Bayesian designs with frequentist and Bayesian error rate considerations

So far, most Phase II trials have been designed and analysed under a frequentist framework. Under this framework, a trial is designed so that the overall Type I and Type II errors of the trial are controlled at some desired levels. Recently, a number of articles have advocated the use of Bavesian designs in practice. Under a Bayesian framework, a trial is designed so that the trial stops when the posterior probability of treatment is within certain prespecified thresholds. In this article, we argue that trials under a Bayesian framework can also be designed to control frequentist error rates. We introduce a Bayesian version of Simon's well-known two-stage design to achieve this goal. We also consider two other errors, which are called Bayesian errors in this article because of their similarities to posterior probabilities. We show that our method can also control these Bayesian-type errors. We compare our method with other recent Bayesian designs in a numerical study and discuss implications of different designs on error rates. An example of a clinical trial for patients with nasopharyngeal carcinoma is used to illustrate differences of the different designs.

Use of Petrifilm(R) 3M to assess coliform numbers on lamb carcasses.

Petrifilm(R) (6410) was used directly on lamb carcasses to enumerate coliforms. 10 sites on 30 carcasses were sampled at each of 4 separate meat processing establishments (works). Coliform counts obtained by this technique were statistically analysed using analysis of variance (ANOVA) to select the optimum sampling sites on the carcass and to assess contamination of the carcass by gut flora at a particular establishment. There was a large variation between sites and between works. In general, works 3 and 4 produced cleaner carcasses than works 2, which in turn was cleaner than works 1. Works 1, 2 and 4 used conventional dressing techniques and works 3 used the inverted dressing method, therefore, the coliform counts found at works 3 and 4 are achievable regardless of dressing technique. Coliform bacteria were most concentrated around the posterior pelvic rim and less prevalent at the carcass extremities. The posterior pelvic rim (sites 3 and 4) had higher (P < 0.05) coliform counts than the exterior ventral flank area (sites 5, 6, 7 and 8), which in turn had higher (P < 0.05) counts than the proximal hind and proximal fore limbs (sites 1, 2, 9 and 10) across all works. With in-line routine testing it is recommended that the majority of carcasses sampled should give coliform counts of <50 cfu/20 cm2 for sites 4 and 8. Reprinted with permission from Journal of Food Protection. Copyright held by the International Association of Food Protection, Des Moines, Iowa, USA. Authors affifiation. J.A.Guthrie & K.J.Dunlop International Food Institute of Queensland, Department of Primary Industries, Rockhampton and G.A.Saunders Veterinary Public Health Division, Livestock and Meat Authority of Queensland, Emerald.

Partial intervertebral fusion secures successful outcomes after thoracoscopic anterior scoliosis correction: A low-dose computed tomography study

Study Design Retrospective review of prospectively collected data. Objectives To analyze intervertebral (IV) fusion after thoracoscopic anterior spinal fusion (TASF) and explore the relationship between fusion scores and key clinical variables. Summary of Background Information TASF provides comparable correction with some advantages over posterior approaches but reported mechanical complications, and their relationship to non-union and graft material is unclear. Similarly, the optimal combination of graft type and implant stiffness for effecting successful radiologic union remains undetermined. Methods A subset of patients from a large single-center series who had TASF for progressive scoliosis underwent low-dose computed tomographic scans 2 years after surgery. The IV fusion mass in the disc space was assessed using the 4-point Sucato scale, where 1 indicates <50% and 4 indicates 100% bony fusion of the disc space. The effects of rod diameter, rod material, graft type, fusion level, and mechanical complications on fusion scores were assessed. Results Forty-three patients with right thoracic major curves (mean age 14.9 years) participated in the study. Mean fusion scores for patient subgroups ranged from 1.0 (IV levels with rod fractures) to 2.2 (4.5-mm rod with allograft), with scores tending to decrease with increasing rod size and stiffness. Graft type (autograft vs. allograft) did not affect fusion scores. Fusion scores were highest in the middle levels of the rod construct (mean 2.52), dropping off by 20% to 30% toward the upper and lower extremities of the rod. IV levels where a rod fractured had lower overall mean fusion scores compared to levels without a fracture. Mean total Scoliosis Research Society (SRS) questionnaire scores were 98.9 from a possible total of 120, indicating a good level of patient satisfaction. Conclusions Results suggest that 100% radiologic fusion of the entire disc space is not necessary for successful clinical outcomes following thoracoscopic anterior selective thoracic fusion.

