Objective: Dental casts are an important aspect in the treatment planning, documentation, and analysis of the dental arch forms of infants with cleft lip and palate (CLP). Impression taking in a neonate is a technique-sensitive procedure, which can result in foreign body dislodgement and carries a small risk of aspiration and airway obstruction. The advent of digital dental technologies and intraoral scanning may facilitate safer, more effective, and accurate impressions for CLP infants. Design: A digital intraoral scan of a 3-month-old with bilateral CLP (BCLP) was compared with a conventional alginate impression taken prior to primary lip repair. Setting: Princess Margaret Hospital for Children. Main Outcome Measures: To test the applicability and accuracy of digital impression taking for a neonate with BCLP and palate using digital morphometrics. Results: The average deviation of points ranged above and below the plane of superimposition from +0.78 mm to −0.42 mm with a maximum range of +2.80 mm to −2.80 mm and standard deviation of 0.88 mm. The premaxillary segment showed the greatest degree of variation. Conclusions: This is to our knowledge the first report that illustrates the use of a digital impression system to scan the oral structures of a neonate with BCLP. Digital scanning was found to be fast, accurate, and safe, when compared to a conventional alginate impression technique.

Elevated prenatal testosterone exposure has been associated with Autism Spectrum Disorder (ASD) and facial masculinity. By employing three-dimensional (3D) photogrammetry, the current study investigated whether prepubescent boys and girls with ASD present increased facial masculinity compared to typically-developing controls. There were two phases to this research. 3D facial images were obtained from a normative sample of 48 boys and 53 girls (3.01-12.44 years old) to determine typical facial masculinity/femininity. The sexually dimorphic features were used to create a continuous 'gender score', indexing degree of facial masculinity. Gender scores based on 3D facial images were then compared for 54 autistic and 54 control boys (3.01-12.52 years old), and also for 20 autistic and 60 control girls (4.24-11.78 years). For each sex, increased facial masculinity was observed in the ASD group relative to control group. Further analyses revealed that increased facial masculinity in the ASD group correlated with more social-communication difficulties based on the Social Affect score derived from the Autism Diagnostic Observation Scale-Generic (ADOS-G). There was no association between facial masculinity and the derived Restricted and Repetitive Behaviours score. This is the first study demonstrating facial hypermasculinisation in ASD and its relationship to social-communication difficulties in prepubescent children.

There is a pattern of progressive facial dysmorphology in mucopolysaccharidosis type I (MPS I). Advances in 3D facial imaging have facilitated the development of tools, including dysmorphometrics, to objectively and precisely detect these facial phenotypes. Therefore, we investigated the application of dysmorphometrics as a noninvasive therapy-monitoring tool, by longitudinally scoring facial dysmorphology in a child with MPS I receiving enzyme replacement therapy (ERT) and bone marrow transplantation (BMT). Both dysmorphometric measures showed a decreasing trend, and the greatest differences were found in the severity of facial discordance (Z-RMSE), displaying scores >3 SD higher than the mean at their peak, in comparison to Z-RSD scores that mostly fell within the normative range (maximum; 1.5 SD from the mean). In addition to the general trend of reduced facial dysmorphology with treatment, initial fluctuations were also evident that may have related to transient subcutaneous facial fluctuations, in the context of conditioning for bone marrow transplant. These findings support the potential of our approach as a sensitive, noninvasive, and rapid means of assessing treatment response or failure in clinical trials, and for established therapies, and would be applicable for other inherited disorders of metabolism.

There are many current and evolving tools to assist clinicians in their daily work of phenotyping. In medicine, the term ‘phenotype’ is usually taken to mean some deviation from normal morphology, physiology and behaviour. It is ascertained via history, examination and investigations, and a primary aim is diagnosis. Therefore, doctors are, by necessity, expert ‘phenotypers’. There is an inherent and partially realised power in phenotypic information that when harnessed can improve patient care. Furthermore, phenotyping developments are increasingly important in an era of rapid advances in genomic technology. Fortunately, there is an expanding network of phenotyping tools that are poised for clinical translation. These tools will preferentially be implemented to mirror clinical workflows and to integrate with advances in genomic and information‐sharing technologies. This will synergise with and augment the clinical acumen of medical practitioners. We outline key enablers of the ascertainment, integration and interrogation of clinical phenotype by using genetic diseases, particularly rare ones, as a theme. Successes from the test bed or rare diseases will support approaches to common disease.

