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Do patient requests for antidepressants enhance or hinder physicians' evaluation of depression? A randomized controlled trial.

OBJECTIVE: We sought to ascertain whether patients' requests for antidepressants affect visit duration or history taking by primary care physicians (PCPs) for patients with depressive symptoms and a coexisting musculoskeletal disorder and to determine whether more thorough history taking is associated with diagnostic accuracy or with provision of minimally acceptable initial care for major depression. DESIGN: This was a randomized trial using standardized patients (SPs). Six roles involved 2 conditions (major depression and adjustment disorder, both with coexisting musculoskeletal conditions) and 3 patient request types (brand-specific, general, or none). We conducted the study in 152 PCP offices in Northern California and Rochester, New York. Physicians were assigned randomly to see 2 SPs with depression/wrist pain or adjustment disorder/back pain. MAIN OUTCOME MEASURES: Physician history-taking for depression and the musculoskeletal condition; depression diagnosis in the medical record; antidepressant prescriptions/samples; referral/follow-up recommendations; visit duration; and provision of minimally acceptable initial depression care. RESULTS: General antidepressant requests were associated with more depression history-taking (Adjusted Parameter Estimate = 0.80 more questions of 10 (95% confidence interval = 0.31-1.29, P < 0.001); brand-specific requests were marginally associated with more depression history-taking (Adjusted Parameter Estimate = 0.45, 95% confidence interval = -0.04-0.93, P = 0.07). Antidepressant medication requests were not related to musculo-skeletal question asking (P > 0.3) or visit length (P > 0.8). Depression history taking was directly associated with the likelihood of a chart diagnosis of depression and the provision of minimally acceptable initial depression care. CONCLUSION: General antidepressant requests increase depression history taking, including screening for suicide. Patients' requests for medication do not appear to short-circuit history taking for depression or distract the physician's attention from coexisting musculoskeletal conditions.

Adjustment Disorders↗

Generalized circular autoregressive models for isotropic and anisotropic Gaussian textures.

A new class of random field models, called generalized circular autoregressive (GCAR) models, is introduced. GCAR models have noncausal neighbors that have the same autoregressive parameter values if they are on the same circle or ellipse and that have circular or elliptical correlation structures. This model is better for modeling isotropic or anisotropic natural textures than earlier approaches to modeling of isotropic textures and can represent complex textures with a small number of parameters. Parameter estimation is also considered, and a multistep estimation algorithm is presented. Properties of estimators of GCAR models are also investigated. The efficacy of GCAR models in modeling real textures is demonstrated by synthesizing images resembling real textures by use of parameters estimated from textures selected from the Brodatz texture album. Limitations of GCAR models are also discussed.

Journal Article↗

Accumulator and random-walk models of psychophysical discrimination: a counter-evaluation.

In a recent assessment of models of psychophysical discrimination, Heath criticises the accumulator model for its reliance on computer simulation and qualitative evidence, and contrasts it unfavourably with a modified random-walk model, which yields exact predictions, is susceptible to critical test, and is provided with simple parameter-estimation techniques. A counter-evaluation is presented, in which the approximations employed in the modified random-walk analysis are demonstrated to be seriously inaccurate, the resulting parameter estimates to be artefactually determined, and the proposed test not critical. It is pointed out that Heath's specific application of the model is not legitimate, his data treatment inappropriate, and his hypothesis concerning confidence inconsistent with experimental results. Evidence from adaptive performance changes is presented which shows that the necessary assumptions for quantitative analysis in terms of the modified random-walk model are not satisfied, and that the model can be reconciled with data at the qualitative level only by making it virtually indistinguishable from an accumulator process. A procedure for deriving exact predictions for an accumulator process is outlined.

Choice Behavior↗

Resolution of genetic and cultural inheritance in twin families by path analysis: application to HDL-cholesterol.

