Patterns of correlation of facial shape with physiological measurements are more integrated than patterns of correlation with ratings.

This article exploits a method recently incorporated in the geometric morphometric toolkit that complements previous approaches to quantifying the facial features associated with specific body characteristics and trait attribution during social perception. The new method differentiates more globally encoded from more locally encoded information by a summary scaling dimension that is estimated by fitting a line to the plot of log bending energy against log variance explained, partial warp by partial warp, for some sample of varying shapes. In the present context these variances come from the regressions of shape on some exogenous cause or effect of form. We work an example involving data from male faces. Here the regression slopes are steepest, and the sums of explained variances over the uniform component, partial warp 1 and partial warp 2 are greatest, for the conventional body mass index, followed by cortisol and, lastly, perceived health. This suggests that physiological characteristics may be represented at larger scale (global patterns), whereas cues in perception are of smaller scale (local patterns). Such a polarity within psychomorphospace, the global versus the focal, now has a metric by which patterns of morphology can be modeled in both biological and psychological studies.

Suggested statistical standards for NTT manuscripts: notes from two of your reviewers.

The purpose of a scientific paper in this journal is to persuade the reader of some important or potentially important facts. For a reader to be persuaded, first the manuscript reviewers must be persuaded, and if the manuscript involves statistical reasoning, at least one of those reviewers is likely to be a statistician. This invited article, by two long-time reviewers for Neurotoxicology and Teratology (NTT) who are also contributors of statistical papers, surveys some of the principles that render a manuscript more persuasive or less persuasive in our eyes. These principles are overwhelmingly not statistical but logical. For one typical NTT manuscript theme, the relation between some toxic exposure and one or more negative outcomes in humans, the aspects of manuscripts we scrutinize most closely include biological plausibility, dose-response relationships, breadth of evidence, adjustments for measurement bias, attention to assumptions and scatterplots in the search for confounds, and, in general, a sincere attempt to enunciate and then refute plausible hypotheses rival to the one the investigators prefer. The literature of excellent studies in other fields provides ample instances of good practice in these matters; we review it in those fields for applications in ours. Formal statistical significance testing plays almost no role in the most persuasive papers. In particular, findings that appear only after "adjustment for covariates" are never considered credible by these reviewers; we explain our reasons at length, and suggest alternatives.

Challenges in presenting high dimensional data to aid in triage in the DARPA virtual soldier project.

One of the goals of the DARPA Virtual Soldier Project is to aid the field medic in the triage of a casualty. In Phase I, we are currently collecting 12 baseline experimental physiological variables and a cardiac gated Computed Tomography (CT) imagery for use in an prototyping a futuristic electronic medical record, the "Holomer". We are using physiological models and Kalman filtering to aid in diagnosis and predict outcomes in relation to cardiac injury. The physiological modeling introduces another few hundred variables. Reducing the complexity of the above into easy-to-read text to aid in the triage by the field medic is the challenge with multiple display solutions. A description of the possible techniques follows.

Regional dissociated heterochrony in multivariate analysis.

Heterochrony, the classic framework to study ontogeny and phylogeny, in essence relies on a univariate concept of shape. Though principal component plots of multivariate shape data seem to resemble classical bivariate allometric plots, the language of heterochrony cannot be translated directly into general multivariate methodology. We simulate idealized multivariate ontogenetic trajectories and demonstrate their behavior in principal component plots in shape space and in size-shape space. The concept of "dissociation", which is conventionally regarded as a change in the relationship between shape change and size change, appears to be algebraically the same as regional dissociation - the variation of apparent heterochrony by region. Only if the trajectories of two related species lie along exactly the same path in shape space can the classic terminology of heterochrony apply so that pure dissociation of size change against shape change can be detected. We demonstrate a geometric morphometric approach to these issues using adult and subadult crania of 48 Pan paniscus and 47 P. troglodytes. On each specimen we digitized 47 landmarks and 144 semilandmarks on ridge curves and the external neurocranial surface. The relation between these two species' growth trajectories is too complex for a simple summary in terms of global heterochrony.

