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PubMed1991

Robust estimation of the variance in moment methods for extra-binomial and extra-Poisson variation.

When faced with data in the form of overdispersed counts or proportions, moment methods allow consistent parameter estimation when only the form of the mean and variance is specified. If the variance form is misspecified, these methods still yield consistent parameter estimates, though with lower efficiency, and the variances of the estimates will be inconsistent. A variance correction is available that yields consistent variance estimates in these circumstances. The asymptotic and small-sample efficiencies of this correction are calculated, and its performance under variance misspecification is studied. A group-randomized breast self-examination prevention study that is now underway serves as a focal point for the study of these properties. The use of the variance correction in modelling is illustrated on a teratology data set.

Analysis of Variance↗

PubMed2005

New method for estimation of adult skeletal age at death from the morphology of the auricular surface of the ilium.

A new method for estimating skeletal age at death from the morphology of the auricular surface of the ilium is presented. It uses a multiple regression analysis with dummy variables, and is based on the examination of 700 modern Japanese skeletal remains with age records. The observer using this method needs only to check for the presence or absence of nine (for a male) or seven (for a female) features on the auricular surface and to select the parameter estimates of each feature, calculated by multiple regression analysis with dummy variables. The observer can obtain an estimated age from the sum of parameter estimates. It is shown that a fine granular texture of the auricular surface is typical of younger individuals, whereas a heavily porous texture is characteristic of older individuals, and that both of these features are very useful for estimating age. Our method is shown here to be more accurate than other methods, especially in the older age ranges. Since the auricular surface allows more expedient observations than other parts of the skeleton, this new method can be expected to improve the overall accuracy of estimating skeletal age at death.

Adolescent↗

PubMed1996

Software for attributable risk and confidence interval estimation in case-control studies.

The increasing interest in obtaining model-based estimates of attributable risk (AR) and corresponding confidence intervals, in particular when more than one risk factor and/or several confounding factors are jointly considered, led us to develop a program based on the procedure described by Benichou and Gail for case-control data. This program is structured as an SAS-macro. It is suited to analysis of the relationship between risk factors and disease in case-control studies with simple random sampling of controls, in terms of relative risks and ARs, by means of unconditional logistic regression analysis. The variance of the AR is obtained by the delta method and is based on three components, namely, (i) the variance-covariance matrix of the vector of the estimated probabilities of belonging to joint levels of the exposure and confounding factors conditional on being a case, (ii) the variance-covariance matrix of the odds ratio parameter estimates from the logistic model, and (iii) the covariances between these probability and parameter estimates. Only a limited number of commands is requested from the user (i.e., the name of the work file and the names of the variables considered). The estimated relative risks for all the factors included in the model, the attributable risk for the exposure factor under consideration, and the corresponding 95% confidence intervals are given as outputs by the macro. Computational problems, if any, may arise for large numbers of covariates because of the resulting large size of vectors and matrices. The macro was tested for reliability and consistency on published data sets of case-control studies.

Age Factors↗

PubMed2003

Maximizing quantitative accuracy of lung airway lumen and wall measures obtained from X-ray CT imaging.

To objectively quantify airway geometry from three-dimensional computed tomographic (CT) images, an idealized (circular cross section) airway model is parameterized by airway luminal caliber, wall thickness, and tilt angle. Using a two-dimensional CT slice, an initial guess for the airway center, and the full-width-half-maximum principle, we form an estimate of inner and outer airway wall locations. We then fit ellipses to the inner and outer airway walls via a direct least squares fit and use the major and minor axes of the ellipses to estimate the tilt and in-plane rotation angles. Convolving the airway model, initialized with these estimates, with the three-dimensional scanner point-spread function forms the predicted image. The difference between predicted and actual images is minimized by refining the model parameter estimates via a multidimensional, unconstrained, nonlinear minimization routine. When optimization converges, airway model parameters estimate the airway inner and outer radii and tilt angle. Results using a Plexiglas phantom show that tilt angle is estimated to within +/-4 degrees and both inner and outer radii to within one-half pixel when a "standard" CT reconstruction kernel is used. By opening up the ability to measure airways that are not oriented perpendicular to the scanning plane, this method allows evaluation of a greater sampling of airways in a two-dimensional CT slice than previously possible. In addition, by combining the tilt-angle compensation with the deconvolution method, we provide significant improvement over the previous full-width-half-maximum method for assessing location of the luminal edge but not the outer edge of the airway wall.

