QPHI - Precision Health

PRECISION HEALTH: Transforming the Future of Healthcare in Qatar

PROGRESS REPORT 2012-2023

Transforming the Future of Healthcare in Qatar

This report is a product of more than a decade of visionary leadership in precision health initiated by Her Highness Sheikha Moza bint Nasser, Chairperson of Qatar Foundation. It was written through a collaboration between key experts across Qatar Foundation’s ecosystem.

The overall coordination of the report as well as consultations, desktop research, and reviews were facilitated by Hanieh Khataee, Strategy and Impact Director with Jessica DuPlessis, Manager of Impact and Advisory Services.

Expert consultations and technical reviews were carried out by members of the editorial committee from Hamad Bin Khalifa University, Qatar Precision Health Institute, Sidra Medicine, and Weill Cornell Medicine-Qatar. We would like to thank the following members of the editorial committee (in alphabetical order) for their invaluable expertise and commitment to this report:

PRECISION HEALTH:

Dr. Omar Albagha – Acting Executive Director of Qatar Biomedical Research Institute and Professor of Genomics and Precision Medicine at the College of Health and Life Sciences, Hamad Bin Khalifa University

Dr. Georges Nemer – Associate Dean for Research at the College of Health and Life Sciences and Professor of Genomics and Precision Medicine, Hamad Bin Khalifa University

Dr. David Brown – Advisor to the Qatar Precision Health Institute Board

We would also like to thank Sultana N. Afdhal, Chief Executive Officer of the World Innovation Summit for Health for her contributions to the report and express our gratitude to our key partners in Qatar:

Dr. Khalid Fakhro – Chief Research Officer at Sidra Medicine, Professor of Genomics and Precision Medicine at the College of Health and Life Sciences, Hamad Bin Khalifa University Dr. Mohammed Ghaly – Professor of Islam and Biomedical Ethics at the Research Center for Islamic Legislation and Ethics, College of Islamic Studies, Hamad Bin Khalifa University

Transforming the Future of Healthcare in Qatar

Dr. Said I. Ismail – Director of Qatar Genome Programme Dr. Khaled Machaca – Professor and Senior Associate Dean for Research, Innovation, and Commercialization, Weill Cornell MedicineQatar

PROGRESS REPORT 2012-2023

Dr. Abdulla Al Ansari – Chief Medical Officer, Hamad Medical Corporation Dr. Jassim Al Suwaidi – Chief of Scientific, Academic and Faculty Affairs, Hamad Medical Corporation Dr. Salha Bujassoum – Director of Cancer Genetics, Hamad Medical Corporation and Primary Health Care Corporation

Transforming the Future of Healthcare in Qatar

Acronyms and Abbreviations

02

Introduction

04

Chapter 1:

08

Bringing the Vision to Life: Over 10 Years of Innovation 1.1

Laying the Foundation: Genome Sequencing

12

1.2

Standards, Practices and Policy

18

1.3

Research and Planning

20

1.4

Disease Prevention and Detection

25

Chapter 2:

30

Leveraging Key Advances in Precision Health 2.1

Public Health Efforts

34

2.2

Enhanced Diagnostics

38

2.3

Treatment of Rare Hereditary Diseases

54

2.4

Pharmacogenomics Efforts

60

2.5

Delivering on the Promise of Precision Health in Qatar

66

Chapter 3:

68

Equipping the Precision Health Workforce of the Future 3.1

Shaping Global Discussions

Chapter 4:

77

78

Strategic Convening for Policy Advocacy and Global Collaboration 4.1

The World Innovation Summit for Health

Conclusion

81

84

Shaping the Future of Precision Medicine

CONTENTS

Bibliography

90

References

96 *Pictures used are the property of Qatar Foundation (QF).

Transforming the Future of Healthcare in Qatar

ACRONYMS AND ABBREVIATIONS ACMG

HMC

MSc

QCRI-HBKU

American College of Medical Genetics and Genomics

Hamad Medical Corporation

Master of Science

ADHD

ISAC

NCCCR

Qatar Computing Research Institute at Hamad Bin Khalifa University

National Center for Cancer Care and Research (HMC)

QF

Attention deficit hyperactivity disorder

International Scientific Advisory Committee

ADOS-2

ISBER

NDDs

Autism Diagnostic Observation Schedule, 2nd edition

International Society for Biological and Environmental Repositories

QGP

Neurodevelopmental Disorders

Qatar Genome Program

AI

ISO

PCR

QGPRC

Polymerase Chain Reaction

Artificial Intelligence

International Organization for Standardization

Qatar Genome Program Research Consortium

ASD

PHCC

Low-Density Lipoprotein Cholesterol

Body Mass Index

Lipopolysaccharide-Responsive Beige-Like Anchor Protein Gene

CHLS

MD Doctor of Medicine

CSE-HBKU

Maturity-Onset Diabetes Of The Young

College of Science and Engineering at Hamad Bin Khalifa University

MoPH

DNA

Ministry of Public Health (State of Qatar)

GBMI

Qatar Precision Health Institute

PPP

QTRG

Public-Private Partnership

Qatar Reference Genome

RNA Ribonucleic Acid

QBB

SMA

Qatar Biobank

Spinal Muscular Atrophy

Q-BIG

MoU

Food and Drug Administration (United States)

QPHI

Polygenic Risk Score

MODY

FDA

PPM

PRS

College of Health and Life Sciences at Hamad Bin Khalifa University

Deoxyribonucleic Acid

Qatar National Research Fund

Path towards Precision Medicine

LRBA

BMI

QNRF

Doctor of Philosophy

LDL-C

Biobanking Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium

Qatari Birth Cohort Study

PhD

Lactate Dehydrogenase C

BBMRI-ERIC

QBiC

Primary Health Care Corporation

LDHC

Autism Spectrum Disorder

Qatar Foundation

Qatar BioInformatics Group

TCIC

QBRI-HBKU

Translational Cancer and Immunity Center

Memorandum Of Understanding

Qatar Biomedical Research Institute at Hamad Bin Khalifa University

MRI

Q-chip

Magnetic Resonance Imaging

Qatar Chip

WHO World Health Organization

WISH World Innovation Summit for Health

Global Biobank Meta-Analysis Initiative

02

ACRONYMS AND ABBREVIATIONS

INTRODUCTION

CHAPTER 1

CHAPTER 2

CHAPTER 3

CHAPTER 4

CONCLUSION

BIBLIOGRAPHY

REFERENCES

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Transforming the Future of Healthcare in Qatar

In Qatar, we are drawing on the power of precision health to reimagine our healthcare system. Our agenda is to optimize patient outcomes by detecting the onset of disease early, preempting the progression of disease, and providing targeted care and treatment options for individual patients. In doing so, we are shifting from a conventional one-size-fitsall healthcare delivery model to a precision healthcare system that is prevention-based, cost-effective and patient-centered.

