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Mohammed Alawad,1 Abdulrhman Aljouie,1 Suhailah Alamri,2,3 Mansour Alghamdi,4 Balsam Alabdulkader,4 Norah Alkanhal,2 Ahmed Almazroa2 1Department of Biostatistics and Bioinformatics, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 2Department of Imaging Research, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for health Sciences, Riyadh, Saudi Arabia; 3Research Labs, National Center for Artificial Intelligence, Riyadh, Saudi Arabia; 4Department of Optometry and Vision Sciences College of Applied Medical Sciences, King Saud University, Riyadh, Saudi ArabiaCorrespondence: Ahmed Almazroa; Abdulrhman Aljouie, Email almazroaah@ngha.med.sa; aljouieab@NGHA.MED.SABackground: Globally, glaucoma is the second leading cause of blindness. Detecting glaucoma in the early stages is essential to avoid disease complications, which lead to blindness. Thus, computer-aided diagnosis systems are powerful tools to overcome the shortage of glaucoma screening programs.Methods: A systematic search of public databases, including PubMed, Google Scholar, and other sources, was performed to identify relevant studies to overview the publicly available fundus image datasets used to train, validate, and test machine learning and deep learning methods. Additionally, existing machine learning and deep learning methods for optic cup and disc segmentation were surveyed and critically reviewed.Results: Eight fundus images datasets were publicly available with 15,445 images labeled with glaucoma or non-glaucoma, and manually annotated optic disc and cup boundaries were found. Five metrics were identified for evaluating the developed models. Finally, three main deep learning architectural designs were commonly used for optic disc and optic cup segmentation.Conclusion: We provided future research directions to formulate robust optic cup and disc segmentation systems. Deep learning can be utilized in clinical settings for this task. However, many challenges need to be addressed before using this strategy in clinical trials. Finally, two deep learning architectural designs have been widely adopted, such as U-net and its variants.Keywords: glaucoma, glaucoma screening, fundus images, big images data

Laith N AL-Eitan,1 Barakat Z Elsaqa,2 Ayah Y Almasri,1 Hatem A Aman,1 Rame H Khasawneh,3 Mansour A Alghamdi4,5 1Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan; 3Department of Hematopathology, King Hussein Medical Center (KHMC), Royal Medical Services (RMS), Amman 11118, Jordan; 4Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabi; 5Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaCorrespondence: Laith N AL-EitanDepartment of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, JordanTel +962-2-7201000 ext 23464Email lneitan@just.edu.joBackground: Cardiovascular disease is one of the most common causes of morbidity and mortality worldwide. Several cardiovascular diseases require therapy with warfarin, an anticoagulant with large interindividual variability resulting in dosing difficulties. The selected genes and their polymorphisms have been implicated in several Genome-Wide Association Study (GWAS) to be associated with cardiovascular disease.Objective: The goal of this study is to discover if there are any associations between rs646776 of PSRC1, rs660240 and rs12740374 of CELSR2, and rs602633 of SORT1 to coronary heart disease (CHD) and warfarin dose variability in patients diagnosed with cardiovascular disease undergoing warfarin therapy.Methods: The study was directed at the Queen Alia Hospital Anticoagulation Clinic in Amman, Jordan. DNA was extracted and genotyped using the Mass ARRAY™ system, statistical analysis was done using SPSS.Results: The study found several associations between the selected SNPs with warfarin, but none with cardiovascular disease. All 4 studied SNPs were found to be correlated to warfarin sensitivity during the stabilization phase except rs602633 and with warfarin dose variability at the initiation phase. CELSR2 SNPs also showed association with dose variability during the stabilization phase. Also, rs646776 and rs12740374 were linked to warfarin sensitivity over the initiation phase. Only rs602633 was associated with INR treatment outcomes.Conclusion: The findings presented in this study found new pharmacogenomic associations for warfarin, that warrant further research in the field of genotype-guided warfarin dosing.Keywords: warfarin, SNPs, pharmacogenetics, Jordan

