Joseph Haddad

Association of candidate genes with nonsyndromic clefts in Honduran and Colombian populations.

Orofacial clefts are the most common craniofacial birth defects in humans, with the majority of orofacial clefts occurring as nonsyndromic cleft lip with or without cleft palate (NSCLP). We previously demonstrated associations between single‐nucleotide polymorphisms (SNPs) in the IRF6 gene and NSCLP in the Honduran population. Here we investigated other candidate genes and chromosomal regions associated with NSCLP identified from genome‐wide association studies (GWAS), including MAFB, ABCA4, 8q24, 9q22, 10q25, and 17q22 in two independent Hispanic populations.

Antimicrobial resistance among isolates causing invasive pneumococcal disease before and after licensure of heptavalent conjugate pneumococcal vaccine.

Background The impact of the pneumococcal conjugate vaccine (PCV-7) on antibiotic resistance among pneumococcal strains causing invasive pneumococcal disease (IPD) has varied in different locales in the United States. We assessed trends in IPD including trends for IPD caused by penicillin non-susceptible strains before and after licensure of PCV-7 and the impact of the 2008 susceptibility breakpoints for penicillin on the epidemiology of resistance. Methodology/Principal Findings We performed a retrospective review of IPD cases at Morgan Stanley Childrens Hospital of NewYork-Presbyterian, Columbia University Medical Center. Subjects were ≤18 years of age with Streptococcus pneumoniae isolated from sterile body sites from January 1995–December 2006. The rate of IPD from 1995–1999 versus 2002–2006 significantly decreased from 4.1 (CI95 3.4, 4.8) to 1.7 (CI95 1.3, 2.2) per 1,000 admissions. Using the breakpoints in place during the study period, the proportion of penicillin non-susceptible strains increased from 27% to 49% in the pre- vs. post-PCV-7 era, respectively (p = 0.001), although the rate of IPD caused by non-susceptible strains did not change from 1995–1999 (1.1 per 1,000 admissions, CI95 0.8, 1.5) when compared with 2002–2006 (0.8 per 1,000 admissions, CI95 0.6, 1.2). In the multivariate logistic regression model controlling for the effects of age, strains causing IPD in the post-PCV-7 era were significantly more likely to be penicillin non-susceptible compared with strains in the pre-PCV-7 era (OR 2.46, CI95 1.37, 4.40). However, using the 2008 breakpoints for penicillin, only 8% of strains were non-susceptible in the post-PCV-7 era. Conclusions/Significance To date, there are few reports that document an increase in the relative proportion of penicillin non-susceptible strains of pneumococci causing IPD following the introduction of PCV-7. Active surveillance of pneumococcal serotypes and antibiotic resistance using the new penicillin breakpoints is imperative to assess potential changes in the epidemiology of IPD.

Factors contributing to cost in partial versus total tonsillectomy

To examine differences between total tonsillectomy and partial intracapsular tonsillectomy techniques that may lead to differences in overall cost and resource utilization between these procedures. Preoperative, perioperative, and postoperative management and outcome factors were examined.

Association of common variants, not rare mutations, in IRF6 With nonsyndromic clefts in a honduran population†

Cleft lip with or without cleft palate (CL/P) is a common birth defect throughout the world. Linkage studies have shown interferon regulatory factor 6 (IRF6) to be associated with CL/P in multiple populations, including one in Honduras. It is unknown, however, whether rare sporadic mutations or common variants are the cause of this association, and reports exist supporting both hypotheses. Thus, it is important to determine the cause for this association in a Honduran population.

Novel IRF6 mutations in Honduran Van der Woude syndrome patients.

Van der Woude syndrome (VWS) is an autosomal dominant inherited disease characterized by lower lip pits, cleft lip and/or cleft palate. Missense, nonsense and frameshift mutations in IRF6 have been revealed to be responsible for VWS in European, Asian, North American and Brazilian populations. However, the mutations responsible for VWS have not been studied in Central American populations. Here, we investigated the role of IRF6 in patients with VWS in a previously unstudied Honduran population. IRF6 mutations were identified in four out of five VWS families examined, which strongly suggests that mutations in IRF6 are responsible for VWS in this population. We reported three novel mutations and one previously described mutation. In the first family, a mother and daughter both exhibited a p.N88I mutation in the DNA-binding region of IRF6 that was not present in unaffected family members. In the second, we found a unique p.K101QfsX15 mutation in the affected patient, leading to a frameshift and early stop codon. In the third, we identified a p.Q208X mutation occurring in exon 6. In the fourth, we found a nonsense mutation in exon 9 (p.R412X), previously described in Brazilian and Northern European populations. In the fifth, we did not identify any unique exonic missense, nonsense or frameshift mutations. This study reports the first cases of IRF6 mutations in VWS patients in a Central American population, further confirming that the causal link between IRF6 and VWS is consistent across multiple populations.

The association between interferon regulatory factor 6 (IRF6) and nonsyndromic cleft lip with or without cleft palate in a Honduran population.

Interferon regulatory factor 6 (IRF6), the gene that causes van der Woude syndrome (VWS), is a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCLP) because a number of studies have supported an association between NSCLP and single nucleotide polymorphisms (SNPs) in IRF6 in several populations. This project investigated the contribution of IRF6 to NSCLP in the Honduran population, a previously unstudied group with a high prevalence of NSCLP.