Gender score is the cognitive judgement of the degree of masculinity or femininity of a face which is considered to be a continuum. Gender scores have long been used in psychological studies to understand the complex psychosocial relationships between people. Perceptual scores for gender and attractiveness have been employed for quality assessment and planning of cosmetic facial surgery. Various neurological disorders have been linked to the facial structure in general and the facial gender perception in particular. While, subjective gender scoring by human raters has been a tool of choice for psychological studies for many years, the process is both time and resource consuming. In this study, we investigate the geometric features used by the human cognitive system in perceiving the degree of masculinity/femininity of a 3D face. We then propose a mathematical model that can mimic the human gender perception. For our experiments, we obtained 3D face scans of 64 subjects using the 3dMDface scanner. The textureless 3D face scans of the subjects were then observed in different poses and assigned a gender score by 75 raters of a similar background. Our results suggest that the human cognitive system employs a combination of Euclidean and geodesic distances between biologically significant landmarks of the face for gender scoring. We propose a mathematical model that is able to automatically assign an objective gender score to a 3D face with a correlation of up to 0.895 with the human subjective scores.

There are many current and evolving tools to assist clinicians in their daily work of phenotyping. In medicine, the term 'phenotype' is usually taken to mean some deviation from normal morphology, physiology and behaviour. It is ascertained via history, examination and investigations, and a primary aim is diagnosis. Therefore, doctors are, by necessity, expert 'phenotypers'. There is an inherent and partially realised power in phenotypic information that when harnessed can improve patient care. Furthermore, phenotyping developments are increasingly important in an era of rapid advances in genomic technology. Fortunately, there is an expanding network of phenotyping tools that are poised for clinical translation. These tools will preferentially be implemented to mirror clinical workflows and to integrate with advances in genomic and information-sharing technologies. This will synergise with and augment the clinical acumen of medical practitioners. We outline key enablers of the ascertainment, integration and interrogation of clinical phenotype by using genetic diseases, particularly rare ones, as a theme. Successes from the test bed or rare diseases will support approaches to common disease.

We used morphological, immunohistochemical and functional assessments to determine the impact of genetically-modified peripheral nerve (PN) grafts on axonal regeneration after injury. Grafts were assembled from acellular nerve sheaths repopulated ex vivo with Schwann cells (SCs) modified to express brain-derived neurotrophic factor (BDNF), a secretable form of ciliary neurotrophic factor (CNTF), or neurotrophin-3 (NT3). Grafts were used to repair unilateral 1 cm defects in rat peroneal nerves and 10 weeks later outcomes were compared to normal nerves and various controls: autografts, acellular grafts and grafts with unmodified SCs. The number of regenerated βIII-Tubulin positive axons was similar in all grafts with the exception of CNTF, which contained the fewest immunostained axons. There were significantly lower fiber counts in acellular, untransduced SC and NT3 groups using a PanNF antibody, suggesting a paucity of large caliber axons. In addition, NT3 grafts contained the greatest number of sensory fibres, identified with either IB4 or CGRP markers. Examination of semi- and ultra-thin sections revealed heterogeneous graft morphologies, particularly in BDNF and NT3 grafts in which the fascicular organization was pronounced. Unmyelinated axons were loosely organized in numerous Remak bundles in NT3 grafts, while the BDNF graft group displayed the lowest ratio of umyelinated to myelinated axons. Gait analysis revealed that stance width was increased in rats with CNTF and NT3 grafts, and step length involving the injured left hindlimb was significantly greater in NT3 grafted rats, suggesting enhanced sensory sensitivity in these animals. In summary, the selective expression of BDNF, CNTF or NT3 by genetically modified SCs had differential effects on PN graft morphology, the number and type of regenerating axons, myelination, and locomotor function.