Laith N AL-Eitan,1,2 Islam M Al-Dalala,3 Afrah K Elshammari,4 Wael H Khreisat,4 Aseel F Nimiri,4 Adan H Alnaamneh,1 Hanan A Aljamal,1 Mansour A Alghamdi5,6 1Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Blood Banking, King Hussein Medical Centre, Royal Medical Services, Amman, Jordan; 4Queen Rania Hospital for Children, King Hussein Medical Center, Royal Medical Services, Amman, Jordan; 5Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia; 6Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaCorrespondence: Laith N AL-EitanJordan University of Science and Technology, P.O. Box 3030, Irbid 22110, JordanTel +962-2-7201000 Ext.:23464Fax +962-2-7201071Email lneitan@just.eduPurpose: The aim of this study was to investigate the possible effects of single-nucleotide polymorphisms (SNPs) within SLC1A1, SLC6A1, FAM131B, GPLD1, F2, GABRG2, GABRA1, and CACNG5 genes on response to anti-epileptic drugs (AEDs) and the genetic predisposition of epilepsy in Jordanian patients.Patients and Methods: A total of 299 healthy individuals and 296 pediatric patients from the Jordanian population were recruited. Blood samples are collected, and genotyping was performed using a custom platform array analysis.Results: The SLC1A1 rs10815018 and FAM131B rs4236482 polymorphisms found to be associated with epilepsy susceptibility. Moreover, SLC1A1 rs10815018 and GPLD1 rs1126617 polymorphisms were associated with generalized epilepsy (GE), while FAM131B rs4236482 is associated with the focal phenotype. Regarding the therapeutic response, the genetic polymorphisms of FAM131B rs4236482, GABRA1 rs2279020, and CACNG5 rs740805 are conferred poor response (resistance) to AEDs. There was no linkage of GLPD1 haplotypes to epilepsy, its subtypes, and treatment responsiveness.Conclusion: Our findings suggested that SLC1A1, FAM131B, and GPLD1 polymorphisms increasing the risk of generating epilepsy, while FAM131B, GABRA1, and CACNG5 variants may play a role in predicting drug response in patients with epilepsy (PWE).Keywords: pharmacogenetics, anti-epileptic drugs, generalized epilepsy, focal epilepsy, pharmacotherapy, Jordan

Mansour Alghamdi, Stephen J Derbes Department of Medicine, Rheumatology Section, Louisiana State University School of Medicine, New Orleans, LA, USACorrespondence: Mansour AlghamdiDepartment of Medicine, Rheumatology Section, Louisiana State University School of Medicine, New Orleans, LA, USAEmail mmalgh@hotmail.comAbstract: Systemic sclerosis sine scleroderma (ssSSc) is a rare disease in which patients present with internal organ manifestations of systemic sclerosis in the absence of cutaneous findings. They tend to have serological markers characteristic of systemic sclerosis (SSc), including positive antinuclear antibodies (ANA) and anticentromere antibodies (ACA). The disease has been rarely reported in the literature, and the diagnosis can be easily missed due to a lack of relevant skin findings. Here we report a patient who presented with chronic gastrointestinal bleeding with angioectasia, antiphospholipid syndrome (APS), positive ANA, positive ACA, and positive anti-RNA polymerase III antibody. The constellation of all these findings has, to our knowledge, never been described in the literature. The purpose of presenting this case is to raise the clinician’s awareness of the occurrence of this disease when similar internal organs manifestations of scleroderma are encountered, and to monitor for the development of other internal manifestations and intervene promptly and accordingly.Keywords: systemic sclerosis sine scleroderma, scleroderma, systemic sclerosis, angioectasia/angiodysplasia, anti-RNA polymerase III antibody