Chiari-II malformation: a biometric analysis.

INTRODUCTION: Chiari-II malformation is a complex set of anatomic abnormalities of the posterior fossa, brainstem, and cerebellum seen in myelomeningocele. Previous studies have tried to understand this condition and its clinical consequences by studying a few fixed anatomic landmarks as dependent variables and clinical symptoms as outcome variables. These studies have led to conflicting and limited results. As a first step towards a more comprehensive study of the structural-functional relationships in Chiari-II malformation, we undertook a biometric case-series analysis of a group of individuals with MMC, using both traditional methods to study size, and thin-plate spline methodology to study shape. MATERIALS AND METHODS: The traditional analysis was a retrospective, randomly obtained case-series of 25 individuals with myelomeningocele and Chiari-II malformation. MRIs were digitized for biometric analysis of the component structures and compared to 25 controls. Landmarks on the digitized images were measured using Scion Image. Data were statistically analyzed using SPSS. The thin-plate spline analysis used a subset of these individuals (n = 14). Landmarks on digitized MRIs were identified and marked with TPSDig software. Landmark data was then imported into Splus to generate a series of shape variables. Statistical analysis using Splus was then undertaken. RESULTS: Traditional analysis revealed relationships between vermian herniation and pontomedullary junction position (p < 0.05) as well as between the height (and overall size) of the posterior fossa and degree of vermian herniation (p < 0.05). The degree of brainstem herniation/elongation did not correlate with the degree of vermian herniation. The shape analysis revealed that there is as much shape variability within the group of Chiari-II patients as there is between this group and unaffected controls. Thin-plate spline analysis shows that the position of the caudal-most aspect of the vermis is the point of greatest brain rearrangement; likewise, the opisthion is the point of greatest bony rearrangement. Partial least-squares analysis shows that in Chiari-II patients, a strong correlation (r = 0.821) exists between the extent to which the brain is warped (specifically, in regard to vermian descent) and the extent to which the bone is warped (specifically, in regard to the displacement of the opisthion) (p < 0.05). CONCLUSION: Traditional biometric analysis of size confirms that the degree of vermian herniation and cervicomedullary junction herniation are independent variables in Chiari-II malformation. Posterior fossa size is an important factor in explaining the variability of vermian herniation. The relationship between IPN position and vermian herniation suggests the possibility of a common etiology. The phenomenon of cervicomedullary junction descent appears to be independent, suggesting a different etiology. Analysis of shape indicated that shape changes in bone and brain are related, and that the Chiari-II-associated abnormalities vary greatly in their degree of abnormality. The extreme morphological variability argues against the use of mean differences as a statistical technique in analyzing morphological abnormalities in the structures we investigated.

"Voxel-based morphometry" should not be used with imperfectly registered images.

John Ashburner and Karl Friston (2000) introduced a standardized method of "voxel-based morphometry" (VBM) for comparisons of local concentrations of gray matter between two groups of subjects. Segmented images of gray matter from grossly normalized high-resolution images are smoothed and their group differences analyzed by the now-conventional voxelwise Worsley approach to Gaussian random fields of differences. This comment concerns an unfortunate interaction between the algorithm's spatial normalization and voxelwise comparison steps, whereby several obvious quantitative confounds are injected at the core of the inference engine the authors put forward. Specifically, the statistics of the resulting voxelwise comparisons are uninformative about group differences wherever the spatial normalization algorithm has failed to register on any robustly appearing image gradient. The method of Ashburner and Friston is defensible only far from all image gradients.

Pulse-spray thrombolysis with reteplase: optimization and comparison with tPA in a rabbit model.