With advances in therapeutics for rare, genetic and syndromic diseases, there is an increasing need for objective assessments of phenotypic endpoints. These assessments will preferentially be high precision, non-invasive, non-irradiating, and relatively inexpensive and portable. We report a case of a child with an extensive lymphatic vascular malformation of the head and neck, treated with an mammalian target of Rapamycin (mTOR) inhibitor that was assessed using 3D facial analysis. This case illustrates that this technology is prospectively a cost-effective modality for treatment monitoring, and it supports that it may also be used for novel explorations of disease biology for conditions associated with disturbances in the mTOR, and interrelated, pathways.

BACKGROUND:Some lysosomal storage disorders (LSDs), including Muccopolysaccharidosis type 1 (MPSI), are associated with characteristic facies. METHODS such as three-dimensional (3D) facial scanning and geometric morphometric techniques can potentially generate detailed objective descriptions of these facial phenotypes. This approach can facilitate discriminating the inherent overlap in facial phenotypes within these disease spectra, and the non-invasive monitoring of disease progression and treatment.METHODS:3D facial images of three MPS I-affected individuals and 400 reference subjects (aged 5-25 years) were obtained using a 3dMD camera (Atlanta, Georgia). Images were fitted with an anthropometric mask, comprising a set of spatially dense quasi-landmarks. A statistical face-space was constructed from the reference image set and the MPS I-affected individuals were compared to this face-space utilising an emerging methodology known as dysmorphometrics. This facilitated simultaneous identification of harmonic and discordant facial regions. A relative significant discordance (RSD) score quantified proportional facial discordance for a given individual, whilst a root-mean-squared-error (RMSE) score measured the degree of facial discordance providing a severity measure.RESULTS:A consistent facial pattern, with differential severities, primarily affecting the frontal, nasal, infraorbital and cheek regions, was detected in all three individuals. As expected, there was greater discordance (RMSE, RSD) with clinically severe MPS I when compared to attenuated disease.CONCLUSIONS:Objective detection and localisation of MPS I facial characteristics was achieved, and severity scores were attributed. This spatially dense dysmorphometric facial phenotyping technique has the potential to be used for non-invasive treatment monitoring and as a discriminatory tool.

Accurate measurement of facial sexual dimorphism is useful to understanding facial anatomy and specifically how faces influence, and have been influenced by, sexual selection. An important facial aspect is the display of bilateral symmetry, invoking the need to investigate aspects of symmetry and asymmetry separately when examining facial shape. Previous studies typically employed landmarks that provided only a sparse facial representation, where different landmark choices could lead to contrasting outcomes. Furthermore, sexual dimorphism is only tested as a difference of sample means, which is statistically the same as a difference in population location only. Within the framework of geometric morphometrics, we partition facial shape, represented in a spatially dense way, into patterns of symmetry and asymmetry, following a two-factor anova design. Subsequently, we investigate sexual dimorphism in symmetry and asymmetry patterns separately, and on multiple aspects, by examining (i) population location differences as well as differences in population variance-covariance; (ii) scale; and (iii) orientation. One important challenge in this approach is the proportionally high number of variables to observations necessitating the implementation of permutational and computationally feasible statistics. In a sample of gender-matched young adults (18-25 years) with self-reported European ancestry, we found greater variation in male faces than in women for all measurements. Statistically significant sexual dimorphism was found for the aspect of location in both symmetry and asymmetry (directional asymmetry), for the aspect of scale only in asymmetry (magnitude of fluctuating asymmetry) and, in contrast, for the aspect of orientation only in symmetry. Interesting interplays with hypotheses in evolutionary and developmental biology were observed, such as the selective nature of the force underpinning sexual dimorphism and the genetic independence of the structural patterns of fluctuating asymmetry. Additionally, insights into growth patterns of the soft tissue envelope of the face and underlying skull structure can also be obtained from the results.