Quantifying progressive anterior overgrowth in the thoracic vertebrae of adolescent idiopathic scoliosis patients

Study design Anterior and posterior vertebral body heights were measured from sequential MRI scans of adolescent idiopathic scoliosis (AIS) patients and healthy controls. Objective To measure changes in vertebral body height over time during scoliosis progression to assess how vertebral body height discrepancies change during growth. Summary of background data Relative anterior overgrowth has been proposed as a potential driver for AIS initiation and progression. This theory proposes that the anterior column grows faster, and the posterior column slower, in AIS patients when compared to healthy controls. There is disagreement in the literature as to whether the anterior vertebral body heights are proportionally greater than posterior vertebral body heights in AIS patients when compared to healthy controls. To some extent, these discrepancies may be attributed to methodological differences. Methods MRI scans of the major curve of 21 AIS patients (mean age 12.5 ± 1.4 years, mean Cobb 32.2 ± 12.8º) and between T4 and T12 of 21 healthy adolescents (mean age 12.1 ± 0.5 years) were captured for this study. Of the 21 AIS patients, 14 had a second scan on average 10.8 ± 4.7 months after the first. Anterior and posterior vertebral body heights were measured from the true sagittal plane of each vertebra such that anterior overgrowth could be quantified. Results The difference between anterior and posterior vertebral body height in healthy, non-scoliotic children was significantly greater than in AIS patients with mild to moderate scoliosis. However there was no significant relationship between the overall anterior-posterior vertebral body height difference in AIS and either severity of the curve or its progression over time. Conclusions Whilst AIS patients have a proportionally longer anterior column than non-scoliotic controls, the degree of anterior overgrowth was not related to the rate of progression or the severity of the scoliotic curve.

Overfitting Bayesian mixture models with an unknown number of components

This paper proposes solutions to three issues pertaining to the estimation of finite mixture models with an unknown number of components: the non-identifiability induced by overfitting the number of components, the mixing limitations of standard Markov Chain Monte Carlo (MCMC) sampling techniques, and the related label switching problem. An overfitting approach is used to estimate the number of components in a finite mixture model via a Zmix algorithm. Zmix provides a bridge between multidimensional samplers and test based estimation methods, whereby priors are chosen to encourage extra groups to have weights approaching zero. MCMC sampling is made possible by the implementation of prior parallel tempering, an extension of parallel tempering. Zmix can accurately estimate the number of components, posterior parameter estimates and allocation probabilities given a sufficiently large sample size. The results will reflect uncertainty in the final model and will report the range of possible candidate models and their respective estimated probabilities from a single run. Label switching is resolved with a computationally light-weight method, Zswitch, developed for overfitted mixtures by exploiting the intuitiveness of allocation-based relabelling algorithms and the precision of label-invariant loss functions. Four simulation studies are included to illustrate Zmix and Zswitch, as well as three case studies from the literature. All methods are available as part of the R package Zmix, which can currently be applied to univariate Gaussian mixture models.

Accelerating Pseudo-Marginal MCMC using Gaussian Processes

Pseudo-marginal methods such as the grouped independence Metropolis-Hastings (GIMH) and Markov chain within Metropolis (MCWM) algorithms have been introduced in the literature as an approach to perform Bayesian inference in latent variable models. These methods replace intractable likelihood calculations with unbiased estimates within Markov chain Monte Carlo algorithms. The GIMH method has the posterior of interest as its limiting distribution, but suffers from poor mixing if it is too computationally intensive to obtain high-precision likelihood estimates. The MCWM algorithm has better mixing properties, but less theoretical support. In this paper we propose to use Gaussian processes (GP) to accelerate the GIMH method, whilst using a short pilot run of MCWM to train the GP. Our new method, GP-GIMH, is illustrated on simulated data from a stochastic volatility and a gene network model.

The impact of inter-fraction set-up errors on the probability of pulmonary and cardiac complication in left-sided breast cancer patients

