Browsing by Author "Hallgrimsson, Benedikt"

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    3D micro-CT imaging of human cortical bone porosity: a novel method for estimating age at death
    (2005) Cooper, David M. L.; Katzenberg, M. Anne; Hallgrimsson, Benedikt
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    Anatomy and physiology in the University of Calgary's undergraduate medical curriculum
    (2011) Esmail, Kaisra; Hallgrimsson, Benedikt; Wright, Bruce
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    The assessment of fragility fracture risk using HR-pQCT as a novel tool for diagnosis of osteoporosis
    (2021-08) Whittier, Danielle Elizabeth Wein; Boyd, Steven Kyle; Schneider, Prism Steorra; Manske, Sarah Lynn; Edwards, William Brent; Forkert, Nils Daniel; Hallgrimsson, Benedikt; Jepsen, Karl
    Osteoporosis is a systemic skeletal disease, characterized by reduced bone density and deterioration of bone microarchitecture, leading to increased fracture risk. However, current diagnosis using dual-energy X-ray absorptiometry (DXA) only accounts for density and consequently fails to capture most individuals who fracture. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a medical imaging modality capable of characterizing three-dimensional bone microarchitecture at peripheral skeletal sites, and has demonstrated that bone microarchitecture can improve prediction of fracture risk. However, to date the improvement is modest, as interpretation of the interaction between fracture and the numerous parameters provided by HR-pQCT is complex. The objective of this dissertation was to elucidate the key microarchitectural characteristics that underpin bone fragility, and use these insights to improve assessment of fracture risk with HR-pQCT. First, reference data in the form of centile curves was established for HR-pQCT parameters using a population-based cohort (n=1,236, age 18–90 years), and a new intuitive parameter called void space was developed to capture localized regions of bone loss in HR-pQCT images. In a separate prospective multi-center cohort (n=5,873, age 40–90 years), unsupervised machine learning was implemented to identify common groupings (i.e., phenotypes) of bone microarchitecture in older adults. Three phenotypes were identified and characterized as low density, structurally impaired, and healthy bone, where the low density phenotype had the strongest association with incident osteoporotic fractures (hazard ratio = 3.28). Using the same cohort, a fracture risk assessment tool, called µFRAC, was developed using supervised machine learning methods to provide a 5-year risk of major osteoporotic fracture based on HR-pQCT parameters, and was demonstrated to significantly outperform DXA in predicting fracture risk. Finally, a new retrospective cohort of patients with fragility fractures at the hip (n=108, age 56–96 years) was used to characterize bone fragility. Hip fracture patients were significantly associated with the low density phenotype and had bone void spaces that were 2–3 times larger than controls. Together, these findings provide insight into the characteristics of bone that lead to osteoporotic fractures and introduces tools that enable insightful interpretation of HR-pQCT data for clinical use.
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    Correlated Evolution of the Skeletal System in Mice Selectively Bred for Longer Tibiae
    (2024-07-10) Unger, Colton Michael; Rolian, Campbell; Cobb, John; Hallgrimsson, Benedikt; Jamniczky, Heather; Young, Nathan; Biernaskie, Jeff
    Organisms are complex systems of traits, which grow together and influence each other during development, leading to covariation among anatomical structures. Underlying genetic and developmental correlations between traits can influence evolutionary trajectories, and may lead to indirect, non-adaptive, or mal-adaptive responses to selection in a process called correlated evolution. Thus, distinct traits that are developmentally or functionally related are unlikely to evolve independently, and selection can result in off-target phenotypic change. Skeletal tissues tend to covary significantly in length and shape due to their shared functional role (e.g., locomotion) and shared mechanism of development, known as endochondral ossification (EO). Together, these features of mammalian skeletal tissues lead to strong covariation between skeletal elements, such as limb bones, vertebrae, and to a lesser extent, the cranial bones. The mechanism of EO in bone development is also reinitiated during the repair of long bone fractures. Therefore, there is great potential for correlated responses to selection in skeletal traits, potentially leading to correlated phenotypic changes when a given skeletal trait is under direct selection. To study correlated evolution in skeletal traits, I used the Longshanks mouse, which was selectively bred for increases in adult tibia length independent of body mass, resulting in 15-20% longer tibiae than Controls due to increased rates of EO during development. Using bone imaging, geometric morphometrics, histomorphometry, and transcriptomics, I characterized potential correlated changes to other traits in Longshanks that utilize the program of EO, including other off-target long bones, the cranium, and the repair of bone fractures. Using this multifaceted approach, I demonstrated that the cranium and postcranial skeleton of Longshanks have differentially elongated during the selection process, which coincided with changes to gene expression and chondrocyte behavior that resembled documented trends in the tibia. In doing so, I identified molecular and cellular signatures underlying skeletal trait correlations and identified pathways contributing to the local and global scaling of skeletal traits. Moreover, I demonstrated that Longshanks repairs unstabilized tibia fractures faster than Controls without compromising bone quality, owing to an accelerated EO phase of repair at the genetic and tissue levels. Together, this work provides strong empirical evidence of correlated trait evolution and furthers our understanding of how covariation shapes evolutionary trajectories at the microevolutionary scale, with implications for understanding morphological divergence in skeletal form and function.