Copy Number Changes Identified Using Whole Exome Sequencing in Nonsyndromic Cleft Lip and Palate in a Honduran Population

BACKGROUND The majority of cleft lip with or without cleft palate cases appear as an isolated, nonsyndromic entity (NSCLP). With the advent of next generation sequencing, whole exome sequencing (WES) has been used to identify single nucleotide variants and insertion/deletions which cause or increase the risk of NSCLP. However, to our knowledge, there are no published studies using WES in NSCLP to investigate copy number changes (CNCs), which are a major component of human genetic variation. Our study aimed to identify CNCs associated with NSCLP in a Honduran population using WES. METHODS WES was performed on two to four members of 27 multiplex Honduran families. CNCs were identified using two algorithms, CoNIFER and XHMM. Priority was given to CNCs that were identified in more than one patient and had variant frequencies of less than 5% in reference data sets. RESULTS WES completion was defined as >90% of the WES target at >8 × coverage and >80% of the WES target at >20 × coverage. Twenty-four CNCs that met our inclusion criteria were identified by both CoNIFER and XHMM. These CNCs were confirmed using quantitative PCR. Pedigree analysis produced three CNCs corresponding to ADH7, AHR, and CRYZ segregating with NSCLP. Two of the three CNCs implicate genes, AHR and ADH7, whose known biological functions could plausibly play a role in NSCLP. CONCLUSION WES can be used to detect candidate CNCs that may be involved in the pathophysiology of NSCLP. Birth Defects Research 109:1257-1267, 2017.

Inferring gene and protein interactions using PubMed citations and consensus Bayesian networks

The PubMed database offers an extensive set of publication data that can be useful, yet inherently complex to use without automated computational techniques. Data repositories such as the Genomic Data Commons (GDC) and the Gene Expression Omnibus (GEO) offer experimental data storage and retrieval as well as curated gene expression profiles. Genetic interaction databases, including Reactome and Ingenuity Pathway Analysis, offer pathway and experiment data analysis using data curated from these publications and data repositories. We have created a method to generate and analyze consensus networks, inferring potential gene interactions, using large numbers of Bayesian networks generated by data mining publications in the PubMed database. Through the concept of network resolution, these consensus networks can be tailored to represent possible genetic interactions. We designed a set of experiments to confirm that our method is stable across variation in both sample and topological input sizes. Using gene product interactions from the KEGG pathway database and data mining PubMed publication abstracts, we verify that regardless of the network resolution or the inferred consensus network, our method is capable of inferring meaningful gene interactions through consensus Bayesian network generation with multiple, randomized topological orderings. Our method can not only confirm the existence of currently accepted interactions, but has the potential to hypothesize new ones as well. We show our method confirms the existence of known gene interactions such as JAK-STAT-PI3K-AKT-mTOR, infers novel gene interactions such as RAS- Bcl-2 and RAS-AKT, and found significant pathway-pathway interactions between the JAK-STAT signaling and Cardiac Muscle Contraction KEGG pathways.

Radiology quiz case 2. Bronchogenic cyst.

A 3-MONTH-OLD GIRL PRESENTED WITH A HIStory of stridor since birth. The patient’s mother reported that her inspiratory stridor was more pronounced than her expiratory stridor, which worsened with agitation and eating. The patient also had associated mild subcostal retractions but no apnea or cyanosis. Examination of the patient’s neck revealed a vague “fullness” in the right lower neck area but no obvious mass. Fiberoptic laryngoscopy demonstrated poor abduction of the right vocal cord and a narrowed glottic inlet without substantial supraglottic collapse. A magnified high-kilovoltage tomogram of the airway showed tracheal narrowing on the lateral view. Magnetic resonance imaging of the neck and chest without contrast was performed, and a 3-mm coronal slice from the T2weighted sequence is shown in Figure 1. Computed tomography of the neck and chest with contrast was also performed (Figure 2 and Figure 3). What is your diagnosis?

An Implementation of Parallel Bayesian Network Learning

Bayesian networks may be utilized to infer genetic relations among genes. This has proven useful in providing information about how gene interactions influence life. However, Bayesian network learning is slow as it is an NP-hard algorithm. K2, a search space reduction, helps speed up the algorithm but may introduce bias. The bias arises from the fact that K2 enforces topologies which makes it impossible for subsequent nodes to become parents of previous nodes while the algorithm builds the network. To eliminate this bias, multiple Bayesian networks must be computed to ensure every node has the chance to be a parent to every other node. The purpose of this paper is to propose a hybrid algorithm for generating consensus networks utilizing OpenMP and MPI. This paper evaluates the parallelization of network generation and provides commentary on learning and implementing OpenMP and MPI. The OpenMP and MPI accelerations are implemented in a single library and can be switched on or off. These accelerations are for computing multiple Bayesian networks simultaneously. Methods are developed and tested to evaluate the results of the implemented accelerations. The results show generating networks across multiple cores results in a linear speed-up with negligible overhead. Distributing the generation of networks across multiple machines also introduces linear speed-up, but results in additional overhead.