INTRODUCTION 04

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INTRODUCTION

CHAPTER 1

CHAPTER 2

Precision medicine goes beyond disease symptoms to address the causes of disease, and it integrates data on the individual’s genetic makeup, molecular profiles, and other factors into clinical decision-making. Datadriven precision medicine will disrupt the way healthcare is provided around the world, but specifically in Qatar. Routine genetic screening, for example, could lead to a future where fewer Qataris suffer from chronic ill health or die prematurely. We now have a deeper understanding of complex chronic diseases and inherited conditions, and we are better able to diagnose and treat Qataris at CHAPTER 3

CHAPTER 4

CONCLUSION

much earlier stages of disease progression than was possible using our current, symptom-driven models of care.

Human genome research has long used a Eurocentric lens, narrowing the possibilities of science and discounting people’s genetic diversity. Recognizing this gap, Qatar Foundation (QF), through the research capabilities of Sidra Medicine and Weill Cornell Medicine-Qatar, began genomic research to better understand the health of Qatari and Arab populations. One result of this work was the formal establishment of the Qatar Biobank (QBB) in 2012, and the Qatar Genome Program (QGP) in 2014, to further generate evidence and develop systems and tools for genomics and precision medicine in Qatar. The scope of work offers an opportunity to integrate research and evidence into health centers, clinics, and other service delivery platforms.

Such advances demonstrate that precision medicine has the potential to optimize health outcomes in Qatar and throughout the Middle East.

BIBLIOGRAPHY

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Transforming the Future of Healthcare in Qatar

QF’s introduction of precision health is part of a broader government strategy to deliver world-class healthcare in Qatar. The Government of Qatar aspires to transform the health system; it seeks to do more than simply treat the symptoms of disease but to create a sustainable healthcare ecosystem in which advanced treatments are made available to all those who need them – but only as a last resort, if active prevention and early intervention measures did not achieve good outcomes for the patient (National Health Strategy, 2018–2022). Indeed, QF’s work with national partners demonstrates a shared commitment to giving Qataris a better chance to survive, be healthy, and ultimately realize their full potential.

This report, Precision Health: Transforming the Future of Healthcare in Qatar, charts QF’s progress towards achieving a medical

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INTRODUCTION

and scientific vision for precision health. It documents our efforts in longitudinal, populationbased, deep-phenotypic profiling and genome sequencing – and captures new knowledge and understanding that we have acquired in the process – for the purposes of advancing genomic and precision medicine in healthcare settings in Qatar and the Middle East. The report describes how we are applying precision medicine and exploring new therapies for the treatment of critically ill children with rare genetic disorders and complex diseases, as well as developing personalized medicine to address the needs of adults and children with a range of conditions.

The wide range of achievements include QF’s contributions to the national and global COVID-19 public health response, which advanced both diagnostic capacity and disease surveillance, and evaluated vaccine efficacy for new COVID-19 variants. Numerous studies published by QF and its partners that contribute to global science – the results of this extensive work and research over the past 10 years – are contained in the bibliography at the end of this report.

CHAPTER 1

CHAPTER 2

Precision Health: Transforming the Future of Healthcare in Qatar highlights our multidisciplinary genomic and precision medicine research and innovations with some of the world’s leading institutions, which have brought international recognition to QF and solidified our reputation as a leader in innovative healthcare and knowledge.

CHAPTER 3

CHAPTER 4

CONCLUSION

In consideration of the shift to a precision health approach, the report examines efforts to equip our workforce to adapt to a new mode of working and keep up with the pace of technological changes. In addition, the report covers our pivotal role in shaping global discussions around ethical and policy aspects of healthcare innovations.

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Transforming the Future of Healthcare in Qatar

CHAPTER 1

BRINGING THE VISION TO LIFE: OVER 10 YEARS OF INNOVATION

08

ACRONYMS AND ABBREVIATIONS

INTRODUCTION

CHAPTER 1

CHAPTER 2

CHAPTER 3

CHAPTER 4

CONCLUSION

BIBLIOGRAPHY

REFERENCES

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Transforming the Future of Healthcare in Qatar

CHAPTER 1 BRINGING THE VISION TO LIFE: OVER 10 YEARS OF INNOVATION

For the past 10 years, QF has been working closely with the Ministry of Public Health (MoPH), healthcare providers, and research and academic institutions to set the stage for the implementation of precision health.

A shift to a precision healthcare system that personalizes a patient’s treatment – based on their genes and lifestyle, and environmental factors – has the potential to reduce the impact of a diagnostic odyssey for many Qatari families.

Reports from the Middle East have raised concerns about the higher burden of chronic diseases in Qatar and the rest of the Gulf region compared to rates in the developed world (Fahed et al. 2012; Mabry et al. 2010; Forouzanfar et al. 2015). Almost half of Qataris are at high risk of developing chronic diseases (WHO 2015). Rapid economic growth has resulted in notable changes in lifestyle

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INTRODUCTION

One of the major goals of precision health is to optimize medical care for specific individuals based on their genetic and molecular profiles.

In this chapter we focus on QF’s pivotal role and contributions in this area. Specifically, QF has been a catalyst for foundational research and the development of tools to advance precision health and translate new knowledge into practice, and for implementing clinical initiatives and developing replicable processes to introduce precision health services within the healthcare system.

Our unique ecosystem and partnerships with national and international stakeholders have helped to advance research, evidenced

behaviors. Despite Qatar’s young population (the median age was 30 years old in 2012) and its wealth and economic prosperity, there has been an increase in the prevalence of noncommunicable diseases (WHO 2015).

by the many articles published by QF scientists and our local and international collaborators in reputable journals, such as The Lancet, New England Journal of Medicine, and Nature. This ecosystem allows for a multidisciplinary, collaborative, and specialized approach at national and international levels. Furthermore, our investments in the latest technology infrastructure and in human capital have resulted in high throughput analyses, sequencing capabilities and biobanking resources not only for Qatar, but also for the region and worldwide.

WE ARE SHIFTING FROM A CONVENTIONAL ONESIZE-FITS-ALL HEALTHCARE DELIVERY MODEL TO A PRECISION HEALTHCARE SYSTEM THAT IS PREVENTION-BASED, COST-EFFECTIVE AND PATIENT-CENTERED.

A recent population-based genomic analysis

by QF found that Qataris have a diverse genetic background of different ancestries, representing general Arabs, African Arabs, Peninsular Arabs, Persian Arabs, South Asian Arabs, and admixed Arabs (Razali et al. 2021). The rate of consanguineous and tribal marriages is high, which consequently leads to clustering within families of globally rare diseases at an elevated prevalence.

Similar clustering within families of complex conditions such as obesity and metabolic syndrome are further compounded by unhealthy dietary habits and generally sedentary lifestyles.

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CHAPTER 2

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CONCLUSION

BIBLIOGRAPHY

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Transforming the Future of Healthcare in Qatar

1.1 LAYING THE FOUNDATION: GENOME SEQUENCING

MAPPING THE QATARI GENOME AT A POPULATION LEVEL In the Middle East and globally, Qatar is considered a pioneer in its decision to map the Qatari genomic architecture at the population level, alongside earlier work undertaken

by Weill Cornell Medicine-Qatar to map the population structure of Qatar. Qatar Genome Programme (QGP) was created to study and analyze the specimens and data from the large QBB population cohort. The analyses conducted include whole-genome sequencing, genome-wide association studies, polygenic risk scores (PRS), and various other omics (proteomics, transcriptomics, metabolomics, epigenomics, and microbiomics). The data generated has provided researchers and healthcare providers with unparalleled new insights at the molecular level into the Qatari Arab population as well as other Middle Eastern and Arab communities that are of high relevance to precision health.