PURPOSE: To critically evaluate and optimize methodology for pulse-spray thrombolysis with reteplase in a rabbit inferior vena cava (IVC) thrombosis model and to compare results with optimized parameters for the use of tissue plasminogen activator (tPA). MATERIALS AND METHODS: Occlusive IVC thrombus was produced in 102 rabbits and treated 2 days later for 1 hour with pulse-spray thrombolysis using reteplase. Methodologic variables included pulse frequency, concentration and amount of reteplase, infusion versus pulse therapy, and admixture of heparin. After the rabbits were killed, residual thrombus was weighed and percent lysis was estimated on the basis of previous control values. Results were compared with those achieved with tPA in 18 additional rabbits and also with previous tPA results. RESULTS: As in earlier tPA studies, pulse-spray methods were far more effective than constant infusion. Pulses at 30-second intervals produced better results than pulses at 2-minute intervals. At the optimal concentration of 0.02 U/mL (molarity 90 x 10(-8) ), reteplase produced 79% lysis. At two-fold higher or lower concentrations, lysis was reduced by approximately 25%, and at eight-fold higher or six-fold lower concentrations, lysis was reduced by approximately 50%. Optimal concentration of tPA was 0.02 mg/mL, yielding 78% lysis. Admixture of reteplase with heparin suggested improvement, but differences were statistically insignificant. CONCLUSION: When used with pulse-spray methodology, reteplase demonstrated a steep bell-shaped response-concentration curve similar in pitch and amplitude to that of tPA. The optimal molar concentration of reteplase was approximately three times that of tPA. However, at their respective optimal concentrations, reteplase and tPA were equally effective.

Diaphragmatic shape change after lung volume reduction surgery.

Diaphragmatic shape in normal patients was significantly different from shape in emphysema patients. Postoperative diaphragmatic shape in patients with good clinical outcome differed from preoperative shape and was similar to shape in normal patients. In patients with poor clinical outcome, surgery appeared to have little effect on diaphragm shape.

Geometric morphometrics of corpus callosum and subcortical structures in the fetal-alcohol-affected brain.

BACKGROUND: Although experienced clinicians have been diagnosing fetal alcohol syndrome (FAS) for nearly 30 years, the rest of the spectrum of fetal alcohol damage is not being classified effectively. This article describes a quantification of neuroanatomical structure that may supply a useful discriminator of prenatal brain damage from alcohol. It is demonstrated in a data set of adults of both sexes. METHODS: Ninety adults (45 males) were examined by magnetic resonance imaging (MRI). These subjects were group-matched for age and ethnicity across three diagnoses: FAS, fetal alcohol effects (FAE), and normals. All FAS and FAE were heavily alcohol-exposed in utero; normals were not. From T(1)-weighted MR brain images, we extracted 3D morphometric representations of shape for 33-landmark point configurations and 40-point outlines of the corpus callosum along its midline (a slightly nonplanar structure). RESULTS: There are striking differences between exposed and unexposed in the statistical distributions of these two shapes. The differences are better characterized by excess variance in the exposed group than by any change in average landmark or outline shape. For each sex, combining the callosal outline data with the landmark data leads to a powerful quadratic discriminator of exposed from unexposed. The discriminating features include the relationship of brain stem to diencephalon, and localized variabilities of callosal outline shape, but not diagnosis (FAS vs. FAE). CONCLUSIONS: Statistical analysis of brain shape is a powerful new source of information relevant to fetal alcohol spectrum nosology and etiology. Patients with FAS and FAE do not differ in these brain shape features, but both differ from the unexposed. The aspects of brain shape that are especially variable may be entailed in the underlying neuroteratogenetic mechanisms.

Pain in U.S. nursing homes: validating a pain scale for the minimum data set.

PURPOSE: The aim of this study was to validate a pain scale for the Minimum Data Set (MDS) assessment instrument and examine prevalence of pain in major nursing home subpopulations, including type of admission and cognitive status. DESIGN AND METHODS: This study considered validation of the MDS pain items and derivation of scale performed against the Visual Analogue Scale (VAS), using Automatic Interaction Detection. The derivation data describe 95 postacute care nursing home patients who are able to communicate. The scale is then used in retrospective analysis of 34,675 Michigan nursing home residents. RESULTS: A four-group scale was highly predictive of VAS pain scores (variance explanation 56%) and therefore quite valid in detecting pain. In the prevalence sample, only 47% of postacute patients compared to 63% of postadmission patients reported no pain, and these percentages rose with increasing cognitive impairment. IMPLICATIONS: Pain is prevalent in nursing home residents, especially in those with cognitive dysfunction, and often untreated.