Laith N AL-Eitan,1,2 Hatem Aman,2 Rami Alkhatib,1,2 Mansour A Alghamdi3 1Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan; 3College of Medicine, King Khalid University, Abha 61421, Saudi ArabiaCorrespondence: Laith N AL-EitanDepartment of Applied Biological Sciences, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, JordanTel +962 2 7201000Fax +962 2 7201071Email lneitan@just.edu.joObjective: To investigate the genotypic and allelic association of Src homology 2 B adapter protein 1 (SH2B1) gene polymorphisms with type 2 diabetes mellitus (T2DM) in Jordanian patients.Patients and Methods: Three hundred patients were screened, but only 200 adult Jordanian patients diagnosed with T2DM (53.5% male and 46.5% female) have participated in this study. Blood samples were collected from both patients and healthy individuals for DNA extraction according to well-established procedures. Exon 1 and exon 9 of the SH2B1 gene were sequenced using an efficient and sensitive DNA sequencing method in order to identify specific single nucleotide polymorphisms (SNPs) in the SH2B1 gene associated with T2DM. Genetic and haplotype correlation analysis was performed for the chosen SNPs to detect any association if existent. In addition, SNPStats Web Tool and Hardy–Weinberg equilibrium (HWE) analyses for the genotype distribution were used. The significance was determined according to the P-value, and the level of significance taken as P < 0.05. The normality of the data distribution was statically analysed by the Shapiro–Wilk test with a P-value > 0.05. Also, the patient’s characteristics and clinical data about all participants were mentioned.Results: Two novel variations were present in the SH2B1 gene in Jordanian patients with T2DM: c.827C>G and c.2026G>A, and previously reported five SNPs: rs146946750, rs565131715, rs370302573, rs143212778, rs200470848. Our results showed a strong genetic association of rs565131715 SNP polymorphism within the SH2B1 gene in T2DM patients (χ2 test, P < 0.001). Additionally, rs143212778 SNP presented a genetic correlation with T2DM patients (χ2 test, P = 0.035) as compared to control individuals. GTACG haplotype of SH2B1 has a highly significant association with responders (P< 0.0001).Conclusion: Our findings indicated a strong association between the rs565131715 polymorphism and the risk of T2DM among the Jordanian population. Moreover, our data showed that the rs143212778 polymorphism significantly elevated the danger of T2DM among this population. This study reveals the first data regarding the SH2B1 gene polymorphisms in Jordanian patients of Arab descent with diabetes.Keywords: SH2B1, type 2 diabetes mellitus, Jordan, Arab

Laith N AL-Eitan,1,2 Rawan O Al Momani,1 Khalid K Al Momani,3 Ahmad M Al Warawrah,3 Hanan A Aljamal,1 Mansour A Alghamdi,4 Alsharif M Muhanna,3 Firas A Al-Qarqaz5,6 1Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Dermatology, King Hussein Medical Center (KHMC), Jordan Royal Medical Services (RMS), Amman, Jordan; 4College of Medicine, King Khalid University, Abha, Saudi Arabia; 5Department of Internal Medicine, Jordan University of Science and Technology, Irbid, Jordan; 6Division of Dermatology, Department of Internal Medicine, King Abdullah University Hospital, Irbid, JordanCorrespondence: Laith N AL-EitanToxicology and Pharmacogenetics, Department of Biotechnology & Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, JordanTel +962-2-7201000 ext. 23464Email lneitan@just.edu.joBackground: Alopecia areata (AA) is a non-cicatricial patchy hair loss on the scalp, face or other parts of the body. AA was found to be responsive to immunosuppressive therapies, a finding that supports an autoimmune basis for the disease. Several genetic studies have shown the significance of immunological factors as key genetic components in AA.Objective: In this study, we aimed to investigate the genetic association of 7 single-nucleotide polymorphisms (SNPs) within five candidate genes including TAP1, CXCL1, CXCL2, HSPA1B, and TNFα with AA susceptibility in the Jordanian Arab population.Methods: A case–control genetic association study conducted in 152 patients and 150 healthy individuals was performed using the sequenom MassARRAY system (iPLEX GOLD) to genotype the selected SNPs.Results: rs1800629 SNP of the TNFα gene was significantly associated with AA in the heterozygous and rare homozygous genotypes (P=0.022 and P=0.0079, respectively) with no linkage of the TAP1, CXCL1, CXCL2 and HSPA1B variants.Conclusion: This is the first study of its kind among the Jordanian population providing evidence of genetic association of the TNFα with AA susceptibility. Further genetic studies on Arab descent including other variants are required to clarify and strengthen the association of these genes with susceptibility to develop AA.Keywords: alopecia areata, TAP1, CXCL1, CXCL2, genetic association studies, immunological factors, Jordan

