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Proportional hazards model for interval-censored failure times and time-dependent covariates: application to hazard of HIV infection of injecting drug users in prison.

Interval-censored survival data are data in which the failure times are not known precisely, but are known to lie within an interval. Such data can be analysed using a proportional hazards model with piecewise-exponential baseline hazard, a model which can be fitted by an EM algorithm easily programmed in standard statistical software. In this paper we extend the model to allow for time-dependent covariates and left-truncation, and demonstrate its use by assessing the effect of imprisonment on hazard of HIV infection in a cohort of injecting drug users from Edinburgh. No conclusive effect of incarceration on hazard of HIV infection was found, but there was a suggestion that imprisonment might have been a significant relative risk factor for infection in the later period, when risk behaviour among drug users in the community was reduced.

Adolescent↗

Modelling variation of lower leg length growth in early life.

We consider the estimation of sources of variation for panel data with repeated measurements. With no repeated measurements and known measurement error, models for variation decomposition have been proposed when there are one or more types of measurements. Estimation was performed using the EM algorithm accompanied by model augmentation that demands more computational efforts. In this article we extend previous variation models and modify the estimation methods in order to estimate various variation components after eliminating the unknown effects of measurement error. Specifically, methods that dispense with model augmentation and estimation of time-dependent covariates are considered. A set of lower leg length data from Chinese infants is analysed by using the proposed model. Interestingly, our results are consistent with the well-accepted three-phase (infancy-childhood-puberty) growth transition proposition for human growth. Moreover, gender effect is found to be time-varying.

Anthropometry↗

Complete imputation of missing repeated categorical data: one-sample applications.

Longitudinal studies with repeated measures are often subject to non-response. Methods currently employed to alleviate the difficulties caused by missing data are typically unsatisfactory, especially when the cause of the missingness is related to the outcomes. We present an approach for incomplete categorical data in the repeated measures setting that allows missing data to depend on other observed outcomes for a study subject. The proposed methodology also allows a broader examination of study findings through interpretation of results in the framework of the set of all possible test statistics that might have been observed had no data been missing. The proposed approach consists of the following general steps. First, we generate all possible sets of missing values and form a set of possible complete data sets. We then weight each data set according to clearly defined assumptions and apply an appropriate statistical test procedure to each data set, combining the results to give an overall indication of significance. We make use of the EM algorithm and a Bayesian prior in this approach. While not restricted to the one-sample case, the proposed methodology is illustrated for one-sample data and compared to the common complete-case and available-case analysis methods.

Algorithms↗

Maximum likelihood estimation of a survival function with a change point for truncated and interval-censored data.

This paper considers estimation of a survival function when there exists a change point and the survival time of interest is defined as elapsed time between two related events. Furthermore, there exists censoring on observations on the occurrences of both events and truncation on observations on the occurrence of the second event and thus the survival time of interest. To obtain the maximum likelihood estimator of a survival function, an EM algorithm is developed when the survival function is completely unknown before the change point and known up to a vector of unknown parameters after the change point. The idea is a generalization of that discussed in Moeschberger and Klein. Simulations and an example are used to evaluate and illustrate the algorithm.

Acquired Immunodeficiency Syndrome↗

A local likelihood proportional hazards model for interval censored data.

We discuss the use of local likelihood methods to fit proportional hazards regression models to right and interval censored data. The assumed model allows for an arbitrary, smoothed baseline hazard on which a vector of covariates operates in a proportional manner, and thus produces an interpretable baseline hazard function along with estimates of global covariate effects. For estimation, we extend the modified EM algorithm suggested by Betensky, Lindsey, Ryan and Wand. We illustrate the method with data on times to deterioration of breast cosmeses and HIV-1 infection rates among haemophiliacs.

Algorithms↗

Sample Size Requirements of a Mixture Analysis Method with Applications in Systematic Biology.