Objectives To (1) audit dental arch relationships of all children born between 1982 and 1999 with complete unilateral cleft lip and palate (UCLP) treated at the Cleft Lip and Palate Unit, Princess Margaret Hospital for Children (PMH), Perth, Western Australia, (2) assess the distribution of GOSLON ratings from dental casts taken at 9 years, (3) compare the 9-year GOSLON ratings for “High” and “Low” caseload surgeons, and (4) compare the 9-year PMH GOSLON ratings with published ratings from other units. Design Retrospective audit of dental casts and medical charts. Patients Dental casts were retrieved for 71 children (47 boys and 24 girls) at 9 years of age. Main Outcome Measures GOSLON ratings. Results Sixty-eight percent of patients had an excellent to satisfactory dental arch relationship (GOSLON Yardstick ratings 1 to 3) at 9 years with a mean rating of 2.85. High caseload surgeons achieved statistically better mean GOSLON ratings than low caseload surgeons (2.72 and 3.33, respectively). Conclusions PMH Cleft Unit's dental arch relationship outcomes are comparable to published series of units using similar treatment protocols. High caseload surgeons achieved better dental arch relationships than low caseload surgeons.

BACKGROUND:The study of typical morphological variations using quantitative, morphometric descriptors has always interested biologists in general. However, unusual examples of form, such as abnormalities are often encountered in biomedical sciences. Despite the long history of morphometrics, the means to identify and quantify such unusual form differences remains limited.METHODS:A theoretical concept, called dysmorphometrics, is introduced augmenting current geometric morphometrics with a focus on identifying and modelling form abnormalities. Dysmorphometrics applies the paradigm of detecting form differences as outliers compared to an appropriate norm. To achieve this, the likelihood formulation of landmark superimpositions is extended with outlier processes explicitly introducing a latent variable coding for abnormalities. A tractable solution to this augmented superimposition problem is obtained using Expectation-Maximization. The topography of detected abnormalities is encoded in a dysmorphogram.RESULTS:We demonstrate the use of dysmorphometrics to measure abrupt changes in time, asymmetry and discordancy in a set of human faces presenting with facial abnormalities.CONCLUSION:The results clearly illustrate the unique power to reveal unusual form differences given only normative data with clear applications in both biomedical practice & research.

Three-dimensional (3D) facial analysis is ideal for high-resolution, nonionizing, noninvasive objective, high-throughput phenotypic, and phenomic studies. It is a natural complement to (epi)genetic technologies to facilitate advances in the understanding of rare and common diseases. The face is uniquely reflective of the primordial tissues, and there is evidence supporting the application of 3D facial analysis to the investigation of variation and disease including studies showing that the face can reflect systemic health, provides diagnostic clues to disorders, and that facial variation reflects biological pathways. In addition, facial variation has been related to evolutionary factors. The purpose of this review is to look backward to suggest that knowledge of human evolution supports, and may instruct, the application and interpretation of studies of facial morphology for documentation of human variation and investigation of its relationships with health and disease. Furthermore, in the context of advances of deep phenotyping and data integration, to look forward to suggest approaches to scalable implementation of facial analysis, and to suggest avenues for future research and clinical application of this technology.

OBJECTIVE:To assess the effect of orthodontic treatment on Goslon Yardstick outcome. DESIGN:Retrospective study. PATIENTS:A series of 66 consecutive patients born with a complete unilateral left lip and palate. Patients were sorted into a nontreatment group (n = 47) and a treatment group (n = 19). METHOD:Three assessors trained in the use of the Goslon Yardstick ranked the dental arch relationships of study casts taken at 6 and 9 years. RESULTS:There was only a fair agreement (κ = .33) between 6- and 9-year Goslon Yardstick scores for the cohort of 66 patients, with a significant (p < .05) difference in the mean score at 6 years (3.17 ± 0.8) and at 9 years (2.88 ± 1.0). Removal of 19 subjects who had orthodontic inventions prior to taking of the 9-year-old study cast improved the agreement to moderate (κ = .52). There was no significant difference (p > .05) in mean scores at 6 and 9 years (3.13 ± 0.9 and 3.17 ± 1.03, respectively). The treatment group exhibited significant differences (p < .001) with mean Goslon Yardstick scores of 3.0 ± 0.9 at 6 and 2.25 ± 0.45 at 9 years. CONCLUSIONS:The inclusion of patients who had received orthodontic treatment prior to taking of study casts being used for Goslon Yardstick scoring can result in a more favorable outcome. Patients who have received active orthodontic treatment prior to taking of dental casts should be excluded or accounted for in audits to assess primary cleft surgical outcome in patients with a unilateral cleft lip and palate.