Laith N AL-Eitan,1,2 Doaa M Rababa’h,1 Mansour A Alghamdi,3 Rame H Khasawneh4 1Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan; 3College of Medicine, King Khalid University, Abha, Saudi Arabia; 4Department of Hematopathology, King Hussein Medical Center (KHMC), Jordan Royal Medical Services (RMS), Amman 11118, JordanCorrespondence: Laith N AL-EitanJordan University of Science and Technology, PO Box 3030, Irbid 22110, JordanTel +962 2 720 1000 Ext 23464Fax +962 2 720 1071Email lneitan@just.edu.joPurpose: Breast cancer (BC) is a complex disease that is governed by several different environmental and inherited factors. There are many genes have been linked with BC development by screening specific genetic variants within these genes. In this study, we aim to investigate the correlation between Variable Number Tandem Repeat (VNTR) in XRCC5 gene and BC.Materials and methods: Polymerase Chain Reaction (PCR) and Gel electrophoresis were used to genotype the XRCC5 gene polymorphism in 200 cases with breast cancer and 200 healthy individuals. All participants were Jordanian women from Arab descents. Clinical and pathological characteristics for BC patients were summarized and categorized according to their medical records.Results: In this study, we found a strong correlation between the VNTR polymorphism in the XRCC5 gene and BC risk (P-value

Laith N AL-Eitan,1,2 Doaa M Rababa’h,1 Mansour A Alghamdi,3 Rame H Khasawneh4 1Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan; 3Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia; 4Department of Hematopathology, King Hussein Medical Center (KHMC), Jordanian Royal Medical Services (RMS), Amman 11118, JordanCorrespondence: Laith N AL-EitanJordan University of Science and Technology, P.O. Box 3030, Irbid 22110, JordanTel +962-2-7201000 Ext 23464Fax +962-2-7201071Email lneitan@just.edu.joPurpose: Genetic predisposition to disease has become one of the most investigated risk factors in recent years, and breast cancer (BC) is no exception. In this study, we investigated specific genetic variants of three candidate genes belonging to the glutathione-S-transferase superfamily that have been implicated in increased risk of cancers.Materials and methods: This case-control study comprised 241 Jordanian women who were diagnosed with BC in addition to 219 matched controls. Gel electrophoresis of PCR products was used to visualize and genotype both the GSTM1 and GSTT1 genes, while PCR-RFLP was employed to genotype the rs1695 of the GSTP1 gene.Results: Our findings did not reveal any correlation between the investigated polymorphisms of GST genes and BC risk among Jordanian women. Otherwise, the combination of GSTM1 entire gene deletion and (GG) genotype of GSTP1 polymorphism (rs1695) was significantly associated with BC with p-value

Laith N AL-Eitan1,2, Islam M Al-Dalalah1, Mohamed M Mustafa3, Mansour A Alghamdi4, Afrah K Elshammari5, Wael H Khreisat5, Mohammed N Al-Quasmi6, Hanan A Aljamal1 1Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Neuroscience, Jordan University of Science and Technology, Irbid, Jordan; 4Anatomy Department, College of Medicine, King Khalid University, Abha, Saudi Arabia; 5Department of Pediatric Neurology, Queen Rania Hospital for Children, King Hussein Medical Center, Royal Medical Services, Amman, Jordan; 6Department of Medical Laboratory, King Abdullah University Hospital, Irbid, JordanCorrespondence: Laith N AL-EitanJordan University of Science and Technology, P.O. Box 3030, Irbid 22110, JordanTel +962 2 720 1000 Ext.:23464Fax +962 2 720 1071Email lneitan@just.edu.joBackground: A total of 50 million persons were diagnosed worldwide with epilepsy. One-third of them are experiencing debilitating seizures despite optimum anti‐epileptic drugs (AEDs) treatment. Several studies have suggested that CYP3A5, CHRM2, and ZNF498 influence the pharmacokinetics of AEDs. Therefore, the severity of the disease as well as the degree of response to the AEDs could be affected by the genetic polymorphisms within these genes.Objectives: In this study, we assessed the effect of certain single nucleotide polymorphisms (SNPs) within CYP3A5, CHRM2, and ZNF498 genes on the susceptibility to develop epilepsy and the responsiveness to AEDs treatment.Methods: A case–control and pharmacogenetic study was conducted on samples of 299 healthy individuals in addition to 296 epileptic patients. Genotypic, allelic, and clinical data association were performed for the selected polymorphisms within the (rs324649, rs420817, rs15524, and rs1859690) in the Jordanian population.Results: The analysis revealed no significant association of the investigated SNPs with epilepsy in general, partial and generalized epilepsy as well as drug responsiveness. CYP3A5 and ZNF498 were associated with family history (P=0.003 and P=0.002, respectively) and the classification of epilepsy for the ZNF498 variant (P=0.009). On the other hand, CHRM2 was not linked to either disease severity or treatment responsiveness.Conclusion: Our results failed to confirm the association of CYP3A5, ZNF498, and CHRM2 variants with either disease development or treatment response. Clinical pharmacogenetic studies may contribute to treatment personalization, appropriate drug dose selection, minimizing drug adverse reactions, increasing drug efficacy, and reducing the costive burdens.Keywords: epilepsy, seizures, cytochrome P-450 CYP3A, pharmacogenetics, humans, anti-epileptic drugs