The available information on sample size requirements of mixture analysis methods is insufficient to permit a precise evaluation of the potential problems facing practical applications of mixture analysis. We use results from Monte Carlo simulation to assess the sample size requirements of a simple mixture analysis method under conditions relevant to biological applications of mixture analysis. The mixture model used includes two univariate normal components with equal variances but assumes that the researcher is ignorant as to the equality of the variances. The method used relies on the EM algorithm to compute the maximum likelihood estimates of the mixture parameters, and the likelihood ratio test to assess the number of components in the mixtures. Our results suggest that sample sizes close to 500 or 1000 data may be required to adequately solve mixtures commonly found in biology. Sample sizes of 500 or 1000 are difficult to achieve. However, use of this MA method may be a reasonable option when the researcher deals with problems which are intractable by other means. Copyright 1999 Academic Press.

Journal Article↗

A general statistical analysis for fMRI data.

We propose a method for the statistical analysis of fMRI data that seeks a compromise between efficiency, generality, validity, simplicity, and execution speed. The main differences between this analysis and previous ones are: a simple bias reduction and regularization for voxel-wise autoregressive model parameters; the combination of effects and their estimated standard deviations across different runs/sessions/subjects via a hierarchical random effects analysis using the EM algorithm; overcoming the problem of a small number of runs/session/subjects using a regularized variance ratio to increase the degrees of freedom.

Algorithms↗

Classical and Bayesian inference in neuroimaging: theory.

This paper reviews hierarchical observation models, used in functional neuroimaging, in a Bayesian light. It emphasizes the common ground shared by classical and Bayesian methods to show that conventional analyses of neuroimaging data can be usefully extended within an empirical Bayesian framework. In particular we formulate the procedures used in conventional data analysis in terms of hierarchical linear models and establish a connection between classical inference and parametric empirical Bayes (PEB) through covariance component estimation. This estimation is based on an expectation maximization or EM algorithm. The key point is that hierarchical models not only provide for appropriate inference at the highest level but that one can revisit lower levels suitably equipped to make Bayesian inferences. Bayesian inferences eschew many of the difficulties encountered with classical inference and characterize brain responses in a way that is more directly predicated on what one is interested in. The motivation for Bayesian approaches is reviewed and the theoretical background is presented in a way that relates to conventional methods, in particular restricted maximum likelihood (ReML). This paper is a technical and theoretical prelude to subsequent papers that deal with applications of the theory to a range of important issues in neuroimaging. These issues include; (i) Estimating nonsphericity or variance components in fMRI time-series that can arise from serial correlations within subject, or are induced by multisubject (i.e., hierarchical) studies. (ii) Spatiotemporal Bayesian models for imaging data, in which voxels-specific effects are constrained by responses in other voxels. (iii) Bayesian estimation of nonlinear models of hemodynamic responses and (iv) principled ways of mixing structural and functional priors in EEG source reconstruction. Although diverse, all these estimation problems are accommodated by the PEB framework described in this paper.

Algorithms↗

Classical and Bayesian inference in neuroimaging: applications.

In Friston et al. ((2002) Neuroimage 16: 465-483) we introduced empirical Bayes as a potentially useful way to estimate and make inferences about effects in hierarchical models. In this paper we present a series of models that exemplify the diversity of problems that can be addressed within this framework. In hierarchical linear observation models, both classical and empirical Bayesian approaches can be framed in terms of covariance component estimation (e.g., variance partitioning). To illustrate the use of the expectation-maximization (EM) algorithm in covariance component estimation we focus first on two important problems in fMRI: nonsphericity induced by (i) serial or temporal correlations among errors and (ii) variance components caused by the hierarchical nature of multisubject studies. In hierarchical observation models, variance components at higher levels can be used as constraints on the parameter estimates of lower levels. This enables the use of parametric empirical Bayesian (PEB) estimators, as distinct from classical maximum likelihood (ML) estimates. We develop this distinction to address: (i) The difference between response estimates based on ML and the conditional means from a Bayesian approach and the implications for estimates of intersubject variability. (ii) The relationship between fixed- and random-effect analyses. (iii) The specificity and sensitivity of Bayesian inference and, finally, (iv) the relative importance of the number of scans and subjects. The forgoing is concerned with within- and between-subject variability in multisubject hierarchical fMRI studies. In the second half of this paper we turn to Bayesian inference at the first (within-voxel) level, using PET data to show how priors can be derived from the (between-voxel) distribution of activations over the brain. This application uses exactly the same ideas and formalism but, in this instance, the second level is provided by observations over voxels as opposed to subjects. The ensuing posterior probability maps (PPMs) have enhanced anatomical precision and greater face validity, in relation to underlying anatomy. Furthermore, in comparison to conventional SPMs they are not confounded by the multiple comparison problem that, in a classical context, dictates high thresholds and low sensitivity. We conclude with some general comments on Bayesian approaches to image analysis and on some unresolved issues.

