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R. Saturas, M.A., Ph.D.

Clinical Director, Ohio University Heritage College of Osteopathic Medicine

If we consider the causal variant to have been found if it is ranked in the top 5, random forest succeeds on an average of 15. As in the 50/50 split, we excluded from training any positive examples within the same gene as the held-out variant. We repeated this process 10 times with different random subsets of control variants and averaged the rank of the heldout deleterious variant within the test dataset. This leave-one-out cross-validation method allows us to estimate the number of disorders for which our method is able to rank the deleterious variant among the top few variants genome-wide. Results were aggregated across 50 iterations of stratified 50/50 cross-validation. Per-feature forward and backward feature selection was also tried but the redundancy between different features within each category made it difficult to interpret the underlying importance. Several feature importance measures can actually be calculated straight from trained random forests (Archer & Kimes, 2008), but these measures can be biased when the scales of the features are different, as they are in this case (Strobl et al. Harmfulness classification Based on the benchmarking results, the random forest method was selected and all features were kept. We computed the scores of the 33 harmful variants using leave-one-out cross-validation and the scores of all common polymorphisms from the 1000 Genomes Project (May 2011 phase 1 release v2) and found the harmful variants to have a significantly higher mean score (0. Further, we still find a significant difference when comparing against rare synonymous variants from a healthy individual (0. When applied to the original dataset of 33 deleterious variants, 11 were classified as likely pathogenic, 6 as potentially pathogenic, and 16 as likely benign. Though we have features that attempt to capture these mechanisms, the machine learning algorithms did not find these specific features to be informative in training. Two of the novel mutations are suspected of causing Meckel syndrome through the disruption of splice donor motifs. These variants were not included in our training dataset because they did not meet our criterion of experimental validation. Each variant is analyzed by a molecular diagnostician, who classifies it as benign or harmful based on an interpretation of its likely molecular effect and a literature review. The Molecular Diagnostic Laboratory provided us with six pathogenic synonymous variants and six benign polymorphisms identified during their analyses, with two of the pathogenic variants already appearing in our training data. However, as detailed in the previous sections, synonymous substitutions can exert a phenotypic effect and thus be selected against. Previously, there have been several attempts to understand the fraction of synonymous sites that are under constraint, and the strength of selection at these sites both overall (see review: Chamary et al. The heterogeneity of both the genome and even individual genes, and substantial methodological differences, have resulted in widely-varying estimates, with some suggesting that up to 39% of synonymous substitutions are under selection (Hellmann et al. Simultaneously all such studies have used comparison of multiple mammalian genomes, and not analysis of human polymorphisms; constraint observable from human polymorphisms would represent generally stronger selection, due to the small human effective population size (Ne 104) (Tenesa et al. The matched random mutation was controlled for: 1) creation or destruction of CpG dinucleotides and 2) splice site proximity (the random mutation created/destroyed a CpG site only if the synonymous variant did, and whether or not the mutation was within three bases of an exon boundary). While the mean observed scores for polymorphisms and random mutations were similar (0. The overall higher scores of random mutations suggest that factors beyond CpG and exon boundaries impose purifying selection at synonymous sites of the human genome that is statistically significant. To further quantify this constraint, we measured the difference in the number of random mutations and true polymorphisms (Figure 2. This difference can be interpreted as the number of mutations "rejected" during evolution as being unfit, and represents synonymous sites under constraint (Cooper et al. The remaining synonymous variants are annotated with features and scored using the pre-trained random forest model. The variants are then output in order of descending score, one per line, with the following tab-delimited fields: 1. The automated prioritization of deleterious variants is an important step towards the realization of genomic medicine. Synonymous variants are usually excluded from analysis pipelines wholesale, despite evidence that some of this "silent" variation has important functional roles. Our results indicate that splicing information and sequence conservation are currently the two most informative features for identifying deleterious synonymous variants, and the performance degrades without either of these features.