Plasminogen-enriched pulse-spray thrombolysis with tPA: further developments.

PURPOSE: To further improve methods for pulsed plasminogen-enriched thrombolysis and to compare results with the best obtainable with use of tissue plasminogen activator (tPA) alone. MATERIALS AND METHODS: Parameters of plasminogen-enriched pulse-spray thrombolysis were manipulated in groups of rabbits with inferior vena cava thrombosis, and weights of 1-hour residual thrombus were compared. Variables evaluated were (i) tPA pulse frequency, (ii) amount of plasminogen used for enrichment, (iii) tPA concentration and amount, (iv) pulsed versus infused tPA, and (v) admixture versus separation of plasminogen and tPA. RESULTS: With use of 3 mg of tPA and approximately 0.9 mg plasminogen enrichment, efficacy varied directly with pulse frequency over a pulse range of every 15 minutes to every 30 seconds. With use of 30-second pulses of tPA at a concentration 0.125 mg/mL, efficacy also correlated directly with increasing plasminogen enrichment up to, but not beyond, approximately 1.8 mg per 1.24 g of clot. Optimized methodology yielded 89% lysis in 1 hour, as compared to 74% lysis previously reported with use of optimized low-concentration (0.01 mg/ mL) tPA alone. Plasminogen enrichment in conjunction with low concentrations of tPA, admixture of tPA and plasminogen, and fractionation of the plasminogen enrichment all proved to be nonproductive or counterproductive. CONCLUSION: Optimized in vivo postthrombotic plasminogen enrichment significantly accelerated thrombolysis of experimental clots compared to use of optimized tPA alone.

Creases as local features of deformation grids.

To help identify underlying developmental or pathological processes, biological shape differences often are represented as diffeomorphisms of a Cartesian coordinate grid. The problem addressed here is the extraction of spatially discrete, localized, organized features of such transformation grids. Some features can be identified with variants of the singularity (x, y) --> (x, x2y + y) that are visually evident as creases in suitably enhanced grid diagrams. The crease is a non-generic singularity at which a pair of cusps appears as a function of a parameter for extrapolation. The examples here show how these representations extract statistically informative and scientifically helpful features from deformations that help characterize two brain diseases, schizophrenia and Fetal Alcohol Syndrome, in two dimensions. Under smoothing by relaxation of bending energy against Euclidean distance, one analogue to multiscale analysis for discrete punctate data, creases are robust in location and orientation.

Accelerated dysfunction among the very oldest-old in nursing homes.

BACKGROUND: The population aged 65 and older is often analyzed in three categories: young-old (65-74), middle-old (75-84), and oldest-old (> or = 85). This may blind heterogeneity within the oldest category. New, large data sets allow examination of the very oldest-old (e.g., aged > or = 95) and contrasts with those who are younger. METHODS: We determined the annual change of prevalence of physical and cognitive function, and of disease problems in the old to very oldest-old, using data from existing Resident Assessment Instrument records from nursing homes in seven states during 1992-1994. We used data from 193,467 unique residents aged 80 or older, including 6,556 residents aged 100 or older. We computed the prevalence, by age, of selected conditions: physical and cognitive function, diseases, problem behavior, mood disturbance, restraint use, falls, weight loss, eating less, body mass index, chewing and swallowing problems, incontinence (bowel and bladder), catheter use, and selected diagnoses. RESULTS: Prevalence of all measures of physical and cognitive dysfunction increased most rapidly with each year of age among the very oldest-old. Most of the slope changes occurred from 95 to 100 years of age. Such changes are less pronounced or not seen in measures of disease prevalence. CONCLUSIONS: Accelerated change in prevalence of dysfunction seen in the nursing home population may suggest a change in the mechanisms of aging that occur after the mid-nineties. Examination of the very oldest-old may provide new insight into the nature of the aging process.

On categorizations in analyses of alcohol teratogenesis.