Algorithms↗

PubMed2005

Kinetic modeling of 3'-deoxy-3'-fluorothymidine in somatic tumors: mathematical studies.

UNLABELLED: We present a method to measure the regional rate of cellular proliferation using a positron-emitting analog of thymidine (TdR) for human imaging studies. The method is based on the use of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) to estimate the flux of TdR through the exogenous pathway. The model reflects the retention of FLT-monophosphate (FLTMP), which is generated by the phosphorylation of FLT by thymidine kinase 1 (TK1), the initial step in the exogenous pathway. METHODS: A model of FLT kinetics has been designed based on the assumptions of a steady-state synthesis and incorporation of nucleotides into DNA, an equilibration of the free nucleoside in tissue with the plasma level, and the relative rates of FLT and TdR phosphorylation from prior data using direct analysis with in vitro assays. A 2-compartment model with 4 rate constants adequately describes the kinetics of FLT uptake and retention over 120 min and leads to an estimation of the rate of cellular proliferation using the measured FLT blood clearance and the dynamic FLT uptake curve. RESULTS: Noise characteristics of kinetic parameter estimates for 3 tissues were assessed under a range of conditions representative of human cancer patient imaging. The FLT flux in these tissues can be measured with a SE of <5%, and FLT transport can be estimated with a SE of <15%. Abbreviating the data collection to 60 min or neglecting k(4), giving a 3-parameter model, results in an unsatisfactory loss of accuracy in the flux constant in tumor simulations. CONCLUSION: These analyses depict model behavior and provide expected values for the accuracy of parameter estimates from FLT imaging in human patients. Our companion paper describes the performance of the model for human data in patients with lung cancer. Further studies are necessary to determine the fidelity of K(FLT) (FLT flux) as a proxy for K(TDR) (thymidine flux), the gold standard for imaging cellular proliferation.

Algorithms↗

PubMedDate not supplied

Modeling blood flow heterogeneity.

It has been known for some time that regional blood flows within an organ are not uniform. Useful measures of heterogeneity of regional blood flows are the standard deviation and coefficient of variation or relative dispersion of the probability density function (PDF) of regional flows obtained from the regional concentrations of tracers that are deposited in proportion to blood flow. When a mathematical model is used to analyze dilution curves after tracer solute administration, for many solutes it is important to account for flow heterogeneity and the wide range of transit times through multiple pathways in parallel. Failure to do so leads to bias in the estimates of volumes of distribution and membrane conductances. Since in practice the number of paths used should be relatively small, the analysis is sensitive to the choice of the individual elements used to approximate the distribution of flows or transit times. Presented here is a method for modeling heterogeneous flow through an organ using a scheme that covers both the high flow and long transit time extremes of the flow distribution. With this method, numerical experiments are performed to determine the errors made in estimating parameters when flow heterogeneity is ignored, in both the absence and presence of noise. The magnitude of the errors in the estimates depends upon the system parameters, the amount of flow heterogeneity present, and whether the shape of the input function is known. In some cases, some parameters may be estimated to within 10% when heterogeneity is ignored (homogeneous model), but errors of 15-20% may result, even when the level of heterogeneity is modest. In repeated trials in the presence of 5% noise, the mean of the estimates was always closer to the true value with the heterogeneous model than when heterogeneity was ignored, but the distributions of the estimates from the homogeneous and heterogeneous models overlapped for some parameters when outflow dilution curves were analyzed. The separation between the distributions was further reduced when tissue content curves were analyzed. It is concluded that multipath models accounting for flow heterogeneity are a vehicle for assessing the effects of flow heterogeneity under the conditions applicable to specific laboratory protocols, that efforts should be made to assess the actual level of flow heterogeneity in the organ being studied, and that the errors in parameter estimates are generally smaller when the input function is known rather than estimated by deconvolution.

