could be used in Bayesian algorithms with a limited sampling strategy to estimate the systemic exposure of individual patients to methotrexate and adapt both folinic acid rescue and methotrexate dosing accordingly.

Adolescent↗

PubMed1992

Correcting bias from the standard linear adjustment of weaning weight to an age-constant basis for beef calves.

Standard linear adjustment of weaning weight to a constant age has been shown to introduce bias in the adjusted weight due to nonlinear growth from birth to weaning of beef calves. Ten years of field records from the five strains of Beefbooster Cattle Alberta Ltd. seed stock herds were used to investigate the use of correction factors to adjust standard 180-d weight (WT180) for this bias. Statistical analyses were performed within strain and followed three steps: 1) the full data set was split into an estimation set (ES) and a validation set (VS), 2) WT180 from the ES was used to develop estimates of correction factors using a model including herd (H), year (YR), age of dam (DA), sex of calf (S), all two and three-way interactions, and any significant linear and quadratic covariates of calf age at weaning deviated from 180 d (DEVCA) and interactions between DEVCA and DA, S or DA x S, and 3) significant DEVCA coefficients were used to correct WT180 from the VS, then WT180 and the corrected weight (WTCOR) from the VS were analyzed with the same model as in Step 2 and significance of DEVCA terms were compared. Two types of data splitting were used. Adjusted R2 was calculated to describe the proportion of total variation of DEVCA terms explained for WT180 from the ES. The DEVCA terms explained .08 to 1.54% of the total variation for the five strains. Linear and quadratic correction factors were both positive and negative. Bias in WT180 from the ES within 180 +/- 35 d of age ranged from 2.8 to 21.7 kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed2006

Influence prediction of injury and vibration on adjacent components of spine using finite element methods.

OBJECTIVES: A three-dimensional finite element (FE) model of the lumbar spine L3-L5 segment, the ligaments of which were assumed to be nonlinear materials, was established based on the actual vertebra geometry to investigate the influence of the injury lumbar spine on its adjacent components on the condition of whole-body vibration. Several injury conditions of the spine components were assumed, such as facetectomy, nucleotomy, and removal of bony posterior elements. METHODS: The dynamic FE analyses were carried out for those FE conditions under cyclic compression loads at the frequencies of 5 and 10 Hz. Then a comparison between the dynamic results and the static results was conducted to analyze the influence of both the nucleus injury and the facet joint injury on the adjacent intervertebral discs. RESULTS AND CONCLUSIONS: The results indicate that the lumbar spine exhibits not only vertical vibration but also the flexion--extension motion during vibration. The denucleation will cause high stress and large disc bulge on the disc annulus under vibration. The facet joints of lumbar spine can limit the motion amplitude of flexion-extension and protect both the posterior regions and the posterolateral regions of disc annulus from large strain and stress during vibration. The facet joint removal will increase the stress of disc annulus by around 15% at the posterior region for the conditions of nucleotomy or no vibration. The stress of annulus circumference is higher at the posterolateral region than that of other regions of annulus circumference, and the facet joint removal may exacerbate the intervertebral disc degeneration on the condition of whole-body vibration.

Compressive Strength↗

PubMed2005

Non-homogeneous Markov processes for biomedical data analysis.

Some time ago, the Markov processes were introduced in biomedical sciences in order to study disease history events. Homogeneous and Non-homogeneous Markov processes are an important field of research into stochastic processes, especially when exact transition times are unknown and interval-censored observations are present in the analysis. Non-homogeneous Markov process should be used when the homogeneous assumption is too strong. However these sorts of models increase the complexity of the analysis and standard software is limited. In this paper, some methods for fitting non-homogeneous Markov models are reviewed and an algorithm is proposed for biomedical data analysis. The method has been applied to analyse breast cancer data. Specific software for this purpose has been implemented.

Algorithms↗

PubMed2005

Information entropy analysis of discrete aiming movements.

Information entropy and mutual information were investigated in discrete movement aiming tasks over a wide range of spatial (20-160 mm) and temporal (250-1250 ms) constraints. Information entropy was calculated using two distinct analyses: (1) with no assumption on the nature of the data distribution; and (2) assuming the data have a normal distribution. The two analyses showed different results in the estimate of entropy that also changed as a function of task goals, indicating that the movement trajectory data were not from a normal distribution. It was also found that the information entropy of the discrete aiming movements was lower than the task defined indices of difficulty (ID) that were selected for the congruence with Fitts' law. Mutual information between time points of the trajectory was strongly influenced by the average movement velocity and the acceleration/deceleration segments of the movement. The entropy analysis revealed structure to the variability of the movement trajectory and outcome that has been masked by the traditional distributional analyses of discrete aiming movements.