Algorithms↗

A bivalent polyploid model for linkage analysis in outcrossing tetraploids.

Polyploids can be classified as either allopolyploids or autopolyploids based on their presumed origins. From a perspective of linkage analysis, however, the nature of polyploids can be better described as bivalent polyploids, in which two chromosomes pair at meiosis, multivalent polyploids, in which more than two chromosomes pair, and general polyploids, in which bivalent and multivalent formations occur simultaneously. In this paper, we develop a statistical method for linkage analysis of polymorphic markers in bivalent polyploids. This method takes into account a unique cytological pairing mechanism for the formation of diploid gametes in tetraploids-preferential bivalent pairings at meiosis during which two homologous chromosomes pair with a higher probability than two homoeologous chromosomes. The higher frequency of homologous over homoeologous pairing, defined as the preferential pairing factor, affects the segregation patterns and linkage analysis of different genes on the same chromosome. A maximum likelihood method implemented with the EM algorithm is proposed to simultaneously estimate linkage and parental linkage phases over a pair of markers from any possible marker cross type between two outbred bivalent tetraploid parents demonstrating preferential bivalent pairings. Simulation studies display that the method can be well used to estimate the recombination fraction between different marker types and the preferential pairing factor typical of bivalent tetraploids. The implications of this method for current genome projects in polyploid species are discussed.

Algorithms↗

Automatic cerebrovascular segmentation by accurate probabilistic modeling of TOF-MRA images.

Accurate automatic extraction of a 3D cerebrovascular system from images obtained by time-of-flight (TOF) or phase contrast (PC) magnetic resonance angiography (MRA) is a challenging segmentation problem due to small size objects of interest (blood vessels) in each 2D MRA slice and complex surrounding anatomical structures, e.g. fat, bones, or grey and white brain matter. We show that due to a multi-modal nature of MRA data blood vessels can be accurately separated from background in each slice by a voxel-wise classification based on precisely identified probability models of voxel intensities. To identify the models, an empirical marginal probability distribution of intensities is closely approximated with a linear combination of discrete Gaussians (LCDG) with alternate signs, and we modify the conventional Expectation-Maximization (EM) algorithm to deal with the LCDG. To validate the accuracy of our algorithm, a special 3D geometrical phantom motivated by statistical analysis of the MRA-TOF data is designed. Experiments with both the phantom and 50 real data sets confirm high accuracy of the proposed approach.

Algorithms↗

Bivariate frailty model for the analysis of multivariate survival time.

Because of limitations of the univariate frailty model in analysis of multivariate survival data, a bivariate frailty model is introduced for the analysis of bivariate survival data. This provides tremendous flexibility especially in allowing negative associations between subjects within the same cluster. The approach involves incorporating into the model two possibly correlated frailties for each cluster. The bivariate lognormal distribution is used as the frailty distribution. The model is then generalized to multivariate survival data with two distinguished groups and also to alternating process data. A modified EM algorithm is developed with no requirement of specification of the baseline hazards. The estimators are generalized maximum likelihood estimators with subject-specific interpretation. The model is applied to a mental health study on evaluation of health policy effects for inpatient psychiatric care.