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    Craniofacial growth patterns in Tanzania: epidemiology and 3D assessment of children both with and without orofacial clefts
    (2012-11-06) Manyama, Mange; Hallgrimsson, Benedikt
    Orofacial clefts [cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP)] are the most common orofacial congenital malformations found among live births, accounting for 65% of all head and neck anomalies. Due to conflicting information on the epidemiology of cleft deformities in African populations, this study was conducted to describe the epidemiology and patterns of orofacial clefts in Tanzania. This thesis also identified and described aspects of facial shape that vary most among normal population of children and between different ethnicities. The established baseline data for normal facial shape variation that can serve as phenotypic basis in genetic association studies to identify genes for orofacial clefts. Lastly, we also compared facial shape between noncleft children and children with repaired/unrepaired orofacial cleft in order to identify aspects of facial shape that differ most. In order to describe the epidemiology of orofacial clefts, a hospital-based retrospective descriptive study was conducted to identify all children with the disease attended or treated from 2004 to 2009. Comparison of facial shape in the general population and in individuals with orofacial clefts was carried using three-dimensional imaging system in combination with geometric morphometric analysis techniques. Isolated cleft lip was found to be the most common cleft type, followed by clefts of both the lip and palate, a pattern broadly similar to other series in African countries, and different from the distribution of orofacial clefts in low and middle income countries in other parts of the world. We also found a significant face shape differences within the population of normal Tanzanian children that were localized to specific regions of the face. Some of these facial shape differences manifested in ethnic-specific manner. Facial shape in noncleft children was also found to be significantly different from both children with repaired and unrepaired orofacial clefts of the same sex, age and ethnic group. Facial phenotypes that have been identified both in the general population and in affected individuals in this study might be used in genetic association and linkage analyses to identify risk markers for orofacial clefting.
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    Facial Shape Variation in Humans
    (2017) Larson, Jacinda R.; Hallgrimsson, Benedikt; Jamniczky, Heather; Harrop, Robertson; Rolian, Campbell
    The human face is a highly variable feature. Facial shape variation is seen between and within multiple populations. However, the source of this variation is mostly unknown. Furthermore, phenotypic variation is observed within syndromes that display a unique craniofacial phenotype. Because of this inherent variation, facial shape has a large clinical important and diagnostic significance. To explore facial shape variation, I have conducted several studies that examine the role of morphological integration in producing coordinated shape changes in the face. In these studies, I hypothesized that the size of the face and skull are correlated with facial shape; and that dysmorphic patients will display different morphological relationships between parts of the face, when compared to controls. These hypotheses were tested in several groups; namely healthy controls, patients with non-syndromic cleft lip and/or palate, and patients with ectodermal dysplasia. While these conditions have different etiologies, genetics, inheritance, mechanism of development, and resultant facial shape, using both of these patient groups has allowed me to explore these hypotheses in starkly different phenotypic groups. My studies have shown that the allometric factors of facial shape variation are complex and overlapping. Size represents a relatively small proportion of facial shape variation in humans. Furthermore, different classifications of cleft phenotypes are crucial when deciphering covariance structure in cleft individuals. Collectively, these studies have furthered the knowledge of complex craniofacial phenotypes, and have extended the knowledge on how allometry affects human facial shapes.
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    Functional basis of cleft lip liability in a-strain mice
    (2012) Schmidt, Eric J; Hallgrimsson, Benedikt; Jirik, Frank
    The "facial shape hypothesis" holds that cleft lip penetrance rates among A-strain lines differ owing to subtle genetic differences in midfacial primordia size, orientation, and rates of growth-summarily "facial shape"-that place more liable lines closer to, and less liable Jines further from, a threshold shape value that is set by physical constraints limiting the range of shape variation tolerated before the primordia fail to contact or consolidate adequately into a unified structure separating the nasal slits from the mouth. Fixation for an IAP allele of Wnt9b, which plays a regulatory role in midfacial development, is a key component of the genetic liability. Variation in genetic maternal effects modifies penetrance rates through an unknown function. I tested the hypothesis that maternal background influences the rate clefted primary palates in litters by differentially shifting the distributions of Wnt9b IAP epigenetic modification toward an expression threshold set by a common level of tolerance for low Wnt9b expression in the developing upper jaw. IAP methylation profiles between a reciprocal pair of hybrids with a two-fold difference in liability did not substantially differ. Nor did a morphometric analysis suggest that genetic maternal effects differences influenced embryonic facial shape. The data imply a role for maternal effects variation impacting palatogenesis via a mechanism outside epigenetic modification of the Wnt9b IAP but also independent of normal variations in midfacial shape with respect to a shape threshold. The significance of the alternative "two state" hypothesis, holding that penetrance rate differences among the A-strain are a function of the rate at which somatic differences arise between normal and cleft penetrant embryos, is considered.