Purpose This study evaluated the impact of patient set-up errors on the probability of pulmonary and cardiac complications in the irradiation of left-sided breast cancer. Methods and Materials Using the CMS XiO Version 4.6 (CMS Inc., St Louis, MO) radiotherapy planning system's NTCP algorithm and the Lyman -Kutcher-Burman (LKB) model, we calculated the DVH indices for the ipsilateral lung and heart and the resultant normal tissue complication probabilities (NTCP) for radiation-induced pneumonitis and excess cardiac mortality in 12 left-sided breast cancer patients. Results Isocenter shifts in the posterior direction had the greatest effect on the lung V20, heart V25, mean and maximum doses to the lung and the heart. Dose volume histograms (DVH) results show that the ipsilateral lung V20 tolerance was exceeded in 58% of the patients after 1cm posterior shifts. Similarly, the heart V25 tolerance was exceeded after 1cm antero-posterior and left-right isocentric shifts in 70% of the patients. The baseline NTCPs for radiation-induced pneumonitis ranged from 0.73% - 3.4% with a mean value of 1.7%. The maximum reported NTCP for radiation-induced pneumonitis was 5.8% (mean 2.6%) after 1cm posterior isocentric shift. The NTCP for excess cardiac mortality were 0 % in 100% of the patients (n=12) before and after setup error simulations. Conclusions Set-up errors in left sided breast cancer patients have a statistically significant impact on the Lung NTCPs and DVH indices. However, with a central lung distance of 3cm or less (CLD <3cm), and a maximum heart distance of 1.5cm or less (MHD<1.5cm), the treatment plans could tolerate set-up errors of up to 1cm without any change in the NTCP to the heart.

CBCT image guidance in head and neck irradiation: The impact of daily and weekly imaging protocols

Purpose This study evaluated the impact of a daily and weekly image-guided radiotherapy protocols in reducing setup errors and setting of appropriate margins in head and neck cancer patients. Materials and methods Interfraction and systematic shifts for the hypothetical day 1–3 plus weekly imaging were extrapolated from daily imaging data from 31 patients (964 cone beam computed tomography (CBCT) scans). In addition, residual setup errors were calculated by taking the average shifts in each direction for each patient based on the first three shifts and were presumed to represent systematic setup error. The clinical target volume (CTV) to planning target volume (PTV) margins were calculated using van Herk formula and analysed for each protocol. Results The mean interfraction shifts for daily imaging were 0·8, 0·3 and 0·5 mm in the S-I (superior-inferior), L-R (left-right) and A-P (anterior-posterior) direction, respectively. On the other hand the mean shifts for day 1–3 plus weekly imaging were 0·9, 1·8 and 0·5 mm in the S-I, L-R and A-P direction, respectively. The mean day 1–3 residual shifts were 1·5, 2·1 and 0·7 mm in the S-I, L-R and A-P direction, respectively. No significant difference was found in the mean setup error for the daily and hypothetical day 1–3 plus weekly protocol. However, the calculated CTV to PTV margins for the daily interfraction imaging data were 1·6, 3·8 and 1·4 mm in the S-I, L-R and A-P directions, respectively. Hypothetical day 1–3 plus weekly resulted in CTV–PTV margins of 5, 4·2 and 5 mm in the S-I, L-R and A-P direction. Conclusions The results of this study show that a daily CBCT protocol reduces setup errors and allows setup margin reduction in head and neck radiotherapy compared to a weekly imaging protocol.

Social perception and cognition : processing of gestures, postures and facial expressions in the human brain

Humans are a social species with the internal capability to process social information from other humans. To understand others behavior and to react accordingly, it is necessary to infer their internal states, emotions and aims, which are conveyed by subtle nonverbal bodily cues such as postures, gestures, and facial expressions. This thesis investigates the brain functions underlying the processing of such social information. Studies I and II of this thesis explore the neural basis of perceiving pain from another person s facial expressions by means of functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). In Study I, observing another s facial expression of pain activated the affective pain system (previously associated with self-experienced pain) in accordance with the intensity of the observed expression. The strength of the response in anterior insula was also linked to the observer s empathic abilities. The cortical processing of facial pain expressions advanced from the visual to temporal-lobe areas at similar latencies (around 300 500 ms) to those previously shown for emotional expressions such as fear or disgust. Study III shows that perceiving a yawning face is associated with middle and posterior STS activity, and the contagiousness of a yawn correlates negatively with amygdalar activity. Study IV explored the brain correlates of interpreting social interaction between two members of the same species, in this case human and canine. Observing interaction engaged brain activity in very similar manner for both species. Moreover, the body and object sensitive brain areas of dog experts differentiated interaction from noninteraction in both humans and dogs whereas in the control subjects, similar differentiation occurred only for humans. Finally, Study V shows the engagement of the brain area associated with biological motion when exposed to the sounds produced by a single human being walking. However, more complex pattern of activation, with the walking sounds of several persons, suggests that as the social situation becomes more complex so does the brain response. Taken together, these studies demonstrate the roles of distinct cortical and subcortical brain regions in the perception and sharing of others internal states via facial and bodily gestures, and the connection of brain responses to behavioral attributes.