In biomedical scientific investigations, expositions of findings are conceptually simplest when they comprise comparisons of discrete groups of individuals or involve discrete features or characteristics of individuals. But the descriptive benefits of categorization become outweighed by their limitations in studies involving dose-response relationships, as in many teratogenic and environmental exposure studies. This article addresses a pair of categorization issues concerning the effects of prenatal alcohol exposure that have important public health consequences: the labeling of individuals as fetal alcohol syndrome (FAS) versus fetal alcohol effects (FAE) or alcohol-related neurodevelopmental disorder (ARND), and the categorization of prenatal exposure dose by thresholds. We present data showing that patients with FAS and others with FAE do not have meaningfully different behavioral performance, standardized scores of IQ, arithmetic and adaptive behavior, or secondary disabilities. Similarly overlapping distributions on measures of executive functioning offer a basis for identifying alcohol-affected individuals in a manner that does not simply reflect IQ deficits. At the other end of the teratological continuum, we turn to the reporting of threshold effects in dose-response relationships. Here we illustrate the importance of multivariate analyses using data from the Seattle, Washington, longitudinal prospective study on alcohol and pregnancy. Relationships between many neurobehavioral outcomes and measures of prenatal alcohol exposure are monotone without threshold down to the lowest nonzero levels of exposure, a finding consistent with reports from animal studies. In sum, alcohol effects on the developing human brain appear to be a continuum without threshold when dose and behavioral effects are quantified appropriately.

Three-dimensional Bolton-Brush Growth Study landmark data: ontogeny and sexual dimorphism of the Bolton standards cohort.

OBJECTIVE: The treatment of craniofacial reconstructive surgery patients may benefit from comparison to average referent three-dimensional landmark data. These data may be useful for diagnosis, treatment planning, prosthetic design, or outcomes assessment. With regard to subadult patients, we hypothesize that the pattern of ontogenetic shape change of same sex, same ethnicity, referent populations will show gross uniformity. We present a preliminary shape analysis of 50 three-dimensional landmarks derived from 317 Bolton-Brush Growth Study biorthogonal image pairs. We determine which landmarks can be collected from scanned radiographs reliably by four operators for the precisely locatable points, ontogenetic trends in landmark configuration shape change, and patterns of sexual dimorphism. PARTICIPANTS: Participants were Bolton standards individuals (16 male and 16 female) who contributed biplane cephalograms seven or more times with annual or greater spacing between ages 3 and 18 years. DESIGN: After removing outliers, we searched for ontogenetic heterogeneity, including sexual dimorphism and within sex-specific Procrustes coordinate shape spaces. RESULTS: A cut-off of 4.3-mm interoperator error left 32 landmarks in our analysis. Three different approaches (principal component analysis, age-trend analysis, and principal components of age residuals) all found no patterns of individual variation around sex-specific average trends of shape change. Male shape change peaks at age 15, a correlate of the growth spurt. CONCLUSIONS: Simultaneous frontal and lateral anatomic landmark identification improves three-dimensional localization reliability. Three-dimensional craniodental shape change from ages 8 to 18 within the Bolton standards presents little heterogeneity. Considerations of ethnicity aside, these may be initial grounds for use of these data as a normative referent.

Augmented experimental pulse-spray thrombolysis with tissue plasminogen activator, enabling dose reduction by one or more orders of magnitude.

PURPOSE: To critically evaluate and optimize methodologic details of pulse-spray thrombolysis with tissue plasminogen activator (tPA) in a subacute rabbit inferior vena cava thrombosis model. MATERIALS AND METHODS: Occlusive inferior vena cava thrombi were produced in 104 rabbits and 2 days later were treated for 1 hour with pulse-spray thrombolysis using tPA. Methodologic variables included pulse frequency, concentration and amount of tPA, infusion versus pulse therapy, and admixture of heparin. After the rabbits were killed, residual thrombus was weighed. RESULTS: The authors' earlier standard regimen (3 mg of tPA in 6 mL of heparinized saline, 0.2-mL hand pulses, frequency 1 pulse per 2 minutes) produced 60% mean lysis. Optimization involved increasing the pulse frequency to two per minute and decreasing tPA concentration by 98% to 0.01 mg/mL, modifications that produced 22% more thrombolysis, despite 92% reduction in amount of tPA to 0.25 mg. CONCLUSION: Consistent with the in vitro work of other investigators, a roughly bell-shaped dose-response curve was elicited in vivo for pulse-spray with tPA. By diluting tPA to an optimal level, and increasing pulse frequency to two per minute, thrombolysis was markedly augmented. These results suggest that the conventional dose of tPA used for clinical pulse-spray thrombolysis can be reduced by one to two orders of magnitude, possibly markedly reducing procedural risk.