QF provided a platform for local researchers and their international partners to fasttrack the generation of credible, locally relevant evidence and tools for precision medicine in Qatar. New and rapidly emerging knowledge about the Arab population is influencing local and international decisions on the wider application of genomics and precision medicine approaches and tools for populations and subgroups in various geographies.

The Qatar Biobank, created for research purposes, established the first and only population-based longitudinal cohort study at a national level in the Middle East. It is an accredited biobank and one of the largest globally. QBB now holds more than 2,000,000 biological specimens (blood, saliva, urine, DNA, RNA, and viable cells) and molecular data profiles derived from its cohort participants, including data on genomics, transcriptomics, proteomics, metabolomics, and epigenomics. Deep phenotypic profiling and imaging are available to researchers for more advanced analytics to inform personalized predictions of health.

Population-based, whole-genome sequencing to characterize the Qatari and Arab genome, and association studies conducted across a range of diseases, medicines, and traits, are main outcomes of such research.

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INTRODUCTION

Currently, the database contains more than 40,000 whole genomes belonging to Qataris as well as Arabs from the Middle East and North Africa. Although the biobank cohort participants are mainly made up of healthy Qatari men and women (76 percent), their genotypes show that they represent variable ancestry populations from throughout the wider Arab region. Non-Qatari participants are from Bahrain, Jordan, Oman, and the United Arab Emirates; their data are also included in the QGP dataset to allow for broader analyses.

In addition to omics data, the dataset also contains deep phenotypic data, including blood work results, multiple imaging scans, electrocardiogram test results, and bonedensity scans.

Establishing the QBB population cohort of healthy adult volunteers has enabled us to collect and store multiple high-quality biological specimens and data, including socio-demographic information, physical measures, health and lifestyle factors, medical history, and blood measurements from the large cohort. Researchers are using these specimens and data to conduct largescale genomic research that is relevant to precision medicine. QBB has established a research portal to facilitate research applications, agreements (material transfer agreements, non-disclosure agreements, etc.), and data sharing.

In 2021, our biobank imaging team, in collaboration with Weill Cornell MedicineQatar, introduced magnetic resonance imaging (MRI) scanning of the brain and whole body, corneal confocal microscopy data, and vibration perception threshold measurements to the database.

CHAPTER 1

CHAPTER 2

CHAPTER 3

CHAPTER 4

CONCLUSION

BIBLIOGRAPHY

REFERENCES

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Transforming the Future of Healthcare in Qatar

CONSTRUCTING THE FIRST QATAR REFERENCE GENOME FOR THE ARAB POPULATION

RESEARCH AND STUDIES IN GENOME SEQUENCING To date, our research findings have prompted us to invest in establishing disease-focused cohorts and in further studies that will address critical knowledge gaps and facilitate

the translation of evidence into healthcare guidelines. Some of the publications are highlighted below. For all publications cited in this report, please refer to the bibliography.

Maximizing the benefit of precision medicine depends on the quality of genome interpretation. To improve interpretation, the Qatar Reference Genome (QTRG) was constructed in 2016 by Sidra Medicine in collaboration with Weill Cornell MedicineQatar, Weill Cornell University-New York, and Hamad Bin Khalifa University (HBKU).

QTRG is the first population-specific reference genome for the indigenous Arab population of Qatar.

In constructing the QTRG, the researchers incorporated allele frequency data derived from sequencing genomes from 1,161 Qataris at Hamad Medical Corporation (HMC) and Primary Health Care Corporation (PHCC) health centers, to improve the performance of the standard reference

UNDERSTANDING THE GENOMIC ARCHITECTURE OF ARAB SUBPOPULATIONS IN THE MIDDLE EAST

IDENTIFYING THE QATAR GENOME VARIANTS AT THE SUBPOPULATION LEVEL QGP – in collaboration with the College of Health and Life Sciences at Hamad Bin Khalifa University (CHLS-HBKU), Weill Cornell Medicine-Qatar, Qatar University, Sidra Medicine, and HMC – conducted sequencing of over 6,000 whole genomes from the QBB population cohort in phase 1 of the study (Mbarek et al. 2022). They identified more than 88 million variants, of which 24.6 million (28 percent) were novel to the Qatari population, not previously reported, or not included in existing global databases. They also found that the

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ACRONYMS AND ABBREVIATIONS

INTRODUCTION

population distribution of the variants was variable, with most (70 percent) of them existing within specific population clusters.

These findings highlight the distinct nature of the Arab population and the influence of cultural practices such as consanguineous marriages. This research also confirmed the value of population-based whole-genome sequencing for public health in targeting health delivery and differentiating precision medicine approaches among populations.

CHAPTER 1

genome (GRCh37). Utilizing the QTRG vis-à-vis the standard reference genome allowed a higher level of genome interpretation, and the researchers were able to compile a catalog of known pathogenic mutations in Qatar, including genomic coordinates on both the GRCh37 and QTRG. Availability of the QTRG should enable doctors to personalize treatment of Arab patients using precision medicine by incorporating information about a patient’s genome in the prediction, diagnosis, and treatment of diseases. The authors of the study (Fahkro et al. 2016) recommend the use of QTRG for comparisons across large samples of genomes that may be obtained through public databases. They further note that the QTRG will need to be modified for single-patient use.

CHAPTER 2

Given the unique genetic nature and history of the Arab population, Qatar is an excellent proxy for the wider Arab region. This was first described in a landmark QTRG paper (Fahkro et al. 2016) and was followed by a QGPRC study published by Sidra Medicine in collaboration with Weill Cornell MedicineNew York, Weill Cornell Medicine-Qatar and HBKU (Razali et al. 2021). They used QBB samples to analyze the genome of Qataris in relation to the history of admixture and migration in the region. They concluded that ancient populations in the Arab Peninsula played a far more important role in the history of early human migration than was

CHAPTER 3

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CONCLUSION

previously understood. These ancestries contributed significantly to gene flow among European, South Asian as well as South American populations, likely because of Islamic expansion over the past 1,400 years. The researchers used the data obtained through the QBB samples to build a reference panel dedicated to Arab populations. Prior to the study, the data had been missing for the region. The reference panel can be used to profile ancestries and provides additional insights for precision medicine program design and targeting for the wider region.

BIBLIOGRAPHY

REFERENCES

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Transforming the Future of Healthcare in Qatar

ESTIMATING ACTIONABLE VARIANTS IN THE SEQUENCING OF QATARI WHOLE GENOMES In clinical settings, whole-genome sequencing can uncover findings unrelated to the rationale for genetic testing. The American College of Medical Genetics and Genomics (ACMG) recommends the evaluation and reporting of 59 genes from genomic sequencing in healthcare settings.

QGPRC studied medically actionable variants in the 59 ACMG genes, using whole-genome sequencing data from

PARTNERING WITH PLATFORMS

biobank participants; the study was led

by HBKU in collaboration with HMC and others (Elfatih et al. 2021). They identified a total of 298 variants, of which 60 were likely actionable variants. Overall, 2.3 percent of the QBB cohort sequence carried a pathogenic variant or likely pathogenic variant in one of the 59 ACMG genes.