Corneal confocal microscopy predicts 4-year incident peripheral neuropathy in Type 1 diabetes

OBJECTIVE This study determined if deficits in corneal nerve fiber length (CNFL) assessed using corneal confocal microscopy (CCM) can predict future onset of diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS CNFL and a range of other baseline measures were compared between 90 nonneuropathic patients with type 1 diabetes who did or did not develop DPN after 4 years. The receiver operator characteristic (ROC) curve was used to determine the capability of single and combined measures of neuropathy to predict DPN. RESULTS DPN developed in 16 participants (18%) after 4 years. Factors predictive of 4-year incident DPN were lower CNFL (P = 0.041); longer duration of diabetes (P = 0.002); higher triglycerides (P = 0.023); retinopathy (higher on the Early Treatment of Diabetic Retinopathy Study scale) (P = 0.008); nephropathy (higher albumin-to-creatinine ratio) (P = 0.001); higher neuropathy disability score (P = 0.037); lower cold sensation (P = 0.001) and cold pain (P = 0.027) thresholds; higher warm sensation (P = 0.008), warm pain (P = 0.024), and vibration (P = 0.003) thresholds; impaired monofilament response (P = 0.003); and slower peroneal (P = 0.013) and sural (P = 0.002) nerve conduction velocity. CCM could predict the 4-year incident DPN with 63% sensitivity and 74% specificity for a CNFL threshold cutoff of 14.1 mm/mm2 (area under ROC curve = 0.66, P = 0.041). Combining neuropathy measures did not improve predictive capability. CONCLUSIONS DPN can be predicted by various demographic, metabolic, and conventional neuropathy measures. The ability of CCM to predict DPN broadens the already impressive diagnostic capabilities of this novel ophthalmic marker.

Dynamics of contour, object and face processing in the human visual cortex

The neural basis of visual perception can be understood only when the sequence of cortical activity underlying successful recognition is known. The early steps in this processing chain, from retina to the primary visual cortex, are highly local, and the perception of more complex shapes requires integration of the local information. In Study I of this thesis, the progression from local to global visual analysis was assessed by recording cortical magnetoencephalographic (MEG) responses to arrays of elements that either did or did not form global contours. The results demonstrated two spatially and temporally distinct stages of processing: The first, emerging 70 ms after stimulus onset around the calcarine sulcus, was sensitive to local features only, whereas the second, starting at 130 ms across the occipital and posterior parietal cortices, reflected the global configuration. To explore the links between cortical activity and visual recognition, Studies II III presented subjects with recognition tasks of varying levels of difficulty. The occipito-temporal responses from 150 ms onwards were closely linked to recognition performance, in contrast to the 100-ms mid-occipital responses. The averaged responses increased gradually as a function of recognition performance, and further analysis (Study III) showed the single response strengths to be graded as well. Study IV addressed the attention dependence of the different processing stages: Occipito-temporal responses peaking around 150 ms depended on the content of the visual field (faces vs. houses), whereas the later and more sustained activity was strongly modulated by the observers attention. Hemodynamic responses paralleled the pattern of the more sustained electrophysiological responses. Study V assessed the temporal processing capacity of the human object recognition system. Above sufficient luminance, contrast and size of the object, the processing speed was not limited by such low-level factors. Taken together, these studies demonstrate several distinct stages in the cortical activation sequence underlying the object recognition chain, reflecting the level of feature integration, difficulty of recognition, and direction of attention.

Human brain networks of auditory attention and working memory

This thesis examines brain networks involved in auditory attention and auditory working memory using measures of task performance, brain activity, and neuroanatomical connectivity. Auditory orienting and maintenance of attention were compared with visual orienting and maintenance of attention, and top-down controlled attention was compared to bottom-up triggered attention in audition. Moreover, the effects of cognitive load on performance and brain activity were studied using an auditory working memory task. Corbetta and Shulman s (2002) model of visual attention suggests that what is known as the dorsal attention system (intraparietal sulcus/superior parietal lobule, IPS/SPL and frontal eye field, FEF) is involved in the control of top-down controlled attention, whereas what is known as the ventral attention system (temporo-parietal junction, TPJ and areas of the inferior/middle frontal gyrus, IFG/MFG) is involved in bottom-up triggered attention. The present results show that top-down controlled auditory attention also activates IPS/SPL and FEF. Furthermore, in audition, TPJ and IFG/MFG were activated not only by bottom-up triggered attention, but also by top-down controlled attention. In addition, the posterior cerebellum and thalamus were activated by top-down controlled attention shifts and the ventromedial prefrontal cortex (VMPFC) was activated by to-be-ignored, but attention-catching salient changes in auditory input streams. VMPFC may be involved in the evaluation of environmental events causing the bottom-up triggered engagement of attention. Auditory working memory activated a brain network that largely overlapped with the one activated by top-down controlled attention. The present results also provide further evidence of the role of the cerebellum in cognitive processing: During auditory working memory tasks, both activity in the posterior cerebellum (the crus I/II) and reaction speed increased when the cognitive load increased. Based on the present results and earlier theories on the role of the cerebellum in cognitive processing, the function of the posterior cerebellum in cognitive tasks may be related to the optimization of response speed.