Algorithms↗

Diagnostic accuracy of simultaneous acquisition of transmission and emission data with technetium-99m transmission source on thallium-201 myocardial SPECT.

PURPOSE: This study evaluates not only the clinical usefulness but also the problems in attenuation correction for thallium-201 (Tl-201) myocardial SPECT by means of simultaneous transmission and emission data acquisition in the detection of coronary artery disease (CAD). METHODS: A three-detector SPECT system equipped with a Tc-99m line source and fan-beam collimators was used for simultaneous transmission and emission data acquisition for Tl-201 myocardial SPECT in 73 patients (18 patients for normal database and 55 patients for the evaluation of diagnostic accuracy). Attenuation-corrected (AC) images and non-attenuation-corrected (NC) images were reconstructed with an iterative maximum-likelihood estimation-corrected (ML-EM) algorithm. Both sets of images were reoriented into the short axis. Normal database polar maps were constructed from the AC and NC images for quantitative analysis. RESULTS: There was a significant difference in specificity between NC and AC images in the RCA territory and those in specificity and accuracy in the LCX territory. There was no significant difference in sensitivity found between NC and AC images in either territory, but sensitivity in both territories tended to decrease with attenuation correction. In the LAD territory, there were various changes in sensitivity and specificity observed with attenuation correction in cases with each quantitative criterion. CONCLUSIONS: Diagnostic performance of significant stenosis in the RCA and LCX territories quantitatively improved with attenuation correction because of an increase in specificity, but no significant improvement in diagnostic performance was obtained in the LAD territory with attenuation correction. We recommend combined interpretation of AC and NC images and careful evaluation of any SPECT image by means of transmission computed tomography.

Coronary Disease↗

Body contour 180 degrees pinhole SPET with or without tilted detector: a phantom study.

This study investigated the feasibility of ordered subsets expectation maximisation (OS-EM) reconstruction of 180 degrees pinhole single-photon emission tomography (SPET) acquired in body contour mode (variable distance between the detector and the axis of rotation for each projection) with or without a tilted detector head. Four non-circular orbits were designed bearing in mind the rotation radius and tilt angle values of previous pinhole SPET acquisitions in patients with circular orbits. The reconstructions were performed using a dedicated OS-EM algorithm. Reconstructed images of line and uniformity phantoms showed that the spatial and uniformity characteristics of the radioactive objects were preserved. In comparison with the circular orbits, the non-circular orbits allowed only a moderate gain (maximum 10%) in resolution. However, body contour pinhole SPET would significantly facilitate the camera set-up and in this way should decrease the camera set-up time, which is an important parameter in patient studies.

Algorithms↗

Improved tolerance to missing data in myocardial perfusion SPET using OSEM reconstruction.

When projection data are incomplete for various technical reasons, artefacts may occur in the reconstructed images. This study examines whether an iterative reconstruction method, the ordered subsets implementation of the EM algorithm (OSEM), can improve reconstruction and minimise the artefacts compared to filtered back-projection (FBP). We varied the number and location of projections removed to investigate when significant artefacts occur, and whether diagnosis is affected. Phantom studies were analysed with sequential orthogonal pairs of projection angles removed (as would typically occur when either data loss or severe motion is detected during acquisition with a right-angled, dual-head cardiac single-photon emission tomography system) and reconstructed with both FBP and OSEM. Twelve normal myocardial perfusion studies were also assessed to study the effect of missing projections on clinical diagnosis. Differences between reconstructions with intact versus missing data were measured. Also, reconstructed images were clinically assessed and scored on a five-point scale based on whether the artefacts would alter clinical interpretation. Although both reconstruction methods showed artefacts, the absolute differences between reconstructed phantom data with intact and missing projection sets were significantly greater (P<0.005) for FBP than for OSEM for all numbers of missing projections. The clinical data showed similar differences between FBP and OSEM reconstructions. The three observers noted superiority of OSEM compared to FBP, with reduced incidence of clinically significant artefacts. However, neither reconstruction method could tolerate six or more missing pairs from 32 projections. There was no significant dependence on the angular location of missing projections. In the absence of any attempt to correct for missing projections, OSEM reduced the influence of artefacts compared to FBP.