Variants associated with cancer were the most frequent (35 percent).

QF has a strong track record of partnering with platforms that enable researchers to produce critical findings using precision medicine. The Anti-Doping Lab Qatar and Weill Cornell Medicine-Qatar joined forces to establish a commercial Metabolon metabolomics platform, used to conduct metabolomics analysis for samples submitted by researchers and enabling Qatar to have access to the latest in technology in the fight against doping in sport. Weill Cornell Medicine-Qatar also established a SomaLogic proteomics platform to empower proteomics analyses in personalized medicine. These platforms have enabled scientists to carry out valuable and meaningful research that is locally relevant and contextualized to the national and regional context. The following are three such examples: • The first genome-wide association study with proteomics in an Arab population,

•

•

investigating the translatability of PGS between populations using data from the QBB (Thareja G et al. 2023).

Researching clustered samples from QBB of people with type 2 diabetes, scientists uncovered metabolic and proteomic characterization that applies to the Arab population. This work helps to advance a precision medicine approach to the treatment of patients with type 2 diabetes (Zaghlool SB et al. 2022).

The identification of human knockouts of genetic variants using metabolomics and proteomics can lead to the discovery of new treatments for diseases. This research showed that QBB has 168 times the potential to identify PCSK-9 like drug targets compared to The Genome Aggregation Database (or gnomAD) and highlights the value of studying consanguineous populations to enable such discoveries (Belkadi A, 2022).

TRANSITIONING TO CLINICAL IMPLEMENTATION Accessible genomic data and their discoveries can be used as basis for evidence in healthcare settings to improve patient outcomes. On the ground, the work of translating the evidence base at major clinical sites was led by HMC in treating adults and by Sidra Medicine in treating children. The main publications in this domain from Qatar included a paper on the first assessment of Mendelian risk in the general population (Rodriguez-Flores et al. 2014) and a publication on the first Mendelian Program (Al-Dewik et al. 2018).

A number of high-impact studies in the last five years covered disorders as wideranging as hypercholesterolemia, immune

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ACRONYMS AND ABBREVIATIONS

INTRODUCTION

CHAPTER 1

CHAPTER 2

CHAPTER 3

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CONCLUSION

dysregulation, diabetes, autism, and cancer (Diboun et al. 2022; Roelands et al. 2021; Elashi et al. 2022; Yousri et al. 2022; Ahmed et al. 2023; Abdi et al. 2023; Al-Sarraj et al. 2021; Alsamman et al. 2022). The Qatar Precision Health Institute (QPHI) and MoPH are working together to transition precision medicine endeavors from a basic research focus to clinical implementation, capitalizing on the wealth of data and knowledge generated by QF. In Chapter 2, we highlight the significant precision medicine clinical projects being implemented that would not be possible without an appropriate regulatory environment.

BIBLIOGRAPHY

REFERENCES

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Transforming the Future of Healthcare in Qatar

1.2 STANDARDS, PRACTICES AND POLICY

DRAFTING POLICIES AND REGULATION Biobanking and genomic testing present legal and ethical considerations that are a main priority for any national program seeking to ensure the protection of its human subjects.

QF has led the way in this field, by producing guidance on ethical and regulatory issues related to research and the implementation of data-driven precision medicine at a national level, in consultation with the College of Islamic Studies at HBKU. In 2017, QF and MoPH produced Guidance for the Design, Ethical Review, and Conduct of Genomic Research in Qatar, which contains a regulatory framework for investigators and institutional review boards and for use in research activities related to genomics (MoPH 2017). The guidance highlights the risks associated with genomic research and data sharing, including privacy, psychological and social risks, and how to

mitigate them. It also provides considerations on such ethical issues as the sharing of study results with subjects; disclosure of incidental findings and obtaining informed consent about current and future studies; the sharing of data samples; and the use of samples for scientific discovery, including for purposes of drug intervention.

Through the World Innovation Summit for Health (WISH), QF thought leaders have drafted several thematic documents to guide our precision medicine implementation in research and clinical settings and to inform related policy, for example, Genomics in the Gulf Region and Islamic Ethics (WISH 2016); Precision Medicine: A Global Action Plan for Impact (WISH 2016); and The Future of Medicine: Healthcare Innovation through Precision Medicine (Qoronfleh et al. 2020).

MAINTAINING QUALITY STANDARDS AND INTERNATIONAL ACCREDITATION In 2022, QF’s accomplishments were recognized by the International Society for Biological and Environmental Repositories (ISBER). QBB has attained International Organization for Standardization (ISO) certification by ISBER for biobank biotechnology standards (ISO 20387) in 2022, after receiving ISO certifications for

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INTRODUCTION

quality management systems (ISO 9001) in 2015 and information security management systems (ISO 27001) in 2013. In late 2022, Qatar was granted observer status in the Biobanking Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium (BBMRI-ERIC).

QBB’s laboratories are accredited by the College of American Pathologists.

CHAPTER 1

CHAPTER 2

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CONCLUSION

BIBLIOGRAPHY

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Transforming the Future of Healthcare in Qatar

1.3 RESEARCH AND PLANNING SPEARHEADING NATIONAL GENOMICS RESEARCH EFFORTS In 2016, QF established the Qatar Genome Program Research Consortium (QGPRC), the first and largest of its kind in the Middle East. The consortium is managed

by QGP and made up of 150 scientists from QGP, QBB, Sidra Medicine, HMC, Weill Cornell Medicine-Qatar, HBKU, and Qatar University, as well as international investigators from institutions such as the Center for Genomic Regulation, Institut Pasteur, National Institutes of Health (United States), Oxford University, Stanford University, University of Trieste, University of Tubingen, and the Wellcome Trust.

The consortium has successfully created multidisciplinary research teams to mine the large genomics and phenotypic data

produced by QF to identify key features of the Qatari genome. The findings and outcomes of this research are being applied to the clinical implementation of precision medicine in Qatar. In recent years, these outcomes include published articles describing the characteristics of the Qatari reference genome and distribution in population substructures; medically actionable genomic variants; the genomic landscape of familial cancers; and pharmacogenomic variants in this population. Notably, these articles appear in high-impact journals thus addressing a long-standing gap in the literature on the genomics of Qatari and Arab populations.