A, At 6 days: the trophoblast is attached to the endometrial epithelium at the embryonic pole of the blastocyst. B, At 7 days: the syncytiotrophoblast has penetrated the epithelium and has started to invade the endometrial connective tissue. Some students have difficulty interpreting illustrations such as these because in histologic studies, it is conventional to draw the endometrial epithelium upward, whereas in embryologic studies, the embryo is usually shown with its dorsal surface upward. Because the embryo implants on its future dorsal surface, it would appear upside down if the histologic convention were followed. In this book, the histologic convention is followed when the endometrium is the dominant consideration. One or two cells (blastomeres) are removed from the embryo known to be at risk of a specific genetic disorder. This procedure has been used to detect female embryos during in vitro fertilization in cases in which a male embryo would be at risk of a serious X-linked disorder. Abnormal Embryos and Spontaneous Abortions Many zygotes, morulae, and blastocysts abort spontaneously. Clinicians occasionally see a patient who states that her last menstrual period was delayed by several days and that her last menstrual flow was unusually profuse. Early spontaneous abortions occur for a variety of reasons, one being the presence of chromosomal abnormalities. More than half of all known spontaneous abortions occur because of these abnormalities. The early loss of embryos, once called pregnancy wastage, appears to represent a disposal of abnormal conceptuses that could not have developed normally, i. Without this screening, the incidence of infants born with congenital abnormalities would be far greater. The fimbriae of the uterine tube sweep the oocyte into the ampulla where it may be fertilized. Sperms are produced in the testes (spermatogenesis) and are stored in the epididymis. Ejaculation of semen during sexual intercourse results in the deposit of millions of sperms in the vagina. After the sperm enters the oocyte, the head of the sperm separates from the tail and enlarges to become the male pronucleus. Fertilization is complete when the male and female pronuclei unite and the maternal and paternal chromosomes intermingle during metaphase of the first mitotic division of the zygote. As it passes along the uterine tube toward the uterus, the zygote undergoes cleavage (a series of mitotic cell divisions) into a number of smaller cells-blastomeres. Approximately 3 days after fertilization, a ball of 12 or more blastomeres-a morula-enters the uterus. A cavity forms in the morula, converting it into a blastocyst consisting of the embryoblast, a blastocystic cavity, and the trophoblast. The trophoblast encloses the embryoblast and blastocystic cavity and later forms extraembryonic structures and the embryonic part of the placenta. Four to 5 days after fertilization, the zona pellucida is shed and the trophoblast adjacent to the embryoblast attaches to the endometrial epithelium. The trophoblast at the embryonic pole differentiates into two layers, an outer syncytiotrophoblast and an inner cytotrophoblast. The syncytiotrophoblast invades the endometrial epithelium and underlying connective tissue. Concurrently, a cuboidal layer of hypoblast forms on the deep surface of the embryoblast. By the end of the first week, the blastocyst is superficially implanted in the endometrium. During in vitro cleavage of a zygote, all blastomeres of a morula were found to have an extra set of chromosomes. In infertile couples, the inability to conceive is attributable to some factor in the woman or the man.

The mesenchyme at the cranial end of the laryngotracheal tube proliferates rapidly, producing paired arytenoid swellings (see. These swellings grow toward the tongue, converting the slitlike aperture-the primordial glottis-into a T-shaped laryngeal inlet and reducing the developing laryngeal lumen to a narrow slit. The laryngeal epithelium proliferates rapidly, resulting in temporary occlusion of the laryngeal lumen. These recesses are bounded by folds of mucous membrane that become the vocal folds (cords) and vestibular folds. The epiglottis develops from the caudal part of the hypopharyngeal eminence, a prominence produced by proliferation of mesenchyme in the ventral ends of the third and fourth pharyngeal arches (see. The rostral part of this eminence forms the posterior third or pharyngeal part of the tongue (see Chapter 9). Because the laryngeal muscles develop from myoblasts in the fourth and sixth pairs of pharyngeal arches, they are innervated by the laryngeal branches of the vagus nerves (cranial nerve X) that supply these arches (see Table 9-1). Growth of the larynx and epiglottis is rapid during the first 3 years after birth. Laryngeal Atresia this rare anomaly results from failure of recanalization of the larynx, which causes obstruction of the upper fetal airway-congenital high airway obstruction syndrome. Distal to the region of atresia (blockage) or stenosis (narrowing), the airways become dilated, the lungs are enlarged and echogenic (capable of producing echoes during ultrasound imaging studies because they are filled with fluid), the diaphragm is either flattened or inverted, and there is fetal ascites and/or hydrops (accumulation of serous fluid in the intracellular spaces causing severe edema). Incomplete atresia (laryngeal web) results from incomplete recanalization of the larynx during the 10th week. A membranous web forms at the level of the vocal folds, partially obstructing the airway. The cartilage, connective tissue, and muscles of the trachea are derived from the splanchnic mesenchyme surrounding the laryngotracheal tube. Figure 10-1 A, Lateral view of a 4-week embryo illustrating the relationship of the pharyngeal apparatus to the developing respiratory system. C, Horizontal section of the embryo illustrating the floor of the primordial pharynx and the location of the laryngotracheal groove. A to C, Lateral views of the caudal part of the primordial pharynx showing the laryngotracheal diverticulum and partitioning of the foregut into the esophagus and laryngotracheal tube. D to F, Transverse sections illustrating formation of the tracheoesophageal septum and showing how it separates the foregut into the laryngotracheal tube and esophagus. The cartilages and muscles of the larynx arise from mesenchyme in the fourth and sixth pairs of pharyngeal arches. Note that the laryngeal inlet changes in shape from a slitlike opening to a T-shaped inlet as the mesenchyme surrounding the developing larynx proliferates. Tracheoesophageal Fistula A fistula (abnormal passage) between the trachea and esophagus occurs once in 3000 to 4500 live births. The usual anomaly is for the superior part of the esophagus to end blindly (esophageal atresia) and for the inferior part to join the trachea near its bifurcation. Gastric and intestinal contents may also reflux from the stomach through the fistula into the trachea and lungs. This refluxed acid, and in some cases bile, can cause pneumonitis (inflammation of the lungs) leading to respiratory compromise. Integration link: Tracheoesophageal fistula Treatment and prognosis Figure 10-4 Transverse sections through the laryngotracheal tube illustrating progressive stages in the development of the trachea. Note that endoderm of the tube gives rise to the epithelium and glands of the trachea and that mesenchyme surrounding the tube forms the connective tissue, muscle, and cartilage. This results in a persistent connection of variable lengths between these normally separated structures. Symptoms of this congenital anomaly are similar to those of tracheoesophageal fistula because of aspiration into the lungs, but aphonia (absence of voice) is a distinguishing feature. Stenoses and atresias probably result from unequal partitioning of the foregut into the esophagus and trachea. Sometimes there is a web of tissue obstructing airflow (incomplete tracheal atresia). Tracheal Diverticulum this extremely rare anomaly consists of a blind, bronchus-like projection from the trachea. The outgrowth may terminate in normal-appearing lung tissue, forming a tracheal lobe of the lung.