Adult↗

PubMed1998

A new method for the analysis of simple and complex planar rapid movements.

Recent developments in the field of simple human movement modelling provide new ways in which to view complete models for analysing and understanding complex movements. Based on a kinematic theory and a vectorial delta-lognormal model recently proposed by Plamondon (1993a); Plamondon (1995a); Plamondon (1995b); Plamondon (1995c) and Plamondon (1998), a new method for exploring and understanding the inherent mechanisms that govern planar movement generation and predict human behaviour is presented here. This paper describes an approach for analysing simple as well as complex movements such as cursive handwriting. It highlights some difficulties encountered in the analysis of complex movements. Problems such as the development of robust approaches to solve the reverse engineering problem of automatic parameter extraction of a succession of time-overlapped nonlinear functions are discussed. The analysis of natural cursive handwriting shows many interesting properties of the model and proposes new ways to study perturbed movement phenomena.

Cues↗

PubMed2003

Age and motives for volunteering: testing hypotheses derived from socioemotional selectivity theory.

Following a meta-analysis of the relations between age and volunteer motives (career, understanding, enhancement, protective, making friends, social, and values), the authors tested hypotheses derived from socioemotional selectivity theory regarding the effects of age on these volunteer motives. The Volunteer Functions Inventory was completed by 523 volunteers from 2 affiliates of the International Habitat for Humanity. Multiple regression analyses revealed, as predicted, that as age increases, career and understanding volunteer motivation decrease and social volunteer motivation increases. Contrary to expectations, age did not contribute to the prediction of enhancement, protective, and values volunteer motivations and the relation between age and making friends volunteer motivation was nonlinear. The results were discussed in the context of age-differential and age-similarity perspectives on volunteer motivation.

Adult↗

PubMed2026

Uric Acid-to-HDL Cholesterol Ratio is Associated with Hepatic Steatosis but Not Fibrosis in Nonobese Adults: A NHANES 2017-2020 Study.

BACKGROUND: Although metabolic dysfunction-associated steatotic liver disease (MASLD) has traditionally been regarded as a disease closely related to obesity, its prevalence is gradually rising in nonobese populations. The uric acid-to-high-density lipoprotein cholesterol ratio (UHR) is a novel metabolic biomarker that has been shown to be associated with MASLD. However, its role in nonobese individuals remains unclear. This study aimed to investigate the association between UHR and nonobese MASLD. METHODS: Data from the 2017 to 2020 National Health and Nutrition Examination Survey (NHANES) were analyzed. UHR was calculated as the serum uric acid (UA) divided by the high-density lipoprotein cholesterol (HDL). Liver steatosis (using controlled attenuation parameters, CAP) and fibrosis (using liver stiffness measurement, LSM) were evaluated through vibration-controlled transient elastography (VCTE). Multivariate linear regression was employed to evaluate associations. Nonlinear relationships were examined using smoothed curve fitting. RESULTS: This analysis included 3573 participants (47.41% male; aged 20-80 years). Log2-UHR was positively associated with CAP (β = 9.96, 95% CI: 6.93-12.98, P < 0.001) and MASLD prevalence (OR = 1.64, 95% CI: 1.38-1.95, P < 0.001). Subgroup analyses revealed significant interactions by sex, age, ethnicity, and smoking status (all P for interaction < 0.05), with stronger associations in females, adults aged 40-59 years, individuals of other Hispanic ethnicity, and never-smokers. Moreover, the association between log2-UHR and CAP was linear and positive (P < 0.01). No significant association was found between log2-UHR and LSM (P > 0.05). CONCLUSIONS: UHR is independently associated with hepatic steatosis but not fibrosis in nonobese US adults, suggesting its potential utility as an early risk assessment to tool. Large scale prospective studies are needed in the future to further validate the conclusions of this study.

Humans↗

PubMed1984

Fluid mechanics of the pulmonary circulation.

Assessment of the fluid mechanics of the pulmonary circulation has been hindered by the relative inaccessibility of the pulmonary vascular bed. Current understanding is based largely on analyses of mathematical models which have been used to simulate hemodynamic characteristics within an architectural representation of that bed. These representations have ranged from simple, lumped parameter structures to anatomically realistic structures based on measurements of casts of the irregular branching network of pulmonary arteries and veins. Nonlinear models have been studied to determine the effects of vessel taper and within beat geometrical variations as cross-sectional shapes change from circular to elliptical and small vessels undergo recruitment, distention, and collapse as a result of the shifting balance in alveolar, pleural, and capillary pressures. This article reviews current concepts of pulmonary circulatory fluid mechanics focusing on mathematical models and relevant hemodynamic studies.