Atmospheric visibility and PM10 as indicators of new particle formation in an urban environment

It is well-known that new particle formation (NPF) in the atmosphere is inhibited by pre-existing particles in the air that act as condensation sinks to decrease the concentration and, thus, the supersaturation of precursor gases. In this study, we investigate the effects of two parameters - atmospheric visibility, expressed as the particle back-scatter coefficient (BSP), and PM10 particulate mass concentration, on the occurrences of NPF events in an urban environment where the majority of precursor gases originate from motor vehicle and industrial sources. This is the first attempt to derive direct relationships between each of these two parameters and the occurrence of NPF. NPF events were identified from data obtained with a neutral cluster and air ion spectrometer over 245 days within a calendar year. Bayesian logistic regression was used to determine the probability of observing NPF as functions of BSP and PM10. We show that the BSP at 08 h on a given day is a reliable indicator of an NPF event later that day. The posterior median probability of observing an NPF event was greater than 0.5 (95%) when the BSP at 08 h was less than 6.8 Mm-1.

Hypoxic corneal changes following 8 hours of scleral contact lens wear

- Purpose To examine the change in corneal thickness and posterior curvature following 8 hours of miniscleral contact lens wear. - Methods Scheimpflug imaging (Pentacam HR, Oculus) was captured before, and immediately following, 8 hours of miniscleral contact lens wear for 15 young (mean age 22 ± 3 years), healthy participants with normal corneae. Natural diurnal variations were considered by measuring baseline corneal changes obtained on a separate control day without contact lens wear. - Results Over the central 6 mm of the cornea, a small, but highly statistically significant amount of edema was observed following 8 hours of miniscleral lens wear, after accounting for normal diurnal fluctuations (mean ± standard deviation percentage swelling 1.70 ± 0.98%, p < 0.0001). Posterior corneal topography remained stable following lens wear (-0.01 ± 0.07 mm steepening over the central 6 mm, p = 0.60). The magnitude of posterior corneal topographical changes following lens wear did not correlate with the extent of lens-related corneal edema (r = -0.16, p = 0.57). Similarly, the initial central corneal vault (maximum post-lens tear layer depth) was not associated with corneal swelling following lens removal (r = 0.27, p = 0.33). - Conclusions While a small amount of corneal swelling was induced following 8 hours of miniscleral lens wear (on average <2%), modern high Dk miniscleral contact lenses that vault the cornea do not induce clinically significant corneal edema or hypoxic related posterior corneal curvature changes during short-term wear. Longer-term studies of compromised eyes (e.g. corneal ectasia) are still required to inform the optimum lens and fitting characteristics for safe scleral lens wear to minimize corneal hypoxia.

A rapid and sensitive method for the estimation of individual tRNA pools

A rapid and sensitive method is described to quantitatively compare tRNA pools for individual aminoacids in a single experiment. The procedure comprises of: (i) charging of total tRNA with a mixture of radiolabeled aminoacids, (ii) deacylation of the esterified tRNA with a volatile base and the recovery of the labeled aminoacid, (iii) derivatisation of the aminoacid with phenylisothiocyanate after mixing with excess of nonradioactive aminoacids, (iv) baseline separation of the phenylthiocarbamyl aminoacids by reverse phase high performance liquid chromatography monitored by A254nm and (v) quantitation of the radioactivity in individual aminoacid peaks. The radioactivity in the aminoacid peak corresponds to the quantity of the aminoacylated tRNA. The method has been successfully applied to quantitate the individual tRNA pools in the developing silk glands of Bombyx mori, a functionally adapted tissue which undergoes considerable variations in tRNA content. PSG, posterior silk gland; PITC, phenylisothiocyanate; DMAA, N,N-dimethyl-N-allylamine; APH, algal protein hydrolysate; ptc-, phenylthiocarbamyl; HPLC, high performance liquid chromatography.