Laith N AL-Eitan,1,2 Doaa M Rababa’h,1 Mansour A Alghamdi,3 Rame H Khasawneh41Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan; 3Anatomy Department, Faculty of Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia; 4Department of Hematopathology, King Hussein Medical Center (KHMC), Jordanian Royal Medical Services (RMS), Amman 11118, JordanCorrespondence: Laith N AL-EitanJordan University of Science and Technology, P.O. Box 3030, Irbid 22110, JordanTel + 962 2 720 1000 Ext. 23464Fax + 962 2 720 1071Email lneitan@just.edu.joBackgrounds: Breast cancer (BC) is one of the most widespread cancers globally. Understanding the etiology of BC may help in determining the various risk factors involved in its malignancy. Certain genetic mutations are considered to play a key role in increasing the risk of BC.Objectives: In this study, we explored the correlation between a variable number tandem repeat (VNTR) polymorphism in the IL-4 gene and BC.Methods: PCR and subsequent gel electrophoresis were used to genotype this variant in 360 Jordanian women (180 BC patients and 180 controls). In addition, phenotype–genotype analysis was carried out.Results: Our findings illustrate that there is no significant relationship between the variant genotypes in the IL-4 gene and BC among Jordanian females. Other than body mass index and tumor differentiation (p< 0.05), none of the clinical and pathological parameters of BC patients exhibited any association with the variant genotypes.Conclusions: From this study, we propose that the IL-4 genetic variant does not impact BC development and progression but that it could influence the disease prognosis.Keywords: breast, cancer, IL-4, genetic variation, prognosis

Laith N AL-Eitan,1,2 Islam M Al-Dalalah,1 Mohamed M Mustafa,3 Mansour A Alghamdi,4 Afrah K Elshammari,5 Wael H Khreisat,5 Hanan A Aljamal11Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Neuroscience, Jordan University of Science and Technology, Irbid, Jordan; 4College of Medicine, King Khalid University, Abha, Saudi Arabia; 5Queen Rania Hospital for Children, King Hussein Medical Center, Royal Medical Services, Amman, JordanBackground: Epilepsy is one of the most common neurological diseases with unclear etiology where its genetic background and treatment regime still need further exploration.Objectives: This study designed to evaluate the pharmacogenomics of MTHFR and ABCC2 genes, and their association with epilepsy susceptibility among Jordanian population.Methods: A case-control study was conducted on Jordanian cohort of 296 epileptic patients and 299 healthy individuals. Custom platform array was used to genotype the genetic polymorphisms within MTHFR (rs1801133) and ABCC2 (rs717620, rs3740066, rs2273697) genes.Results: This study revealed a significant genetic association of MTHFR rs1801133 polymorphism with susceptibility to generalized in general and generalized tonic-clonic epilepsy (GTCE)(p=0.018 and 0.01, respectively). Regarding ABCC2 gene, rs717620 was of linkage with generalized and GTCE subtypes (p=0.045 and 0.048, respectively), while rs717620 was associated with poor responder patients (p=0.036) with no linkage of the ABCC2 haplotypes.Conclusions: MTHFR and ABCC2 polymorphisms showed an association with either epilepsy types in general or subtypes and treatment response among Jordanian population. This study also suggested that these gene polymorphisms have an important role in epilepsy development and drug effectiveness and could be of a great impact in the era of epilepsy diagnosis and treatment.Keywords: methylenetetrahydrofolate reductase deficiency, epilepsy, pharmacogenetics, tonic- clonic epilepsy, psychotic disorders