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    The Genetics Underlying Male-Female Facial Sexual Dimorphism
    (2021-12-21) Da Silva, Cassidy; Hallgrimsson, Benedikt; Wilson, Warren; Cote, Susanne
    The genetic mechanisms underlying facial sexual dimorphism are currently unknown. My thesis addresses this gap by shedding light on the genetic and biological mechanisms underlying sexual dimorphism in human facial shape, as well as normal facial variation more broadly. I evaluated the shape differences between males and females, scored their shapes for sexual dimorphism, and looked for genetic loci and genes that had significant associations with sexually dimorphic facial shape. While none of the SNPs reached genome-wide significance, testing revealed seven independent signals with suggestive associations (p < 1 × 10-5) to facial sexual dimorphism, spanning coding regions in four different genes. Three of these genes, RBFOX1, CACNA2D3 and ATP6V1E1, have previously been implicated in processes of craniofacial development. I also examined the shapes and genetic aetiologies associated with sex chromosome aneuploidies, Turner syndrome (X0) and Klinefelter syndrome (XXY), which yielded no clear indication of the role of the X chromosome in sexual dimorphism of the face. These findings support the most recent evidence that the same genes influence facial sexual dimorphism in both males and females. Furthermore, by identifying genes previously linked to normal facial variation, I provide preliminary evidence for developmental mechanisms underlying shared variation in facial sexual dimorphism between the sexes. Only by properly understanding the mechanisms underlying facial sexual dimorphism will we be able to form a complete picture of its role in human evolution.
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    Genome-wide copy number variations in a large cohort of bantu African children
    (2021-05-17) Yilmaz, Feyza; Null, Megan; Astling, David; Yu, Hung-Chun; Cole, Joanne; Santorico, Stephanie A.; Hallgrimsson, Benedikt; Manyama, Mange; Spritz, Richard A.; Hendricks, Audrey E.; Shaikh, Tamim H.
    Abstract Background Copy number variations (CNVs) account for a substantial proportion of inter-individual genomic variation. However, a majority of genomic variation studies have focused on single-nucleotide variations (SNVs), with limited genome-wide analysis of CNVs in large cohorts, especially in populations that are under-represented in genetic studies including people of African descent. Methods We carried out a genome-wide copy number analysis in > 3400 healthy Bantu Africans from Tanzania. Signal intensity data from high density (> 2.5 million probes) genotyping arrays were used for CNV calling with three algorithms including PennCNV, DNAcopy and VanillaICE. Stringent quality metrics and filtering criteria were applied to obtain high confidence CNVs. Results We identified over 400,000 CNVs larger than 1 kilobase (kb), for an average of 120 CNVs (SE = 2.57) per individual. We detected 866 large CNVs (≥ 300 kb), some of which overlapped genomic regions previously associated with multiple congenital anomaly syndromes, including Prader-Willi/Angelman syndrome (Type1) and 22q11.2 deletion syndrome. Furthermore, several of the common CNVs seen in our cohort (≥ 5%) overlap genes previously associated with developmental disorders. Conclusions These findings may help refine the phenotypic outcomes and penetrance of variations affecting genes and genomic regions previously implicated in diseases. Our study provides one of the largest datasets of CNVs from individuals of African ancestry, enabling improved clinical evaluation and disease association of CNVs observed in research and clinical studies in African populations.
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    Maternal Diet and Infant Brain Sparing Among Ngorongoro Maasai
    (2012-10-04) Powell, Christopher David; Hallgrimsson, Benedikt; Wilson, Warren
    Natural selection for bipedal locomotion and encephalization creates an obstetric dilemma. Consequently, a trade-off occurs between human brain size, locomotory efficiency, and the increased risk of maternal and infant mortality from obstructed labour. The Maasai of Northern Tanzania, attempt to ease the obstetric dilemma by manipulating fetal growth. However, due to the tendency for growth restricted newborns to exhibit brain sparing, these maternal practices would have to achieve corresponding head and body size reductions. To determine the efficacy of this cultural adaptation to the obstetric dilemma, we interviewed traditional birth attendants and mothers about their maternal practices. Maternal diet was measured, and infant anthropometric data were collected on 141 maternal-infant pairs. Participants reported a 50% reduction in dietary intake. Of the 141 infant participants, 36 (25%) were growth restricted. The brain sparing tendency was observed among the growth restricted sample, suggesting that maternal dietary restriction does not overcome the obstetric dilemma.