Algorithms↗

Impact of attenuation correction on the accuracy of FDG-PET in patients with abdominal tumors: a free-response ROC analysis.

The aim of this study was to evaluate image quality and lesion detectability with and without attenuation correction in patients with abdominal tumors, using a free-response receiver operating characteristic (FROC) methodology. Thirty-four patients with various abdominal tumors were evaluated (11 men, 23 women, median age 48 years). Whole-body emission scans were performed 68 min (35-102 min) after intravenous injection of 4.3 MBq/kg fluorine-18 fluorodeoxyglucose (FDG). Images were reconstructed using the OS-EM algorithm and corrected for attenuation either using postinjection singles transmission (n=27) or by calculation and body outline (n=7). Total scan duration did not exceed 70 min. Studies were read independently by four observers unaware of any clinical data. The uncorrected (UC) images were systematically read before the attenuation-corrected (AC) images. All studies were given an image quality score ranging from 1 (unreadable) to 5 (excellent). Each focus of increased activity was then localized and given a probability of malignancy using a five-point scale. The average image quality score was similar for both UC and AC images. At the time of the positron emission tomography (PET) scans, 127 lesions (63 liver metastases, 9 retroperitoneal lesions, 50 peritoneal or bowel lesions, and 5 pancreatic carcinomas) were revealed by pathological or correlative studies. The areas under the FROC curves were consistently greater for AC images (range 0.8663-0.8867) than for UC images (range 0.7774 -0.8613). Overall, the difference between the AC images and the UC images was significant (P=0.019). In particular, correction for attenuation increased the sensitivity regardless of the location of the lesions. In conclusion, correction for attenuation significantly improves the diagnostic accuracy of FDG-PET for abdominal staging of neoplasms, without impairing the image quality.

Abdominal Neoplasms↗

180 degree pinhole SPET with a tilted detector and OS-EM reconstruction: phantom studies and potential clinical applications.

This study investigated the feasibility of ordered subsets expectation maximisation (OS-EM) reconstruction of pinhole single-photon emission tomography (SPET) acquired with a tilted detector head and a 180 degrees orbit. Phantom and patient data were recorded using a standard single-head camera. Reconstructions were performed using a dedicated OS-EM algorithm. Reconstructed images of line, uniformity and Picker's thyroid phantoms showed that the geometry, physical size and uniformity of the radioactive objects were preserved. For the range of radius corresponding to the patient studies, the measured full-widths at half-maximum lay between 4.90+/-0.25 mm and 6.05+/-0.25 mm. Finally, the gain in resolution associated with the use of the pinhole collimator instead of a parallel-hole collimator was highlighted in a parathyroid exploration and in a shoulder bone study.

Aged↗

Unified approach for multiple sclerosis lesion segmentation on brain MRI.

The presence of large number of false lesion classification on segmented brain MR images is a major problem in the accurate determination of lesion volumes in multiple sclerosis (MS) brains. In order to minimize the false lesion classifications, a strategy that combines parametric and nonparametric techniques is developed and implemented. This approach uses the information from the proton density (PD)- and T2-weighted and fluid attenuation inversion recovery (FLAIR) images. This strategy involves CSF and lesion classification using the Parzen window classifier. Image processing, morphological operations, and ratio maps of PD- and T2-weighted images are used for minimizing false positives. Contextual information is exploited for minimizing the false negative lesion classifications using hidden Markov random field-expectation maximization (HMRF-EM) algorithm. Lesions are delineated using fuzzy connectivity. The performance of this algorithm is quantitatively evaluated on 23 MS patients. Similarity index, percentages of over, under, and correct estimations of lesions are computed by spatially comparing the results of present procedure with expert manual segmentation. The automated processing scheme detected 80% of the manually segmented lesions in the case of low lesion load and 93% of the lesions in those cases with high lesion load.

Adult↗