150

QGPRC SCIENTISTS

20

Entities in Qatar

International Investigators

QGP, QBB, Sidra Medicine, HMC, Weill Cornell Medicine-Qatar, HBKU, and Qatar University

Center for Genomic Regulation, Institut Pasteur, National Institutes of Health (United States), Oxford University, Stanford University, University of Trieste, University of Tubingen, and the Wellcome Trust

ACRONYMS AND ABBREVIATIONS

INTRODUCTION

CHAPTER 1

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CONCLUSION

BIBLIOGRAPHY

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Transforming the Future of Healthcare in Qatar

SUPPORTING GENOMICS AND BIOINFORMATIC RESEARCH STRUCTURES FOR SUCCESS QF biomedical research projects are usually conducted by multidisciplinary teams with both local and international research institutions to foster collaboration, leverage existing processes, and harmonize study designs and protocols. In 2015, QF’s joint efforts with the Qatar National Research Fund (QNRF) led to the establishment of a genomic research funding mechanism called Path towards Precision Medicine (PPM). Under this mechanism, grants are awarded annually to research teams and investigators. These PPM research grants capitalize on genomic and phenotypic data produced by QF, allowing researchers to further elaborate disease phenotype/ genotype correlations, and they have been used to translate findings into guidance, new therapies, and tools to apply to precision medicine in Qatar.

enabled QF to conduct whole-genome sequencing to determine genetic variations of disease-causing genes and identify variants impacting disease progression and responses to therapies. Investment in modern, high-technology equipment – automated for high volume of throughput – has enabled both short-read and longread sequencing of billions of base pairs per day. Consequently, this technology has catalyzed genomic knowledge of the Arab region, with study results published in top scientific journals.

BUILDING A NATIONAL GENOMIC DATA NETWORK BY CAPITALIZING ON GENOMIC AND PHENOTYPIC DATA

Our biobank supports over 400 research projects, either as part of international consortia or as PPM projects in addition to PhD, MSc, and undergraduate research.

To manage the high volume of data and computational requirements, Sidra Medicine has implemented a computing platform for genome data management and bioinformatics incorporating highperformance computing for data analytics.

Researchers can request access to whole-genome sequence data by submitting an application to QF through the biobank website.

To further amplify the reach and impact of this research, strategic partnerships were forged early on. For example, we signed a memorandum of understanding (MoU) with Genomics England for researchers to share knowledge and experience, and many of our researchers have benefited from being part of Genomics England Clinical Interpretation Partnership domains. These collaborations have helped to catalyze research in Qatar.

Most of the studies are informed by more advanced research groups, including those affiliated with UK10K in the United Kingdom, and genome projects in Iceland and the Netherlands, among others.

Technological advancements have

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INTRODUCTION

To maximize use of bioinformatics resources in Qatar, we formed the Qatar BioInformatics Group (Q-BIG). The group meets regularly to share ideas and forge partnerships with healthcare and biomedical research stakeholders. QF provides support for bioinformatics, data production, and data analyses in their research and clinical projects. Additionally, QF is establishing the Disease Genomics Database to allow data sharing, genomic

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CONCLUSION

research, and discovery of diseases among researchers, with the goal of making such research a national priority in Qatar and the region. The database supports researchers within healthcare and research institutions to generate comprehensive genotyping, sequencing, and other relevant genomic data for their respective cohorts from their clinical samples, subsequently making these data available for the wider research community.

In addition to the analytical infrastructure supported by collaborating institutions, several large datasets from precision medicine projects are also analyzed at HBKU. The capacity at HBKU allows for data to be distilled using artificial intelligence (AI), to highlight interventions, including treatment choices, and other information that could be important for an individual’s health.

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Transforming the Future of Healthcare in Qatar

1.4 DISEASE PREVENTION AND DETECTION

PARTICIPATING IN THE GLOBAL BIOBANK META-ANALYSIS INITIATIVE QF is part of the Global Biobank MetaAnalysis Initiative (GBMI), a collaborative network integrating 23 large biobanks from four continents, representing more than 2.2 million consenting individuals (Zhou et al. 2022). QBB has reached approximately 43,000 participants in the population cohort study, which represents over 10 percent of

the Qatari population. This is the first time that the Arab population is part of such a global initiative. Given the small population in Qatar, this collaboration will greatly enhance genetic discoveries with specific phenotypes common in Qatar, across ancestries, and for new drug candidates.

PREDICTING DISEASE SUSCEPTIBILITY IN EARLY CHILDHOOD AND LATER IN LIFE In 2018, QF and MoPH, in collaboration with PHCC, Qatar University, and Sidra Medicine, established the Qatari Birth Cohort Study (QBiC) to evaluate how genomic, nutritional, and social factors impact children’s health in early childhood and later in life. This study, the first mother-child cohort study of its kind in the Middle East, builds on the assumption that an adverse uterine environment related to maternal dietary or other causes, or placental insufficiency, impacts neonatal outcomes as well as susceptibility of the fetus to later development of cardiovascular or metabolic diseases (Sadoun et al. 2017).

Obesity, hypertension, insulin resistance, and type 2 diabetes all are common conditions in Qatar.

QBiC aims to enroll and follow 3,000 pregnant women and their children longitudinally from birth until 5 years of

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age. Pregnant women who have lived in Doha for 15 years and are receiving prenatal care at PHCC clinics are invited to participate together with their husbands.

Information from women participating in the study is collected with their consent on several factors related to sociodemographic characteristics, dietary habits, and occupational/environmental exposure.

Maternal characteristics on anthropometric measurements, spirometry, and blood pressure are assessed; biological samples (blood and urine) are collected in each trimester of the pregnancy, and cord blood is collected at delivery. Fathers are also asked to provide biological samples. The study has been reviewed and ethically approved by the Institutional Review Board of the QBB Ethics Committee, and the data generated are stored in an integrated data warehouse for future research.

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DETERMINING THE GENETIC RISKS ASSOCIATED WITH CLINICALLY RELEVANT TRAITS In most settings, clinical decision-making is based on clinical laboratory tests. However, genetic variability within and between populations is not well understood. To aid understanding, genome-wide association studies have provided new insights into genetic determinants of many clinically relevant traits. QBRI-HBKU and Weill Cornell Medicine-Qatar published the first such study conducted on clinically relevant traits using whole-genome sequencing from the Middle East (Thareja et al. 2021).

The researchers examined data from 6,100 biobank specimens from phase 1 and conducted genome-wide association studies on 45 clinically relevant traits.

Heritability estimates showed significant differences across populations, suggesting these were driven by genetic differences.

For example, cholesterol and body mass index (BMI) heritability estimates were lower among Qataris compared to Europeans, while the prevalence of obesity in Qatar is among the highest in the world.

The study provided new insights into the genetic architecture of clinical laboratory tests; it not only reported hundreds of replicated genetic variations, but it also identified genetic variations that are specific to the population of Qatar. The study also showed that findings from genetic studies in European populations do not translate well when applied to populations in the Middle East. This underscores the need for further studies to define the genetic architecture of diseases in our region that can facilitate future implementation of precision medicine.

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A recent analysis of QBB cohort data found that being overweight and obese is a major health problem among both men and women enrolled in the study (QBB Annual Report, 2022-2023). This is in addition to high cholesterol, hypertension, diabetes, asthma, and arthritis self-reported by many of the study participants, and hypothyroidism commonly self-reported by women. Vitamin D deficiency was prevalent in both men and women, with 18 percent of the cohort having severe deficiency and 67 percent having mild to moderate deficiency. These findings align well with some of the reasons for medical referral of cohort participants to the two medical services designated for the study, HMC and PHCC. The main reasons were osteopenia (36 percent), dyslipidemia (15 percent), diabetes (12 percent), thyroid function tests (10 percent), and osteoporosis (5 percent). The analysis and its findings are already providing insights for prioritizing timely and comprehensive interventions and personalized care, as with the environmental and lifestyle changes that need to be made, and for investment in further genomic and other omic analysis.

