The ethics of uncertainty for data subjects

Modern health data practices come with many practical uncertainties. In this paper, I argue that data subjects’ trust in the institutions and organizations that control their data, and their ability to know their own moral obligations in relation to their data, are undermined by significant uncertainties regarding the what, how, and who of mass data collection and analysis. I conclude by considering how proposals for managing situations of high uncertainty might be applied to this problem. These emphasize increasing organizational flexibility, knowledge, and capacity, and reducing hazard

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

The Tabun C2 mandible : an assessment of mandibular ramus and retromolar space morphology

Includes bibliographical references (pages [117]-125)M.A. (Master of Arts

Ontogenetic Scaling of the Human Nose in a Longitudinal Sample: Implications for Genus Homo Facial Evolution

Researchers have hypothesized that nasal morphology, both in archaic Homo and in recent humans, is influenced by body mass and associated oxygen consumption demands required for tissue maintenance. Similarly, recent studies of the adult human nasal region have documented key differences in nasal form between males and females that are potentially linked to sexual dimorphism in body size, composition, and energetics. To better understand this potential developmental and functional dynamic, we first assessed sexual dimorphism in the nasal cavity in recent humans to determine when during ontogeny male-female differences in nasal cavity size appear. Next, we assessed whether there are significant differences in nasal/body size scaling relationships in males and females during ontogeny. Using a mixed longitudinal sample we collected cephalometric and anthropometric measurements from n = 20 males and n = 18 females from 3.0 to 20.0+ years of age totaling n = 290 observations. We found that males and females exhibit similar nasal size values early in ontogeny and that sexual dimorphism in nasal size appears during adolescence. Moreover, when scaled to body size, males exhibit greater positive allometry in nasal size compared to females. This differs from patterns of sexual dimorphism in overall facial size, which are already present in our earliest age groups. Sexually dimorphic differences in nasal development and scaling mirror patterns of ontogenetic variation in variables associated with oxygen consumption and tissue maintenance. This underscores the importance of considering broader systemic factors in craniofacial development and may have important implications for the study of patters craniofacial evolution in the genus Homo. Copyright © 2013 Wiley Periodicals, Inc

Ontogenetic scaling of the human nose in a longitudinal sample: Implications for genus Homo facial evolution

Researchers have hypothesized that nasal morphology, both in archaic Homo and in recent humans, is influenced by body mass and associated oxygen consumption demands required for tissue maintenance. Similarly, recent studies of the adult human nasal region have documented key differences in nasal form between males and females that are potentially linked to sexual dimorphism in body size, composition, and energetics. To better understand this potential developmental and functional dynamic, we first assessed sexual dimorphism in the nasal cavity in recent humans to determine when during ontogeny male-female differences in nasal cavity size appear. Next, we assessed whether there are significant differences in nasal/body size scaling relationships in males and females during ontogeny. Using a mixed longitudinal sample we collected cephalometric and anthropometric measurements from n = 20 males and n = 18 females from 3.0 to 20.0+ years of age totaling n = 290 observations. We found that males and females exhibit similar nasal size values early in ontogeny and that sexual dimorphism in nasal size appears during adolescence. Moreover, when scaled to body size, males exhibit greater positive allometry in nasal size compared to females. This differs from patterns of sexual dimorphism in overall facial size, which are already present in our earliest age groups. Sexually dimorphic differences in nasal development and scaling mirror patterns of ontogenetic variation in variables associated with oxygen consumption and tissue maintenance. This underscores the importance of considering broader systemic factors in craniofacial development and may have important implications for the study of patters craniofacial evolution in the genus Homo. Copyright © 2013 Wiley Periodicals, Inc

The Ontogeny of Nasal Shape: An Analysis of Sexual Dimorphism in a Longitudinal Sample