Algorithms↗

PubMed1997

Effects of dependent errors in the assessment of diagnostic test performance.

Latent class models can be used to assess diagnostic test performance when there is no perfectly accurate gold standard test available for comparison. These models usually assume independent errors between the tests, conditional on the true disease state of the subject. Maximum likelihood estimates of the prevalence of the disease and the error rates of diagnostic tests are then obtained. This paper examines the impact of error dependencies between binary diagnostic tests on the parameter estimates obtained from the latent class models. The independence model often gives parameter estimates having relatively small bias, but in some situations (for example, when disease prevalence is low and the tests have low specificity, such as in population screening) the bias may be more serious.

Bias↗

PubMed1992

Inching toward reality: an improved likelihood model of sequence evolution.

Our previous evolutionary model is generalized to permit approximate treatment of multiple-base insertions and deletions as well as regional heterogeneity of substitution rates. Parameter estimation and alignment procedures that incorporate these generalizations are developed. Simulations are used to assess the accuracy of the parameter estimation procedure and an example of an inferred alignment is included.

Animals↗

PubMed1999

On identification of Na(+) channel gating schemes using moving-average filtered hidden Markov models.

Transitions between distinct kinetic states of an ion channel are described by a Markov process. Hidden Markov models (HMM) have been successfully applied in the analysis of single ion channel recordings with a small signal-to-noise ratio. However, we have recently shown that the anti-aliasing low-pass filter misleads parameter estimation. Here, we show for the case of a Na(+) channel recording that the standard HMM do neither allow parameter estimation nor a correct identification of the gating scheme. In particular, the number of closed and open states is determined incorrectly, whereas a modified HMM considering the anti-aliasing filter (moving-average filtered HMM) is able to reproduce the characteristic properties of the time series and to perform gating scheme identification.

Cell Line↗

PubMed1994

Ontogeny and plasma-membrane domain localization of amino acid transport system L in rat liver.

Na(+)-independent hepatic transport of branched-chain amino acids occurs via at least two distinct transport processes. System L1, characterized by micromolar Km values, predominates in hepatoma and fetal hepatocytes, whereas System L2, distinguished by Km values in the millimolar range and sensitivity to inhibition by N-ethylmaleimide (NEM), predominates in adult hepatocytes. To determine the plasma-membrane domain localization and ontogeny of System L activity in the rat, we prepared membrane vesicles from the livers of suckling (10 days old) and adult rats enriched for either basolateral (BLMV) or canalicular (CMV) domains. The initial rate of [3H]leucine uptake into BLMV and CMV derived from adult liver was significantly inhibited by the addition of 5 mM NEM; transport into BLMV and CMV derived from 10-day-old rat liver was not affected. Michaelis-Menten kinetic parameters estimated in BLMV derived from adult liver were consistent with System L2 (Km = 2.16 +/- 0.62 mM, Vmax. = 781 +/- 109 pmol/5 s per mg of protein), as were those estimated in adult CMV (Km = 0.83 +/- 0.21 mM, Vmax. = 385 +/- 38 pmol/5 s per mg of protein). Conversely, kinetic parameters estimated in BLMV derived from livers of suckling rats were consistent with System L1 (Km = 0.041 +/- 0.024 mM, Vmax. = 8.8 +/- 1.5 pmol/5 s per mg of protein), as were those from CMV of suckling rats (Km = 0.023 +/- 0.09 mM, Vmax. = 28.1 +/- 2.1 pmol/5 s per mg of protein). We conclude that NEM-inhibitable Na(+)-independent leucine transport activity consistent with System L2 is present in both BLMV and CMV derived from adult rat liver, whereas System L1 predominates in 10-day-old rat liver tissue.