MAIN REASONS FOR QBB COHORT REFERRAL TO HMC AND PHCC

Osteopenia 36% Diabetes 12% Thyroid function test 10% CHAPTER 1

Dyslipidemia 15% Osteoporosis 5%

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ANALYZING POLYGENIC RISK SCORES TO PREDICT VARIATIONS IN PREDISPOSITION TO CANCER IN QATARI SUBPOPULATIONS AND TO PROVIDE A MEASURE OF DISEASE RISK DUE TO GENES

Polygenic risk scores (PRS) measure the risk of disease, such as cancer, associated with pathogenic variants. We know from recent reports that cancer rates in the Middle East have increased (Arafa et al. 2020; Arafa and Farhat 2022), and the risk of developing cancer may vary according to race, ethnicity, and ancestry.

However, most genome-wide studies and analyses of PRS are conducted on people of European ancestry. Genome data from Qatar represent six distinct ancestry groups (general Arabs, African Arabs, Peninsular Arabs, Persian Arabs, South Asian Arabs, and admixed Arabs), as reported in the study by Razali et al. 2021.

To respond to this knowledge gap, HBKU and collaborators – at Sidra Medicine, Weill Cornell Medicine-Qatar, Weill Cornell University-New York, Janssen Research and Development in Paris, and the University of Naples – conducted a large-scale study using phase 1 whole genomes in over 6,000 biobank specimens (Saad et al. 2022). PRS were optimized from the Cancer Genome Atlas to assess risk for the most common cancers found in Qatar (breast, colorectal,

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EVALUATING NON-ARAB POLYGENIC RISK SCORES TO DETERMINE RISK OF CORONARY HEART DISEASE AMONG QATARIS The performance of six non-Arab PRS platforms was evaluated by QF, HMC, and the Mayo Clinic in the United States (Saad et al. 2022) for their applicability in predicting risk of coronary heart disease in Qatari patients. The researchers conducted a genome-wide association study involving 1,067 coronary heart disease cases and 6,170 controls from the biobank population.

and prostate cancers). Rare genetic variants in 1,218 known cancer-related genes were also assessed for pathogenicity and actionability among the various genetic subpopulations of Qatar.

The PRS study confirmed a high degree of heterogeneity in risk for common cancers in the six ancestry groups. Qataris of Peninsular Arab ancestry showed the lowest PRS for colorectal cancer, while those of African ancestry showed the highest average for prostate cancer. A cancer gene variant analysis identified 70 Qataris (1.2 percent of the cohort) carried pathogenic variants or likely pathogenic variants. Breast cancer was overrepresented in Qataris of Persian ancestry and completely absent in those of Peninsular Arab ancestry. These data provide important insights for the stratification of screening approaches for precision medicine in healthcare settings.

The researchers called for evaluations of disease-centered variant data in the region to be pooled and further validated through meta-analysis for additional insights.

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They found that the PRS platform obtained from European ancestry performed well compared to others, and they recommended that the platform could be used in clinical settings while Qatar-specific PRS are being developed. This is an important recommendation for catalyzing the application of PRS in precision medicine.

LEVERAGING THE QATAR GENOME PROGRAM FOR COVID-19 RESEARCH AND THE PUBLIC HEALTH RESPONSE COVID-19 research and the pandemic response in Qatar are examples of the additional value of the genotypic and phenotypic data platform for public health in Qatar. QF was able to pivot the genomic program investment in both human capacity and technology to COVID-19 research. Early in the global pandemic response, QGP became part of the International Scientific Community’s COVID-19 Host Genetics Initiative, mandated to study and provide insights on the genetics of COVID-19, including among Arab subpopulations.

during the study year, the viruses found in the population mirrored nearly those of the entire global population’s genomic diversity, and there were a number of genetic deletion mutations (Benslimane et al. 2021). An earlier study by HBKU and collaborators determined that the multiple variants of COVID-19 in Qatar varied significantly among the subpopulations.

These results confirmed the need for a policy that supports continued surveillance of coronavirus characteristics as part of the national public health response in Qatar.

QF and partners published several studies on the COVID-19 pandemic. In their 2021 study characterizing the outbreak, for example, Qatar University, MoPH, Weill Cornell Medicine-Qatar, Weill Cornell University-New York, HMC, and the World Health Organization (WHO) reported that despite restrictions on international travel imposed as a national response

Weill Cornell Medicine-Qatar in collaboration with MoPH and HMC was among the first to report on vaccine efficacy of subsequent dosing to protect against new COVID-19 variants (Chemaitelly et al.

2022) and the importance of polymerase chain reaction (PCR) testing for travelers to determine the profile of those infected after travel (Bertollini et al. 2021).

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CHAPTER 2 Leveraging Key Advances in Precision Health

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CHAPTER 2 LEVERAGING KEY ADVANCES IN PRECISION HEALTH Precision medicine is accelerating innovation and paving the way for a future in which doctors in Qatar can treat complex and rare diseases. QF clinical and research efforts are being fueled by a deeper understanding of the genomic features underlying health and disease in the local population, as well as insights into lifestyle choices and the environment. At QF’s tertiary hospital, Sidra Medicine, children with genetic disorders are being diagnosed and managed with life-saving treatments and care, enabling interventions at much earlier stages. This is just a snapshot of the potential of the precision medicine approach.

QF is merging ongoing biomedical research with clinical and social support initiatives to advance precision medicine, all managed

and coordinated by the newly formed Qatar Precision Health Institute (QPHI). QPHI’s oversight management is supported by a Clinical Council that advises on clinical priorities and implementation modalities. An International Scientific Advisory Committee (ISAC), made up of reputable scientists and specialists from around the world, guides QPHI’s overall strategic direction. QPHI is working to reduce fragmentation among the various efforts being implemented, while maintaining core capacities at QF and in partner institutions where necessary. A key objective for QPHI is to develop repeatable processes for translating precision medicine in priority areas and diseases, including reference datasets for research and clinical decision support in the immediate as well as the long term.

HIGHLIGHTING SOME OF THE CLINICAL EFFORTS THAT WE ARE UNDERTAKING IN THESE FOUR THEMATIC AREAS:

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2.1 PUBLIC HEALTH EFFORTS TYPE 2 DIABETES AND CARDIOMETABOLIC DISORDERS

TYPE 2 DIABETES AND CARDIOVASCULAR DISEASES are the leading causes of morbidity and mortality in Qatar (Al Thani 2017), and they pose significant public health challenges in Qatar. The spectrum of disorders related to type 2 diabetes in Qatar includes coronary artery disease along with cardiovascular disease, hyperglycemia, hyperlipidemia, hypertension, renal failure, and retinopathy.

Type 2 diabetes accounts for about 50 percent of renal failure patients requiring dialysis, 50 percent of acute coronary vascular disease, and 70 percent of stroke and transient ischemic attack cases. Using data from the QBB large-population cohort, QF estimated that around 20 percent of Qataris have type 2 diabetes and over 40 percent are obese (National Diabetes Committee and MoPH 2022).