A path model and associated statistical method for the analysis of data on twin families are introduced and applied to high density lipoprotein cholesterol (HDL-c) observations in the Swedish Twin Family Study. The proposed path model incorporates both genetic and environmental sources of familial resemblance, maternal environmental effects, intergenerational differences in heritabilities, marital resemblance due to either primary or secondary phenotypic homogamy, and twin residual environmental correlations. Application of the model to HDL-c levels resulted in parameter estimates consistent with those reported in earlier reviews and in the analysis of nuclear family and twin data. Genetic heritability was estimated as h2 = .363 +/- .243, cultural heritability as c2 = .187 +/- .082, and the proportion of phenotypic variance due to residual environmental effects as r2 = .450 +/- .207. Although the parameter estimates were comparable, the statistical tests of hypotheses were, relative to other designs, of low statistical power. It appears that environmental indices are necessary for powerful tests of hypotheses.

Analysis of Variance↗

Statistical problems in estimating elimination rates by compartmental models.

The rate of lead elimination in blood by occupationally exposed individuals has been studies using a compartment model with three exponential terms. The analysis of data by exponential regression leads to numerical problems. It is often a difficult task to decide how many measurements should be performed, the length of the observation period, and how the observations should be distributed to get high accuracy. In a simulation study, the sensitivity of the parameter estimates was investigated as a function of these three factors. The effects of missing observations in some interval was also studied. It is shown that a too short observation time leads to a relatively high frequency of outliers in the estimated values of all three half-times. It is also shown that missing values in one compartment affect the parameter estimates of that and faster compartments. The results obtained can be used as a help to decide what experimental accuracy is needed for a given accuracy of compartment model parameters for a variety of medical and biological problems.

Computer Simulation↗

Metabolic flux distribution analysis by 13C-tracer experiments using the Markov chain-Monte Carlo method.

Metabolic flux analysis using 13C-tracer experiments is an important tool in metabolic engineering since intracellular fluxes are non-measurable quantities in vivo. Current metabolic flux analysis approaches are fully based on stoichiometric constraints and carbon atom balances, where the over-determined system is iteratively solved by a parameter estimation approach. However, the unavoidable measurement noises involved in the fractional enrichment data obtained by 13C-enrichment experiment and the possible existence of unknown pathways prevent a simple parameter estimation method for intracellular flux quantification. The MCMC (Markov chain-Monte Carlo) method, which obtains intracellular flux distributions through delicately constructed Markov chains, is shown to be an effective approach for deep understanding of the intracellular metabolic network. Its application is illustrated through the simulation of an example metabolic network.

Carbon Isotopes↗

The validation of a new vascular damage assay for photodynamic therapy agents.

The therapeutic effect of photodynamic therapy (PDT: photodynamic sensitizer + light) is partly due to vascular damage. This report describes a new vascular photodamage assay for PDT agents and a validation of the assay. The method described here quantitates changes in tissue blood perfusion based on the relative amount of injected fluorescein dye in treated and untreated tissues. A specially designed fluorometer uses chopped monochromatic light from an argon laser as a source for exciting fluorescein fluorescence. The fluorescent light emitted from the tissue is collected by a six element fiberoptic array, filtered and delivered to a photodiode detector coupled to a phase-locked amplifier for conversion to a voltage signal for recording. This arrangement permits a rather simple, inexpensive construction and allows for the simultaneous use of the argon laser by other investigators. The routine assay for characterizing a specific photosensitizer at a standard dose consists of the sequential allocation of eight mice to a set of different light doses designed to span the dose-response range of fluorescein fluorescence exclusion (measured 8-10 min after fluorescein injection). The assay validation experiment used an anionic photosensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a at a dose of 0.4 mumol/kg. The parameter estimates (n = 34 mice) from fitting the standard Hill dose-response model to the data were: median fluorescence exclusion light dose FE50 = 275 +/- 8.3 J/cm2 and Hill sigmoidicity parameter m = -3.66 +/- 0.28. Subsets of the full data set randomly selected to simulate a standard eight mice experiment yielded similar parameter estimates. The new assay provides reliable estimates of PDT vascular damage with a frugal sequential experimental design.