Amino Acids, Branched-Chain↗

PubMed1998

Application of an autoregressive process to estimate genetic parameters and breeding values for daily milk yield in a tropical herd of Lucerna cattle and in United States Holstein herds.

The objectives of this study were to estimate from test day records the genetic and environmental (co)variance components, correlations, and breeding values to increase genetic gain in milk yield of Lucerna and US Holstein cattle. The effects of repeated observations (within cow) were explained by first-order autoregressive processes within and across lactations using an animal model. Estimates of variance components and correlation coefficients between test days were obtained using derivative-free REML methodology. The autoregressive structure significantly reduced the model error component by disentangling the short-term environmental effects. The additional information and the more heterogeneous environmental variances between lactations in the multiple-lactation test day model than in the first lactation model provided substantially larger estimates of additive genetic variance (0.62 kg2 for Lucerna; 14.73 kg2 for Holstein), heritability (0.13 for Lucerna; 0.42 for Holstein), and individual genetic merit. Rank correlations of breeding values from multiple lactations and from first lactations ranged from 0.18 to 0.37 for females and from 0.73 to 0.89 for males, respectively. Consequently, more selection errors and less genetic gain would be expected from selection decisions based on an analysis of first lactation only, and greater accuracy would be achieved from multiple lactations. Results indicated that substantial genetic gain was possible for milk yield in the Lucerna herd (34 kg/yr). Estimates of genetic variance for Holsteins were larger than previously reported, which portends more rapid genetic progress in US herds also; under our assumptions, increases would be from 173 to 197 kg/yr.

Aging↗

PubMed2006

Relationship between pretreatment level of plasma Epstein-Barr virus DNA, tumor burden, and metabolic activity in advanced nasopharyngeal carcinoma.

PURPOSE: Plasma Epstein-Barr virus DNA (pEBV DNA) is an important prognostic marker in nasopharyngeal carcinoma (NPC). This study tested the hypotheses that pEBV DNA reflects tumor burden and metabolic activity by evaluating its relationship with tumor volume and 18F-fluorodeoxyglucose (18F-FDG) uptake in NPC. METHODS AND MATERIALS: Pre-treatment pEBV DNA analysis, 18F-FDG positron emission tomography-computed tomography scan (PET-CT) and magnetic resonance imaging (MRI) of the head and neck were performed in 57 patients. Net volume (cm3) of the primary tumor (T(vol)) and regional nodes (N(vol)) were quantified on MRI. 18F-FDG uptake was expressed as the maximum standardized uptake value (SUV(max)) at the primary tumor (T(suv)) and regional nodes (N(suv)). Lesions with SUV(max) > or = 2.5 were considered malignant. Relationship between SUV(max), natural logarithm (log) of pEBV DNA, and square root (sq) of MRI volumes was analyzed using the Wilcoxon test. A linear regression model was constructed to test for any interaction between variables and disease stage. RESULTS: Log-pEBV DNA showed significant correlation with sq-T(vol) (r = 0.393), sq-N(vol) (r = 0.452), total tumor volume (sq-Total(vol) = T(vol) + N(vol), r = 0.554), T(suv) (r = 0.276), N(suv) (r = 0.434), and total SUV(max) (Total(suv) = T(suv) + N(suv), r = 0.457). Likewise, sq-T(vol) was correlated to T(suv) (r = 0.426), and sq-N(vol) with N(suv) (r = 0.651). Regression analysis showed that only log-pEBV DNA was significantly associated with sq-Total(vol) (p < 0.001; parameter estimate = 8.844; 95% confidence interval = 3.986-13.703), whereas Sq-T(vol) was significantly associated with T(suv) (p = 0.002; parameter estimate = 3.923; 95% confidence interval = 1.498-6.348). CONCLUSION: This study supports the hypothesis that cell-free plasma EBV DNA is a marker of tumor burden in EBV-related NPC.

Adult↗

PubMed1991

Radionuclide distribution dynamics in skeletons of beagles fed 90Sr: correlation with injected 226Ra and 239Pu.