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QF is collaborating with PHCC to provide patients with comprehensive wellness, lifestyle, and genomic reports through the PHCC Wellness Program. These reports include advice on the changes patients need to make regarding diet and eating habits, potential food reactions, exercise, and metabolic disorder risk factors. Genomic counseling is offered, and follow-up support is provided to patients who need help with exercise and dieting, smoking cessation, blood pressure monitoring, and adherence to medications. Similarly in collaboration with QF, the PHCC Smart Health Check Program integrates preventive screening for common chronic, metabolic, mental, orthopedic, hematologic, and cardiovascular illnesses.

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Hypercholesterolemia, is an inherited disease characterized by a reduced ability to clear low-density lipoprotein cholesterol (LDL-C) from the blood and an increased risk of coronary vascular disease. Through genome sequencing, scientists at HBKU, Sidra Medicine, Weill Cornell Medicine-Qatar and HMC led large studies using data from 14,500 participants in the QBB cohort and estimated a higher prevalence of familial hypercholesterolemia among Qataris

Complementary to these public health efforts, QF is supporting genomic and molecular studies that are generating new insights into cardiometabolic disorders. One such study – by Weill Cornell Medicine-Qatar, Sidra Medicine, HBKU, and international collaborators (Yousri et al. 2022) – collected data from almost 1,000 Qatari adults with type 2 diabetes. The researchers identified 373 metabolites associated with type 2 diabetes, obesity, retinopathy, dyslipidemia, and lipoprotein levels, of which 161 were

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(1 in 125) compared to the global prevalence (ranging from 1 in 250 to 1 in 500) (Diboun et al. 2022). These studies also identified both known and new variants associated with hypercholesterolemia and PRS that associated higher phenotypic LDL-C scores.

These are important findings that can be used to predict risk and as a necessary consideration for planning early public health interventions in these populations.

novel and had never been reported before.

These metabolites are potential biomarkers for risk prediction and targeting treatment; they may cause oxidative stress, lipotoxicity, glucotoxicity, and proteolysis, resulting in negative health consequences. In another study, Sidra Medicine, HMC, HBKU, and Weill Cornell Medicine-Qatar (Ahmed et al. 2023) have constructed a multi-trait PRS model for type 2 diabetes in Qatar, which can be used for early detection of type 2 diabetes risk.

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2.2 ENHANCED DIAGNOSTICS QATAR CHIP SCREENING TOOL AND INTEGRATED GENOMICS SERVICES FOR DIAGNOSIS Using genomic data generated by QGP and the clinical genetic registry maintained by the Diagnostic Genomic Division at HMC, QF developed the first Qatar chip (Q-chip) as a population-specific genotyping microarray with over 300,000 genetic markers and disease-associated mutations (RodriguezFlores et al. 2022). The Q-chip can be used to screen for a number of pathogenic variants in newborns, premarital couples, and patients presenting in healthcare settings; its high throughput makes it a cost-effective tool. The main collaborators in the Q-chip development were Weill Cornell UniversityNew York, Weill Cornell Medicine-Qatar, Sidra Medicine, QBB, HMC, RUCDR Infinite Biologics, University of Puerto Rico, Qatar University, and Rutgers University.

Sidra Medicine’s Integrated Genomic Services bring together clinical genomics and omics laboratory capabilities with data science and zebrafish analytical units. This integration offers a comprehensive suite of genomic, molecular biology, and informatics services to clinicians and researchers across the country. In 2022, Sidra Medicine validated and optimized whole-genome sequencing, RNA sequencing, and single-cell sequencing pipelines. This new technology has reduced the cost of sequencing by over 50 percent (Sidra Medicine Research Annual Report 2022). During 2023, more than 17,000 whole genomes were sequenced.

Incorporating transcriptome and the zebrafish analyses (see box) into routine genomic sequencing is pivotal in the accurate diagnosis of rare and undiagnosed hereditary disorders and cancers.

ZEBRAFISH: PIONEERING PRECISION MEDICINE THROUGH HUMAN DISEASE MODELS The Zebrafish Facility at Sidra Medicine offers a personalized medicine approach to healthcare that will ultimately pave the way for more effective and precise treatments for rare pediatric diseases.

The zebrafish platform is significant as a versatile and powerful tool for advancing our understanding of genetic disorders and accelerating the development of targeted therapies.

The zebrafish is a small, freshwater tropical fish with a genetic makeup similar to that of humans, which makes

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them widely used as a model organism in biological research. Zebrafish develop rapidly, their embryos are transparent, and their genes can be easily manipulated using advanced technologies like CRISPR/ Cas9. Scientists can observe the gene expression and regulation and disease progression in zebrafish in real time, aiding an understanding of a human patient’s unique genetic and molecular signatures and allowing for the creation of patient-specific disease models and the identification of novel therapies tailored for the individual patient.

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The research on novel genetic variants and genes at Sidra Medicine is truly groundbreaking. Using zebrafish models, our researchers have validated key findings in gene discoveries, clinical manifestations, and disease prognosis. These findings have contributed to the broader landscape of precision medicine and targeted effective healthcare strategies. The zebrafish platform has been used to successfully create pediatric disease models of neurological disorders, cardiovascular diseases, congenital anomalies, and other diseases.

The Zebrafish Facility actively contributes to interpreting the QGP's unique findings, providing a foundation for extrapolating, and applying findings from zebrafish studies to broader contexts, including potential health implications. In a paper published in 2021, the facility generated a model using zebrafish for the VWA1 gene, which is linked to the loss of motor function in 17 individuals from 15 families (Pagnamenta et al. 2021). This model demonstrated that the zebrafish VWA1 model reduced motor neuron axonal growth, impaired synaptic formation in the skeletal muscle, and movement patterns like those observed in the affected patients. The research was in collaboration with scientists based in the United Kingdom.

Recently, we linked novel variants specific to the Qatari population’s cardiac function, progressive vision and hearing loss, and traits associated with hair and eye pigmentation through functional validations in the zebrafish model.

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DIAGNOSIS OF AUTISM SPECTRUM DISORDER Issue: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder (NDD) with a wide range of phenotypic presentations, including difficulties with communication and social interaction, attributed to several genetic, epigenetic, and/or environmental factors. In 2019, a large study conducted by researchers at HBKU estimated ASD prevalence to be as high as 1 in 87 children in Qatar (Alshaban et al. 2019).

There have been several studies globally on the causes or precise genetic markers of ASD, which are important for early diagnosis and early behavioral interventions to improve child outcomes. However, to date there are no globally validated biomarkers for ASD screening and diagnosis. Diagnosis mostly depends on physicians’ assessments and family reports, interviews, and observations, which are often subjective and may result in a delayed diagnosis.

Action: In 2020, a multidisciplinary team of researchers at HBKU leveraged precision health technologies by validating an eyetracking stimuli for early screening and diagnosis of ASD for use with children who speak Arabic. Researchers from HBKU applied a personalized engagement assessment that captures visual, auditory, and social attention for children with ASD during learning. The research, which was run by HBKU’s College of Science and Engineering explored the effect of social and nonsocial visual stimuli on the attention of children with ASD and typically developing children in a simulated virtual classroom. This new approach measures eye-gaze patterns, which are indicative of ASD, using a remote eye-tracking device; the

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child being screened sits in front of an LCD computer monitor, which displays stimuli in the form of pictures and videos in Arabic.