Animals↗

Orientation tuning curves: empirical description and estimation of parameters.

This paper compares the ability of some simple model functions to describe orientation tuning curves obtained in extracellular single-unit recordings from area 17 of the cat visual cortex. It also investigates the relationships between three methods currently used to estimate preferred orientation from tuning curve data: (a) least-squares curve fitting, (b) the vector sum method and (c) the Fourier transform method (Wörgötter and Eysel 1987). The results show that the best fitting model function for single-unit orientation tuning curves is a von Mises circular function with a variable degree of skewness. However, other functions, such as a wrapped Gaussian, fit the data nearly as well. A cosine function provides a poor description of tuning curves in almost all instances. It is demonstrated that the vector sum and Fourier methods of determining preferred orientation are equivalent, and identical to calculating a least-square fit of a cosine function to the data. Least-squares fitting of a better model function, such as a von Mises function or a wrapped Gaussian, is therefore likely to be a better method for estimating preferred orientation. Monte-Carlo simulations confirmed this, although for broad orientation tuning curves sampled at 45 degree intervals, as is typical in optical recording experiments, all the methods gave similarly accurate estimates of preferred orientation. The sampling interval, the estimated error in the response measurements and the probable shape of the underlying response function all need to be taken into account in deciding on the best method of estimating referred orientation from physiological measurements of orientation tuning data.

Animals↗

Strategy for the formation of parametric images under conditions of low injected radioactivity applied to PET studies with the irreversible monoamine oxidase A tracers [11C]clorgyline and deuterium-substituted [11C]clorgyline.

The construction of parametric positron emission tomography images of enzyme or receptor concentration obtained using irreversibly binding radiotracers presents problems not usually encountered with reversibly binding radiotracers. Difficulties are most apparent in brain regions having low blood flow and/or high enzyme or receptor concentration and are exacerbated with noisy data. This is especially true when minimal doses of radiotracer are administered. A comparison was recently reported of the irreversible monoamine oxidase A (MAO A) radiotracers [11C]clorgyline (CLG) and deuterium-substituted [11C]clorgyline (CLG-D) in the human brain using region of interest (ROI) analysis in which the authors observed an unexpected loss of image contrast with CLG-D compared with CLG. In order to more fully investigate patterns of binding of these irreversibly binding radiotracers, a strategy was devised to reduce noise in the generation of parametric images of the model term related to enzyme or receptor concentration. The generalized linear least squares (GLLS) method of Feng et al. (1995), a rapid linear method that is unbiased, was used for image-wide parameter estimation. Since GLLS can fail in the presence of large amounts of noise, local voxels were grouped within the image to increase the signal, and the GLLS method was combined with the standard nonlinear estimation methods when necessary. Voxels were grouped together depending on their proximity and whether they fell within a specified range of the time-integrated image. It was assumed that voxels meeting both criteria are functionally related. Simulations reflecting varying enzyme concentrations were performed to assess precision and accuracy of parameter estimates in the presence of varying amounts of noise. Using this approach, images were generated of the combination parameter lambdak3 (lambda = K1/k2, where K1 and k2 are plasma-to-tissue and tissue-to-plasma transport constants, respectively) that is related to enzyme concentration as well as images of the transport constant K1 for individual subjects. Reasonably high-quality images of both K1 and lambdak3 were obtained for CLG and CLG-D for individual subjects even with low injected doses averaging 6 mCi. While there were no differences in the K1 images, the lambdak3 images revealed the loss of contrast previously reported for CLG-D using the ROI analysis. This method should be generalizable to other tracers and should facilitate the analysis of group differences.

Brain↗

Age-specific back-projection of HIV diagnosis data.