Mild facial asymmetries are common in typical growth patterns. Therefore, detection of disordered facial growth patterns in individuals characterized by asymmetries is preferably accomplished by reference to the typical variation found in the general population rather than to some ideal of perfect symmetry, which rarely exists. This presents a challenge in developing an asymmetry assessment tool that is applicable, without modification, to detect both mild and severe facial asymmetries. In this paper we use concepts from geometric morphometrics to obtain robust and spatially-dense asymmetry assessments using a superimposition protocol for comparison of a face with its mirror image. Spatially-dense localization of asymmetries was achieved using an anthropometric mask consisting of uniformly sampled quasi-landmarks that were automatically indicated on 3D facial images. Robustness, in the sense of an unbiased analysis under increasing asymmetry, was ensured by an adaptive, robust, least-squares superimposition. The degree of overall asymmetry in an individual was scored using a root-mean-squared-error, and the proportion was scored using a novel relative significant asymmetry percentage. This protocol was applied to a database of 3D facial images from 359 young healthy individuals and three individuals with disordered facial growth. Typical asymmetry statistics were derived and were mainly located on, but not limited to, the lower two-thirds of the face in males and females. The asymmetry in males was more extensive and of a greater magnitude than in females. This protocol and proposed scoring of asymmetry with accompanying reference statistics will be useful for the detection and quantification of facial asymmetry in future studies.

Not all detectable differences between face images correspond to a change in identity. Here we measure both sensitivity to change and the criterion difference that is perceived as a change in identity. Both measures are used to test between possible similarity metrics. Using a same/different task and the method of constant stimuli criterion is specified as the 50% “different” point (P50) and sensitivity as the difference limen (DL). Stimuli and differences are defined within a “face-space” based on principal components analysis of measured differences in three-dimensional shape. In Experiment 1 we varied views available. Criterion (P50) was lowest for identical full-face view comparisons that can be based on image differences. When comparing across views P50, was the same for a static 45° change as for multiple animated views, although sensitivity (DL) was higher for the animated case, where it was as high as for identical views. Experiments 2 and 3 tested possible similarity metrics. Experiment 2 contrasted Euclidean and Mahalanobis distance by setting PC1 or PC2 to zero. DL did not differ between conditions consistent with Mahalanobis. P50 was lower when PC2 changed emphasizing that perceived changes in identity are not determined by the magnitude of Euclidean physical differences. Experiment 3 contrasted a distance with an angle based similarity measure. We varied the distinctiveness of the faces being compared by varying distance from the origin, a manipulation that affects distances but not angles between faces. Angular P50 and DL were both constant for faces from 1 to 2 SD from the mean, consistent with an angular measure. We conclude that both criterion and sensitivity need to be considered and that an angular similarity metric based on standardized PC values provides the best metric for specifying what physical differences will be perceived to change in identity.

For decades the relationships of twinning and alterations in body patterning, such as laterality and asymmetry, have been investigated. However, the tools to define and quantify these relationships have been limited and the majority of these studies have relied on associations with subjectively defined phenotypes. The emerging technologies of 3-dimensional (3D) facial scanning and geometric morphometrics are providing the means to establish objective criteria, including measures of asymmetry, which can be used for phenotypic classification and investigations. Additionally, advances in molecular epigenetics provide new opportunities for novel investigations of mechanisms central to early developmental processes, twinning and related phenotypes. We review the evidence for overlapping etiologies of twinning, asymmetry and selected monogenic and complex diseases, and we suggest that the combination of epigenetic investigations with detailed and objective phenotyping, utilizing 3D facial analysis tools, can reveal insights into the genesis of these phenomena.