Adolescent↗

PubMed2000

Canonical modeling: review of concepts with emphasis on environmental health.

The article reviews concepts of canonical modeling in the context of environmental health. Based on biochemical systems theory, the canonical approach was developed over the past thirty years and applied to complex systems primarily in biochemistry and the regulation of gene expression. Canonical modeling is based on nonlinear ordinary differential equations whose right-hand sides consist of products of power-law functions. This structure results from the linearization of complex processes in logarithmic space. The canonical structure has many intriguing features. First, almost any system of smooth functions or ordinary differential equations can be recast equivalently in a canonical model, which demonstrates that the model structure is rich enough to deal with all relevant nonlinearities. Second, a large body of successful applications suggests that canonical models are often valid and accurate representations of quite complex, real-world systems. Third, a set of guidelines supports the modeler in all phases of analysis. These guidelines address model design, algebraic and numerical analysis, and the interpretation of results. Fourth, the structure of canonical models, especially those in S-system form, facilitates algebraic and numerical analyses. Of particular importance is the derivation of steady-state solutions in an explicit symbolic or numerical form, which allows further assessments of stability and robustness. The homogeneous structure of canonical models has also led to the development of very efficient, customized computer algorithms for all steps of a typical analysis. Fifth, a surprising number of models currently used in environmental health research are special cases of canonical models. The traditional models are thus subsumed in one modeling framework, which offers new avenues of analysis and interpretation.

Algorithms↗

PubMed1994

Compressive stress-relaxation behavior of bovine growth plate may be described by the nonlinear biphasic theory.

The compressive behavior of the bovine distal femoral growth plate was studied in vitro. Strain-rate controlled, compression stress-relaxation experiments were performed on cylindrical bone-growth plate-bone specimens from the interior and periphery of the growth plate. The questions addressed in this study were (a) Can the nonlinear biphasic theory, one with strain-dependent permeability, be used to represent the compressive stress-relaxation behavior of bovine growth plate? (b) How do different assumptions concerning the permeabilities of the chondro-osseous interfaces influence the inferred material properties of the growth plate? and (c) Are there any differences in these properties between the periphery and the interior of the growth plate? Intrinsic biphasic material properties--aggregate modulus (HA), Poisson's ratio (v), and nonlinear strain-dependent permeability coefficients (ko and M)--were calculated from the compression stress-relaxation data with use of a finite element model and a least squares curve-fitting procedure. To verify this constitutive model for the growth plate, an independent set of finite element analyses was performed with use of the determined intrinsic biphasic properties, and comparisons were made between these finite element predictions and two additional sets of experimental data subsequently obtained for the same specimens with use of two slower rates of compression. Excellent agreement was achieved between these finite element predictions and the latter two sets of data. The aggregate modulus was found to be insensitive to the permeability of the chondro-osseous interface. The permeability coefficients were very sensitive to, and the Poisson's ratio was only slightly sensitive to the interface permeability condition. Therefore, the periphery of the growth plate is more compliant and permeable than the interior.

Animals↗

PubMed2000

Population extinction and quasi-stationary behavior in stochastic density-dependent structured models.

Density-independent and density-dependent, stochastic and deterministic, discrete-time, structured models are formulated, analysed and numerically simulated. A special case of the deterministic, density-independent, structured model is the well-known Leslie age-structured model. The stochastic, density-independent model is a multitype branching process. A review of linear, density-independent models is given first, then nonlinear, density-dependent models are discussed. In the linear, density-independent structured models, transitions between states are independent of time and state. Population extinction is determined by the dominant eigenvalue lambda of the transition matrix. If lambda < or = 1, then extinction occurs with probability one in the stochastic and deterministic models. However, if lambda > 1, then the deterministic model has exponential growth, but in the stochastic model there is a positive probability of extinction which depends on the fixed point of the system of probability generating functions. The linear, density-independent, stochastic model is generalized to a nonlinear, density-dependent one. The dependence on state is in terms of a weighted total population size. It is shown for small initial population sizes that the density-dependent, stochastic model can be approximated by the density-independent, stochastic model and thus, the extinction behavior exhibited by the linear model occurs in the nonlinear model. In the deterministic models there is a unique stable equilibrium. Given the population does not go extinct, it is shown that the stochastic model has a quasi-stationary distribution with mean close to the stable equilibrium, provided the population size is sufficiently large. For small values of the population size, complete extinction can be observed in the simulations. However, the persistence time increases rapidly with the population size.

Age Factors↗