A method for reconstructing the HIV infection curve from data on both HIV and AIDS diagnoses is enhanced by using age as a covariate and by using the diagnosis data to estimate parameters that were previously assumed known. Maximum likelihood estimation is used for parameters of the induction distribution. Each of the set of parameters that specify the baseline rate of infection over time and the set of parameters giving the relative susceptibility over age are estimated by maximizing the likelihood subject to a smoothness requirement. We find that estimating the extra parameters is feasible, producing estimates with good precision. Including age as a covariate gives 90 per cent confidence intervals for the HIV incidence curve that are about 20 per cent narrower than those obtained when age data are not used.

Acquired Immunodeficiency Syndrome↗

New segregation analysis of panic disorder.

We performed simple segregation analyses of panic disorder using 126 families of probands with DSM-III-R panic disorder who were ascertained for a family study of anxiety disorders at an anxiety disorders research clinic. We present parameter estimates for dominant, recessive, and arbitrary single major locus models without sex effects, as well as for a nongenetic transmission model, and compare these models to each other and to models obtained by other investigators. We rejected the nongenetic transmission model when comparing it to the recessive model. Consistent with some previous reports, we find comparable support for dominant and recessive models, and in both cases estimate nonzero phenocopy rates. The effect of restricting the analysis to families of probands without any lifetime history of comorbid major depression (MDD) was also examined. No notable differences in parameter estimates were found in that subsample, although the power of that analysis was low. Consistency between the findings in our sample and in another independently collected sample suggests the possibility of pooling such samples in the future in order to achieve the necessary power for more complex analyses.

Adult↗

Comparison of variance components and sibpair-based approaches to quantitative trait linkage analysis in unselected samples.

We compared the statistical performance of sibpair-based and variance components approaches to multipoint linkage analysis of a quantitative trait in unselected samples. As a benchmark dataset, we used the simulated family data from Genetic Analysis Workshop 10 [Goldin et al., 1997], and each method was used to screen all 200 replications of the GAW10 genome for evidence of linkage to quantitative trait Q1. The sibpair and variance components methods were each applied to datasets comprising single-sibpairs and complete sibships, and for further comparison we also applied the variance components method to the nuclear family and extended pedigree datasets. For each analysis, the unbiasedness and efficiency of parameter estimation, the power to detect linkage, and the Type I error rate were estimated empirically. Sibpair and variance components methods exhibited comparable performance in terms of the unbiasedness of the estimate of QTL location and the Type I error rate. Within the single-sibpair and sibship sampling units, the variance components approach gave consistently superior power and efficiency of parameter estimation. Within each method, the statistical performance was improved by the use of the larger and more informative sampling units.

Chromosome Mapping↗

Optimal sampling theory and population modelling: application to determination of the influence of the microgravity environment on drug distribution and elimination.

Newer mathematical techniques such as optimal sampling theory and NON-linear Mixed Effects Modelling (NONMEM) allow the determination of pharmacokinetics and pharmacodynamics in populations of individuals previously believed to be "too ill" or "too difficult to study." Optimal sampling determines the most information-rich times to sample the system, allowing robust parameter estimates to be determined from the minimal number of samples. NONMEM, by taking the population as the unit of analysis, allows even fragmentary patient data sets to contribute to population parameter estimates. Obviously, the microgravity environment presents extreme logistical difficulties to the performance of traditional pharmacokinetic and pharmacodynamic studies. Examples of the validation of these techniques are presented, which indicates their likely utility in the important task of determining the influence of the microgravity environment on drug distribution and elimination, even accounting for the limitations of support which will be faced in this circumstance.

Bayes Theorem↗

Testing goodness-of-fit of the logistic regression model in case-control studies using sample reweighting.