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    Morphological integration and modularity of the mouse and hominoid skull: variation and epigenetic interactions during development
    (2011) Parsons, Trish Elizabeth; Hallgrimsson, Benedikt; Jamniczky, Heather A.
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    Osseous skull development of Ambystoma macrodactylum krausei from post-hatching through metamorphosis
    (2014-02-21) Wilson, Sian Caroline; Anderson, Jason; Hallgrimsson, Benedikt
    Salamander developmental morphological data contribute to deciphering evolutionary relationships of modern/fossil amphibians. This study examines the osseous skull morphology of Ambystoma macrodactylum krausei, from post-hatching through metamorphosis using μCT and synchrotron scanning methods. Skull elements and overall skull shape were described through ontogeny (including one adult). Landmark-based principal components analyses examined shape trends across collection years, premetamorphosis (PM) and metamorphosis (M), and scanning methods. Covariance matrices were compared across collection years. Modularity hypotheses were tested. A. m. krausei forms a prefrontolacrimal. Procrustes-transformed coordinates were significantly different for both collection years and PM/M, but were not significantly different for scanning methods. All shape trends had a significant allometric component. Generally, covariance matrices were more similar during PM than during M across collection years. No support for modularity hypotheses was found; however, the strength of cranial integration was different in the lower jaw and cranium, and through PM/M.
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    The Effect of Genetic Variation on Mouse Bone Strength
    (2016) Britz, Hayley M.; Hallgrimsson, Benedikt; Boyd, Steven K.; Jirik, Frank; Rolian, Campbell
    Osteoporosis is a heritable bone disease which is characterized by decreased bone mass and a deterioration in bone microarchitecture. This leads to a decrease in bone strength and therefore the risk of fracturing is greater in people who have been diagnosed as being osteoporotic. The mechanism by which osteoporosis is inherited is still unknown, as are the underlying microarchitectural causes of changes in bone strength. Without knowing more about these two mechanisms we cannot begin to develop more effective treatment plans or even a cure for this disease. The aim of this dissertation was to determine whether bone strength can be influenced by vascular canal microarchitecture and whether bone strength is a heritable trait, which is determined by specific quantitative trait loci. Using the CC founder strains and their F1 crosses in a diallel analysis we found that non-additive variance accounted for the same amount or more of the heritability than additive variance. Using the same CC mice we also found that BMD, canal connectivity, canal diameter, canal orientation, cortical area, cortical thickness, and percent porosity were all heritable determinants of bone strength. The bone strength measures used in this thesis were found to be highly correlated (0.702) and there was no statistical difference between methods (p=1.000). Employing the DO population we found a significant QTL for Imax on Chromosome 1 that is 1.43 cM wide and contained 19 candidate genes, of which Cacna1e looks the most promising. The QTL analysis for MaxF and BMD also found suggestive and near suggestive QTLs on Chromosome 1, which would indicate that Chromosome 1 is important in the genetic determination of bone strength.
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    Tools and Resources for Large-Scale Morphometrics
    (2023-08) Devine, Jay; Hallgrimsson, Benedikt; Gonzalez, Paula; Percival, Christopher; Kurki, Helen; Epp, Jonathan
    Recent advances in imaging and machine learning have revolutionized both the acquisition and analysis of high-dimensional data. Unfortunately, these techniques have not been effectively exported to morphometrics, or the quantitative analysis of shape and form, which is central to biology and related disciplines for understanding phenotypic variation. Lack of implementations, different model systems and experimental designs, small sample sizes, and limited expertise continue to yield self-contained morphometric studies with unstandardized datasets that cannot be aggregated for increasingly powerful analyses. This dissertation presents heuristic and learning-based tools alongside big data resources for large-scale morphometrics. I begin by summarizing key morphometric paradigms, focusing on data acquisition, aggregation, and classification. Next, I develop an automated landmarking and shape optimization pipeline based on image registration and artificial neural networks. After demonstrating its efficacy, I use this phenotyping framework to build MusMorph, a database of mouse morphology data (N=10,056) containing anatomical atlases, aligned micro-computed tomography images, landmark configurations, and segmentations spanning numerous strain/genotype combinations and developmental stages. Finally, I introduce the R package pheble to perform a meta-analysis of learning-based classification algorithms across high-dimensional phenotypic datasets ranging in organismal family and anatomy. My analysis shows how ensemble learning, or combining predictions from individual learners, can maximize classification performance whilst being data agnostic. Altogether, these studies represent tools and resources that can accelerate, standardize, and augment morphometric analyses for novel phenomic inquiries.
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