Syndromes

• Left ventricular assist device (LVAD)
• Have a fever that stays at or keeps rising above 103 °F
• Permanent scarring of the skin
• Too few platelets (thrombocytopenia)
• Dementia
• Decreased sensation
• Have diabetes, premenstrual syndrome, an underactive thyroid, or rheumatoid arthritis.
• Inflammation of the iris
• Forgetting recent events or conversations

Facial development depends on the inductive influence of the prosencephalic and rhombencephalic organizing centers. The prosencephalic organizing center includes prechordal mesoderm located in the midline rostral to the notochord and overlying the presumptive prosencephalic neural plate (see Chapter 17). The midbrain-hindbrain boundary is a signaling center that directs the spatial organization of the caudal midbrain and the rostral hindbrain structures. The five facial primordia that appear as prominences around the stomodeum (see. The prominences are produced mainly by the expansion of neural crest populations that originate from the mesencephalic and rostral rhombencephalic neural folds during the fourth week. These cells are the major source of connective tissue components, including cartilage, bone, and ligaments in the facial and oral regions. The results of experimental studies in chick and mouse embryos indicate that myoblasts, originating from paraxial and prechordal mesoderm, contribute to the craniofacial voluntary muscles. The paired maxillary prominences form the lateral boundaries of the stomodeum, and the paired mandibular prominences constitute the caudal boundary of the stomodeum. The five facial prominences are active centers of growth in the underlying mesenchyme. By the end of the embryonic period, the face has an unquestionably human appearance. They result from merging of the medial ends of the mandibular prominences in the median plane. Initially these placodes are convex, but later they are stretched to produce a flat depression in each placode. Mesenchyme in the margins of the placodes proliferates, producing horseshoe-shaped elevations-the medial and lateral nasal prominences. These pits are the primordia of the anterior nares (nostrils) and nasal cavities (see. Proliferation of mesenchyme in the maxillary prominences causes them to enlarge and grow medially toward each other and the nasal prominences. This proliferation-driven expansion results in movement of the medial nasal prominences toward the median plane and each other. Each lateral nasal prominence is separated from the maxillary prominence by a cleft called the nasolacrimal groove. By the end of the fifth week, the primordia of the auricles (external part of the ears) have begun to develop. Six auricular hillocks (three mesenchymal swellings on each side) form around the first pharyngeal groove (three on each side), the primordia of the auricle, and the external acoustic meatus, respectively. By the end of the sixth week, each maxillary prominence has begun to merge with the lateral nasal prominence along the line of the nasolacrimal groove. This establishes continuity between the side of the nose, formed by the lateral nasal prominence, and the cheek region formed by the maxillary prominence. This thickening gives rise to a solid epithelial cord that separates from the ectoderm and sinks into the mesenchyme. By the late fetal period, the nasolacrimal duct drains into the inferior meatus in the lateral wall of the nasal cavity. Hinrichsen, Medizinische Fakultät, Institut für Anatomie, Ruhr-Universität Bochum, Bochum, Germany. Merging of these prominences requires disintegration of their contacting surface epithelia. Merging of the medial nasal and maxillary prominences results in continuity of the upper jaw and lip and separation of the nasal pits from the stomodeum. As the medial nasal prominences merge, they form an intermaxillary segment. The medial nasal prominences form the nasal septum, ethmoid, and cribriform plate. The mandibular prominences give rise to the chin, lower lip, and lower cheek regions. Recent clinical and embryologic studies indicate that the upper lip is formed entirely from the maxillary prominences.