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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↗

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↗

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↗

A computer program for the statistical analysis of disease prevalence data from survival/sacrifice experiments.

This paper presents a computer program for analyzing disease prevalence data from animal survival experiments in which there may also be some serial sacrifice. The method has been described in Biometrics 35 (1979) 221-234. The user is interrogated about the details of particular models he wishes to fit. Then a generalized EM algorithm is used to compute maximum likelihood estimates of various quantities of interest concerning the effects of treatment, time and presence of other diseases on the prevalences and lethalities of specific diseases of interest.

Animals↗

Estimation of growth curves from longitudinal data collected at irregular time intervals.

A general procedure for fitting growth curves is proposed that can be applied to longitudinal data even if observations are missing or irregularly spaced. Maximum likelihood estimates for mean growths are obtained from an EM algorithm. Estimates for standard errors, percentiles, and growth velocities are also produced. The techniques are demonstrated through the use of growth data from a longitudinal study of sickle cell disease.

Algorithms↗

Parametric inference for epidemic models.

The likelihood function corresponding to epidemic data is often very complicated. We illustrate that the EM algorithm can sometimes help to simplify likelihood inferences. Difficulties with likelihood inferences about parameters of epidemic models have established a role for martingale methods. These are methods of statistical inference based on estimating equations derived from the rich theory of martingales, and they have produced simple methods of inference in a number of important applications to epidemic data. We contrast likelihood methods with martingale methods and determine which specific assumptions cause changes in inferences about the infection potential of a disease. It is found that the martingale-based estimate of the infection potential remains unaltered under a variety of commonly used model specifications but that the precision of this estimate changes as model assumptions are altered.

Algorithms↗

MIXREG: a computer program for mixed-effects regression analysis with autocorrelated errors.

MIXREG is a program that provides estimates for a mixed-effects regression model (MRM) for normally-distributed response data including autocorrelated errors. This model can be used for analysis of unbalanced longitudinal data, where individuals may be measured at a different number of timepoints, or even at different timepoints. Autocorrelated errors of a general form or following an AR(1), MA(1), or ARMA(1,1) form are allowable. This model can also be used for analysis of clustered data, where the mixed-effects model assumes data within clusters are dependent. The degree of dependency is estimated jointly with estimates of the usual model parameters, thus adjusting for clustering. MIXREG uses maximum marginal likelihood estimation, utilizing both the EM algorithm and a Fisher-scoring solution. For the scoring solution, the covariance matrix of the random effects is expressed in its Gaussian decomposition, and the diagonal matrix reparameterized using the exponential transformation. Estimation of the individual random effects is accomplished using an empirical Bayes approach. Examples illustrating usage and features of MIXREG are provided.

Adolescent↗

Sensitivity and specificity of diagnostic tests in acute maxillary sinusitis determined by maximum likelihood in the absence of an external standard.

This study shows how to obtain maximum likelihood estimates of test sensitivities and specificities in case of lack of an external standard, using the Expectation Maximisation (EM) algorithm. This method is used to compare four diagnostic tests in patients suspected of acute maxillary sinusitis. Data were analyzed from published studies. Antral aspiration is the test with the highest diagnostic value. The diagnostic value of a positive clinical examination (according to explicit criteria) and of a positive radiograph or ultrasound are comparable. A negative radiograph is of more diagnostic value than a negative clinical examination or ultrasound. The width of the confidence intervals may be too small, due to model deviations which may give incorrect standard errors. However, the estimated likelihood ratios adequately reflect the relative value of the diagnostic tests considered, even when the assumption of independence is dropped.

Acute Disease↗

Sharpening spots: correcting for bleedover in cDNA array images.

For cDNA array methods that depend on imaging of a radiolabel, we show that bleedover of one spot onto another, due to the gap between the array and the imaging media, can be a major problem. The images can be sharpened, however, using a blind convolution method based on the EM algorithm. The sharpened images look like a set of donuts, which concurs with our knowledge of the spotting process. Oversharpened images are actually useful as well, in locating the centers of each spot.

Algorithms↗

Maximum likelihood and Bayesian methods for estimating the distribution of selective effects among classes of mutations using DNA polymorphism data.

Maximum likelihood and Bayesian approaches are presented for analyzing hierarchical statistical models of natural selection operating on DNA polymorphism within a panmictic population. For analyzing Bayesian models, we present Markov chain Monte-Carlo (MCMC) methods for sampling from the joint posterior distribution of parameters. For frequentist analysis, an Expectation-Maximization (EM) algorithm is presented for finding the maximum likelihood estimate of the genome wide mean and variance in selection intensity among classes of mutations. The framework presented here provides an ideal setting for modeling mutations dispersed through the genome and, in particular, for the analysis of how natural selection operates on different classes of single nucleotide polymorphisms (SNPs).

Bayes Theorem↗

The loss of statistical power to distinguish populations when certain samples are ambiguous.

Case-control studies are used to map loci associated with a genetic disease. The usual case-control study tests for significant differences in frequencies of alleles at marker loci. In this paper, we consider the problem of comparing two or more marker loci simultaneously and testing for significant differences in haplotype rather than allele frequencies. We consider two situations. In the first, genotypes at marker loci are resolved into haplotypes by making use of biochemical methods or by genotyping family members. In the second, genotypes at marker loci are not resolved into haplotypes, but, by assuming random mating, haplotypes can be inferred using a likelihood method such as the expectation-maximization (EM) algorithm. We assume that a causative locus has two alleles with a multiplicative effect on the penetrance of a disease, with one allele increasing the penetrance by a factor pi. We find, for small values of pi-1 and large sample sizes, asymptotic results that predict the statistical power of a test for significant differences in haplotype frequencies between cases and a random sample of the population, both when haplotypes can be resolved and when haplotypes have to be inferred. The increase in power when haplotypes can be resolved can be expressed as a ratio R, which is the increase in sample size needed to achieve the same power when haplotypes are resolved over when they are not resolved. In general, R depends on the pattern of linkage disequilibrium between the causative allele and the marker haplotypes but is independent of the frequency of the causative allele and, to a first approximation, is independent of pi. For the special situation of two di-allelic marker loci, we obtain a simple expression for R and its upper bound.

Alleles↗

A SAS macro for sample size re-estimation.

The assessment of sample size in clinical trials comparing means requires a variance estimate of the main efficacy variable. If no reliable information about the variance of the key response is available at the beginning of a clinical trial, the use of data from the first 'few' patients entered in the trial ('internal pilot') may be appropriate to estimate the variance and thus to recalculate the required sample size. A SAS macro that implements the EM algorithm for carrying out and simulating such interim power evaluations without unblinding the treatment status is presented.

Algorithms↗

A zero-inflated Poisson mixed model to analyze diagnosis related groups with majority of same-day hospital stays.

With increasing trend of same-day procedures and operations performed for hospital admissions, it is important to analyze those Diagnosis Related Groups (DRGs) consisting of mainly same-day separations. A zero-inflated Poisson (ZIP) mixed model is presented to identify health- and patient-related characteristics associated with length of stay (LOS) and to model variations in LOS within such DRGs. Random effects are introduced to account for inter-hospital variations and the dependence of clustered LOS observations via the generalized linear mixed models (GLMM) approach. Parameter estimation is achieved by maximizing an appropriate log-likelihood function using the EM algorithm to obtain approximate residual maximum likelihood (REML) estimates. An S-Plus macro is developed to provide a unified ZIP modeling approach. The determination of pertinent factors would benefit hospital administrators and clinicians to manage LOS and expenditures efficiently.

Algorithms↗