Objectives Potential integration between the nasal region and noncranial components of the respiratory system has significant implications for understanding determinants of craniofacial variation. There is increasing evidence that sexual dimorphism in body size and associated male-female differences in energetically relevant variables influence the development of the nasal region. To better understand this relationship, we examined the ontogeny of sexual dimorphism in nasal shape using a longitudinal series of lateral cephalograms. Methods We collected a series of two dimensional coordinate landmark data from n = 20 males and n = 18 females from 3.0 to 20.0+ years of age totaling n = 290 observations across nine age groups. First, we tested whether there are sex differences in the nasal shape related to ontogenetic increases in body size (i.e., sitting height). Additionally, we examined whether there are male-female differences in patterns of nonallometric variation in nasal shape. Next, we tested whether there are sex differences in the strength of integration between the nasal region and other aspects of the facial skeleton. Results Our results indicate that there are a number of similarities in patterns of morphological variation in the nasal region between males and females. However, as sitting height increases males exhibit a disproportionate increase in nasal region height that is not present in the female sample. Moreover, the male nasal region is less integrated with the surrounding facial skeleton when compared to the female sample. Conclusions These results are consistent with the hypothesis that sex differences in nasal development are associated with male-female differences in energetically relevant variables

The Ontogeny of Nasal Shape: An Analysis of Sexual Dimorphism in a Longitudinal Sample

Objectives Potential integration between the nasal region and noncranial components of the respiratory system has significant implications for understanding determinants of craniofacial variation. There is increasing evidence that sexual dimorphism in body size and associated male-female differences in energetically relevant variables influence the development of the nasal region. To better understand this relationship, we examined the ontogeny of sexual dimorphism in nasal shape using a longitudinal series of lateral cephalograms. Methods We collected a series of two dimensional coordinate landmark data from n = 20 males and n = 18 females from 3.0 to 20.0+ years of age totaling n = 290 observations across nine age groups. First, we tested whether there are sex differences in the nasal shape related to ontogenetic increases in body size (i.e., sitting height). Additionally, we examined whether there are male-female differences in patterns of nonallometric variation in nasal shape. Next, we tested whether there are sex differences in the strength of integration between the nasal region and other aspects of the facial skeleton. Results Our results indicate that there are a number of similarities in patterns of morphological variation in the nasal region between males and females. However, as sitting height increases males exhibit a disproportionate increase in nasal region height that is not present in the female sample. Moreover, the male nasal region is less integrated with the surrounding facial skeleton when compared to the female sample. Conclusions These results are consistent with the hypothesis that sex differences in nasal development are associated with male-female differences in energetically relevant variables

Childhood body mass index is associated with early dental development and eruption in a longitudinal sample from the Iowa Facial Growth Study

Introduction: High BMI (body mass index) children have been demonstrated to have precocious dental development. Existing work has largely focused on cross-sectional datasets, leaving an incomplete understanding of the longitudinal relationship between BMI and dental maturation. Methods: We used a pure longitudinal growth series to examine the relationship between dental development and childhood BMI. Periapical radiographs from 77 children from the Iowa Growth Study were used to estimate dental development for subjects with known BMI. Results: We confirm prior studies in finding that children with higher BMIs were more likely to have advanced dental development for their ages (p<0.001). BMI at age 4 was predictive of timing of dental development at age 12 (p=0.052). The precocity of the rate of dental development accelerated across growth. Overall dental development scores also correlated with age of dental eruption for the mandibular canines and first premolars (p<0.001). Conclusions: High BMI at young ages is predictive of advanced dental development at later time points, suggesting a long-term effect of BMI on dental maturation, and implying the need for earlier orthodontic interventions in obese children. These results corroborate previous studies, building further evidence that relatively early dental eruption is another downstream consequence of childhood obesity

Generation of a multipurpose Prdm16 mouse allele by targeted gene trapping

Gene trap mutagenesis is a powerful tool to create loss-of-function mutations in mice and other model organisms. Modifications of traditional gene trap cassettes, including addition of conditional features in the form of Flip-excision (FlEx) arrays to enable directional gene trap cassette inversions by Cre and Flpe site-specific recombinases, greatly enhanced their experimental potential. By taking advantage of these conditional gene trap cassettes, we developed a generic strategy for generating conditional mutations and validated this strategy in mice carrying a multipurpose allele of the Prdm16 transcription factor gene. We demonstrate that the gene trap insertion creates a null mutation replicating the Pierre Robin sequence-type cleft palate phenotype of other Prdm16 mutant mice. Consecutive breeding to Flpe and Emx1IREScre deleter mice spatially restricted Prdm16 loss to regions of the forebrain expressing the homeobox gene Emx1, demonstrating the utility of the technology for the analysis of tissue-specific gene functions