Data for the bone-by-bone redistribution of 90Sr in the beagle skeleton are reported for a period of 4000 d following a midgestation-to-540-d-exposure by ingestion. The partitioned clearance model (PCM) that was originally developed to describe bone-by-bone radionuclide redistribution of 226Ra after eight semimonthly injections at ages 435-535 d has been fitted to the 90Sr data. The parameter estimates for the PCM that describe the distribution and clearance of 226Ra after deposition on surfaces following injection and analogous parameter estimates for 90Sr after uniform deposition in the skeleton as a function of Ca mass are given. Fractional compact bone masses per bone group (mi,COM) are also predicted by the model and compared to measured values; a high degree of correlation (r = 0.84) is found. Bone groups for which the agreement between the model and experimental values of mi,COM was poor had tissue-to-calcium weight ratios about 1.5 times those for bones that agreed well. Metabolically defined "surface" in PCM is initial activity fraction per Ca fraction in a given skeletal component for intravenously injected alkaline earth (Sae) radionuclides; comparisons are made to similarly defined "surface" (Sact) values from 239Pu injection studies. The patterns of Sae and Sact distribution throughout the skeleton are similar.

Administration, Oral↗

PubMed2006

Pharmacokinetic disposition of inhaled ciclesonide and its metabolite desisobutyryl-ciclesonide in healthy subjects and patients with asthma are similar.

OBJECTIVE: To evaluate whether the inflammatory process and bronchial constriction associated with asthma influence the pulmonary distribution and airway penetration of inhaled ciclesonide by investigating the pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC) in patients with asthma and matched healthy subjects. METHODS: 12 patients with asthma (8 males, 4 females) and 12 healthy subjects matched for age, sex, height, and weight received a single inhaled dose of 1,280 microg (ex-actuator, equivalent to 1,600 microg ex-valve) ciclesonide by metered-dose inhaler in a parallel-group study. Timed blood samples were collected for measurement of serum concentrations of des-CIC and ciclesonide by liquid chromatography with tandem mass spectrometry. RESULTS: There were no differences in the pharmacokinetics of des-CIC between healthy subjects and patients with asthma. Ratio analysis of the primary variable, the area under the concentration-time curve from time 0 to infinity (AUC(0 - inf)) showed equivalence for des-CIC in healthy subjects and patients with asthma, with a ratio of 1.003 (90% confidence interval between 0.815 and 1.234). The mean terminal half-life (t1/2) for des-CIC was also similar in patients with asthma (3.15 hours) and healthy subjects (3.33 hours). Furthermore, the pharmacokinetic parameter estimates for ciclesonide were comparable between the study groups. CONCLUSION: After administration of a single dose of ciclesonide, the pharmacokinetic parameter estimates for des-CIC were equivalent between patients with mild-to-moderate asthma and healthy subjects, suggesting that there is comparable lung deposition and activation of ciclesonide in the 2 populations.

Administration, Inhalation↗

PubMed1995

A single-step method for estimation of local cerebral blood volume from susceptibility contrast MRI images.

A new single-step method is described for estimation of local cerebral blood volume (CBV) from multiple rapidly acquired T2- or T2*-weighted MRI images after bolus administration of a susceptibility contrast agent. This method improves on existing methods in three ways. First, the method includes the baseline scan intensity value as a fitted parameter. Second, the model is fitted directly to the original scan intensity values instead of to transformed concentration curves, avoiding the propagation of errors that occurs in the transformation. Third, the equations are reparameterized with CBV fitted directly as a model parameter. Parameter estimation methods are compared by Monte Carlo simulation. The direct method described here yields more precise parameter estimates, with smaller mean absolute deviations from the true parameter values, than the existing method when compared using simulated data. Implementation is discussed and numerical evaluation of the Digamma or Psi function is described.

Algorithms↗

PubMed1989

Models for in vivo kinetic interactions of dopamine D2-neuroreceptors and 3-(2'-[18F]fluoroethyl)spiperone examined with positron emission tomography.