A new goodness-of-fit test for the logistic regression model is proposed. It exploits the property of this model that when it is correct, i.e. not misspecified, the parameter estimates are (asymptotically) invariant under reweighting the observations by weights wi that are a function of the binary (0/1) outcomes yi. Misspecification of the model can thus be concluded when parameter estimates change under reweighting. A local test, considering weights of the form wi=(1 + epsilonyi) is explored. The test is especially suitable for case-control studies but may be used in other contexts as well.

Adult↗

Analysis of genetic structure and dispersal patterns in a population of sea beet.

A model of the migration pattern in a metapopulation of sea beet (Beta vulgaris L. ssp. maritima), based on the continuous distributions of seed and pollen movements, is fitted to gene frequency data at 12 isozyme and RFLP loci by maximum likelihood by using an approximation of the simultaneous equilibrium distribution of the gene frequencies generated by the underlying multivariate stochastic process of genetic drift in the population. Several alternative restrictions of the general model are fitted to the data, including the island model, a model of complete isolation, and a model in which the seed and pollen dispersal variances are equal. Several likelihood ratio tests between these alternatives are performed, and median bias in the estimated parameters is corrected by using parametric bootstrapping. To assess the fit of the selected model, the predicted covariances are compared with covariances computed from the data directly. The dependency of estimated parameters on the ratio between effective and absolute subpopulation sizes, which is treated as a known parameter in the analysis, is also examined. Finally, we note that the data also appear to contain some information about this ratio.

Alleles↗

Hierarchical bayesian models for regularisation in sequential learning

We show that a hierarchical Bayesian modeling approach allows us to perform regularization in sequential learning. We identify three inference levels within this hierarchy: model selection, parameter estimation, and noise estimation. In environments where data arrive sequentially, techniques such as cross validation to achieve regularization or model selection are not possible. The Bayesian approach, with extended Kalman filtering at the parameter estimation level, allows for regularization within a minimum variance framework. A multilayer perceptron is used to generate the extended Kalman filter nonlinear measurements mapping. We describe several algorithms at the noise estimation level that allow us to implement on-line regularization. We also show the theoretical links between adaptive noise estimation in extended Kalman filtering, multiple adaptive learning rates, and multiple smoothing regularization coefficients.

Journal Article↗

The use of dummy data points when fitting bacterial growth curves.

We consider the problem of fitting mathematical models for bacterial growth and decline to experimental data. Using models which represent the phases of the growth and decline cycle in a piecewise manner, we describe how least-squares fitting can lead to potentially misleading parameter estimates. We show how these difficulties can be overcome by extending a data set to include hypothetical observations (dummy data points) which reflect biological beliefs, and the resulting stabilization of parameter estimates is analysed mathematically. The techniques are illustrated using real and simulated data sets.

Anaerobiosis↗

Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple-dose administration in healthy older adults.

The pharmacokinetics of exogenously administered DHEA have not been well characterized despite its increasing use in therapeutic and research investigations. The purpose of this study was to evaluate the pharmacokinetics of DHEA and its sulfated metabolite (DHEA-S) after single- and multiple-dose oral administration of DHEA 200 mg. Healthy older adult volunteers (7 women, 6 men) ages 65 to 79 years were studied on five visits separated by 1 week. Subjects received daily administration of placebo (days 1 to 7), DHEA 200 mg (days 8 to 22), and placebo (days 23 to 29). Blood samples were collected over 24 hours on days 1, 8, 15, 22, and 29 for DHEA and DHEA-S determinations by RIA. Pharmacokinetic parameter estimates were calculated by noncompartmental methods. Administration of DHEA 200 mg resulted in higher DHEA Cmax, AUC, and overall concentrations in women than in men (p < 0.03); DHEA-S parameter estimates were similar between men and women. Following a single dose of DHEA 200 mg, DHEA concentrations increased 5- to 6-fold in both men and women, and DHEA-S concentrations increased 5-fold in men and 21-fold in women relative to endogenous concentrations. The results of this study indicate that the pharmacokinetics of DHEA differ between older men and women.

Aged↗