Surface-bounded growth modeling applied to human mandibles.

From a set of longitudinal three-dimensional scans of the same anatomical structure, we have accurately modeled the temporal shape and size changes using a linear shape model. On a total of 31 computed tomography scans of the mandible from six patients, 14,851 semilandmarks are found automatically using shape features and a new algorithm called geometry-constrained diffusion. The semilandmarks are mapped into Procrustes space. Principal component analysis extracts a one-dimensional subspace, which is used to construct a linear growth model. The worst case mean modeling error in a cross validation study is 3.7 mm.

Direct and indirect effects of prenatal alcohol damage on executive function.

Patients with Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Effects (FAE) often have difficulty functioning appropriately in everyday life and seem to employ poor problem-solving strategies. Tests of executive function are relevant for quantifying the functional deficits and underlying real-life problems associated with prenatal alcohol exposure. This study considers two pathways for the effects of prenatal alcohol on executive function: a direct effect and an indirect effect through prenatal alcohol's effect on IQ. We compared 30 men who had been diagnosed with FAS or FAE with young adults participating in a longitudinal prospective study (n = 419) and 15 control participants that comprised a comparison group. This study is unique in its analysis of the same battery of assessments of executive function in both a large low dose longitudinal study sample and a clinically diagnosed group. Participants were evaluated on 9 tests (including 58 scores) of executive function. For some but not all of the tests in this executive function battery, the decrement in the alcohol exposure group is greater than would be predicted from their IQ scores. We found that 3 of 6 Stroop scores, 2 of 4 Trails scores, 9 of 16 Wisconsin Card Sorting scores, 1 of 2 Ruff's Figural Fluency scores, and 2 of 4 Consonant Trigrams scores appear to be particularly sensitive to the direct effects of prenatal alcohol damage for patients with FAS and FAE. The findings suggest that these executive function tests would be particularly useful in clinical evaluations of persons suspected of fetal alcohol damage because they would not simply reflect deficits in IQ or facial stigmata.

Individual differences in auditory and visual attention among fetal alcohol-affected adults.

BACKGROUND: Deficits in attention are commonly identified among patients who have been prenatally exposed to alcohol, and they often affect the ability of the patients to function appropriately in society. METHODS: Eleven adult patients with fetal alcohol syndrome (FAS) or fetal alcohol effects (FAE) were compared with nine adult subjects with no history of prenatal alcohol exposure, using four tests of visually and auditorially mediated attention. RESULTS: In relation to the comparison group, patients with FAS/FAE exhibited substantial deficits in both auditory and visual attention; the auditory deficits were greater. We observed two predominant patterns of deficits among patients with FAS/FAE, one involving both auditory and visual attention problems and the other involving less severe auditory problems and even fewer visual problems. Most subjects with FAS or FAE had some manifestations of attention problems in at least one of the tests of attention used in this study. We present a new graphical representation of individual auditory Continuous Performance Test data across a 6-min period, which, compared with conventional scores, more clearly reveals the markedly disrupted and variable attention patterns displayed by some individuals with FAS or FAE. CONCLUSIONS: These findings suggest that detailed analysis of the pattern of individual performance for each subject is an important aspect of Continuous Performance Test assessment. Our findings further suggest that intellectual performance (intelligence quotient score) alone is not sufficient to account for the patterns of disrupted attention for individuals with FAS/FAE. Assessment of individuals with FAS or FAE should include measurement of attentional functioning in both the visual and auditory modalities.