The in vivo tracer kinetics of 3-(2'-[18F]fluoroethyl)spiperone (FESP) in the caudate/striatum and cerebellar regions of the human and monkey brain were studied with positron emission tomography (PET). The minimal model configuration that can describe the kinetics was determined statistically. Three two-compartment model configurations were found to be suitable for describing the kinetics in caudate/striatum and cerebellum: (1) a nonlinear model (five parameters) applicable to studies using nontracer (partially saturating) quantities of FESP in monkey striatum, (2) a linear four-parameter model applicable to the caudate/striatal and cerebellar kinetics in human and monkey studies with tracer quantities of FESP, and (3) a linear three-parameter model derived from the four-parameter model by assuming irreversible binding applicable to tracer studies of the human caudate. In the human studies, when the caudate kinetics (n = 4) were fit by model 2 (with four parameters), the value of the in vivo ligand dissociation constant kd was found to be 0.0015 +/- 0.0032/min. The three-parameter model (model 3) was found to fit the data equally well: this model is equivalent to model 2 with kd set to zero. In the monkey studies, it was found that for short (90 min) studies using tracer quantities of FESP, model 2 fit the striatal kinetics better than model 3. The parameters estimated using model 2 (four parameters) were in better agreement with those estimated by the nonlinear model (model 1) than those estimated using model 3 (three parameters). The use of a graphical approach gives estimates of the plasma-tissue fractional transport rate constant K1 and the net uptake constant K3 comparable to estimates using model 3 for both human and monkey studies.

Adult↗

PubMed2002

Estimating the distribution of worm burden and egg excretion of Schistosoma japonicum by risk group in Sichuan Province, China.

During autumn 2000 an extensive cross-sectional survey of the prevalence of Schistosomiasis japonicum was conducted among about 4000 villagers within 20 villages in the Anning River Valley located in the southwestern Sichuan Province. Two procedures were used to assess infection status, the Kato-Katz thick smear procedure and a miracidia hatch test. Whereas the Kato-Katz procedure provides information on both prevalence and intensity, the hatch test provides only prevalence data, albeit on a much larger volume of stool. In addition, we performed Kato-Katz smears for 15 consecutive samples on a subset of 15 individuals. The proportion of both hatch-test and Kato-Katz positive individuals in the larger cross-sectional survey was 25%. The goal of the study was to estimate both the egg and worm distributions among risk groups using both the hatch and Kato-Katz tests from the cross-sectional data and the repeated Kato-Katz smears from the longitudinal data sets. As a prelude to parameter estimation, individuals were classified into risk groups by natural village and occupation; the proportion of Kato-Katz positive subjects among the risk groups varied from 10% to 60%. We used the statistical model of de Vlas et al. (1992) and Bayesian techniques to derive both estimates of and inference about the worm and egg distribution parameters. The parameter estimates imply (1) similar eggs per gram stool (e.p.g.) per worm pair compared with earlier estimates, (2) a range of worm burdens among the risk groups and (3) estimates of risk heterogeneity within groups is sensitive to prior information on the within-person variability in egg excretion.

Age Factors↗

PubMed1989

The effect of logarithmic transformation on estimating the parameters of the generalized matching law.

The generalized matching law was initially stated as a nonlinear relation between reinforcement-rate ratios and response-rate ratios. Often, the variables of the law are transformed logarithmically to remove the nonlinearity; empirical results are then fit to the model through least-squares regression. However, the logarithmic expression of the matching law is a biased statistical representation of the law itself. In particular, the logarithmic transformation alters the quantitative conclusions to be drawn from a least-squares regression analysis. A Monte Carlo study of the effect of transforming matching-law data demonstrated that (a) the estimates of one or both of the parameters of the generalized matching law are biased, (b) the measure of goodness of fit (R(2)) is inaccurate, and (c) predictions generated by the fitted parameters are incorrect. Alternative approaches to logarithmic transformations are shown to alleviate these problems.

Journal Article↗