Stimuli were developed in collaboration with the Cleveland Clinic in the United States.

Researchers in Qatar adapted the stimuli to the Qatari context and for Arabic speakers; their first version of the stimuli (15–20 minutes) was felt to be too long so they are now working on a shorter version. By aggregating eye-gaze data into an autism risk index, this approach provides an objective and user-friendly tool for early detection and diagnosis of ASD. It is intended to be used to identify children at risk of autism who can then be targeted for referral, which will reduce the burden on the healthcare system. The approach had a success rate of over 85 percent (Frazier et al. 2021), and the tool can be used safely on infants as young as six months of age. The researchers have applied for a patent.

Another project, on digital phenotyping of social communication behaviors, uses computerized machine-learning systems to monitor and analyze social communication behavior in children both with autism and with non-autism NDDs, such as attention deficit hyperactivity disorder (ADHD) and intellectual disabilities. The two-year project – developed in collaboration with Argus Cognitive and Rush University in 2021 – is using smart glasses, standard cameras, and advanced machine-learning software to automatically detect crucial social communication behaviors, including eye gaze, gestures, facial expressions, and speech. Machine learning is in the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2), considered a "goldstandard" tool for ASD diagnosis. But the tool is used manually and requires specialized training of clinicians and others who use it, so it can be slow and subjective; a single assessment can take up to 45 to 60 minutes.

Once validated, this new digital phenotyping approach is expected to save time and increase objectivity among users of the ADOS-2 tool in reaching a diagnosis. With ASD, the earlier the diagnosis and intervention, the better for the child in terms of improvement of symptoms.

as it aims to enhance early detection, intervention, and personalized care for individuals with ASD and other NDDs, ultimately leading to improved health outcomes and quality of life. In a recent study published by QF, HBKU in collaboration with Qatar University (Mesleh et al. 2023), measured the blood proteins of 121 children to identify potential biomarkers of ASD in the Qatari population and to characterize molecular pathways potentially involved in ASD pathogenesis. This study is the first of its kind to comprehensively measure 1,196 blood proteins using all the target panels developed

by Olink, a company based in Uppsala, Sweden.

The researchers identified 15 proteins that are potential biomarkers for ASD diagnosis; however, the proteins are yet to be validated for specificity. The study underlined the need for multi-omics profiling, to identify diagnostic biomarkers with high-performance characteristics. HBKU's laboratory has developed a robust platform to improve existing diagnostic observations with more data-driven methodologies using multiple biomarkers – the connectome, transcriptome, and genome, among others – as well as prenatal components. This multi-biomarker approach is more effective and accurate than using a single biomarker to diagnose NDDs, including ASD. In the largest genomic study of ASD of its kind

Impact: In 2019, HBKU’s ASD diagnostic proteomic biomarkers platform was recognized by QF’s Industry Development and Knowledge Transfer office, and HBKU has applied to the United States Patent and Trademark Office for a provisional patent and a patent cooperation treaty, to protect the invention and to allow

in the region, scientists at Sidra Medicine published the results of the pilot phase of the BARAKA-Qatar study, which looks at the genomic and environmental determinants of ASD in the local population (Abdi 2023). This study analyzed the genomes of 100 families with ASD (372 individuals) using deep wholegenome sequencing and analysis protocols.

The data were analyzed for a wide range of genomic causes of ASD, including small variants, structural variation, mitochondrial variants, and tandem repeats. Altogether, a putatively causative gene was identified in around 24 percent of families, nearly twice the global average. Surprisingly, a significant proportion of gene occurrences were due to recessive mutations, which were present at levels of 10-fold higher in Qatar versus global cohorts. The finding sheds light on a genetic architecture that is not widely considered to contribute to ASD worldwide, and it offers the potential to screen people early for such variants (at a young age or premaritally) for timely intervention. The study has now enrolled another 300 families and is preparing a phase 2 release in which 500 families from Qatar will be fully sequenced and analyzed by mid-2024. Sidra Medicine is collaborating with the Hospital for Sick Children (SickKids) in Canada and the Autism Speaks MSSNG database project in this second phase.

the laboratory to transform the findings into a diagnostic kit. There are plans to commercialize the other digital tools, and to use the newly discovered recessive markers for screening. These technologies, when available on the market, have the potential to transform early diagnosis and intervention for autism in Qatar, the Middle East and globally.

QF research in the field of ASD has significant implications for precision health,

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SCREENING FOR DIABETES MELLITUS IN CHILDREN Issue: The International Diabetes Federation estimates that there are 1.2 million children and adolescents living with diabetes globally (IDF Diabetes Atlas 2021), and the Middle East and North Africa are among the regions with the highest prevalence (Zhang et al. 2023).

Diabetes in children is classified according to the underlying pathology and includes neonatal diabetes, types 1 and 2 diabetes, maturity-onset diabetes of the young (MODY), and autoimmune monogenic and syndromic forms of diabetes.

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Action: Precise characterization of diabetes in children is necessary for personalized clinical care. Among initiatives that are taking place, some include genomics in the molecular evaluation of all sick children presenting with diabetes in Qatar. In a recently published study (Harris et al. 2021), Sidra Medicine used pancreatic β-cell autoantibody and genetic profiling on blood samples from 1,345 diabetic children under the age of 18 years who were attending diabetes clinics and admitted as in-patients between 2018 and 2020.

Type 1 diabetes was the most common type of diabetes, occurring in 83 percent of the study population and 52 percent of Qatari Arab children included in the study.

Type 1B (idiopathic) and type 2 diabetes were the second most common, each at a prevalence of 8 percent. MODY, a rare monogenic form of diabetes, occurred in 1 percent of study participants. MODY is usually misclassified in clinics because of the absence of clinical assessment tools, the occurrence of de novo mutations, and the lack of suitable genetic testing; and most MODY cases are misdiagnosed due to the high prevalence of obesity in Qatar.

In a large population-based study (Elashi

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Impact: In September 2023 Sidra Medicine was awarded a US$1 million grant by the Juvenile Diabetes Research Foundation, the leading global organization that funds type 1 diabetes research and advocacy.

This grant will support the establishment of a four-year program that combines autoimmune antibody diagnosis and genetic screening for children aged 18 months to 14 years with type 1 diabetes.

et al. 2022), HBKU researchers analyzed whole-genome sequence data from 14,364 adults from the QBB participant cohort; they identified genetic variants associated with MODY, including variants not previously reported, and estimated the prevalence of MODY to be 3.4 percent of diabetes patients. The studies highlighted the importance of genetic testing to identify patients with MODY and offer a personalized treatment approach.

Separately, Sidra Medicine is partnering with PHCC to predict the future risks of type 1 diabetes in children in Qatar.

This project will determine the basis for establishing a model for national pediatric type 1 diabetes autoimmune antibody and genetic screening for precision medicine in Qatar and throughout the Middle East and North African region.

Sidra Medicine and collaborators conducted a cohort study to classify diabetes in all children diagnosed with the disease and to study the epidemiology and genetic landscape (Haris et al. 2021). This is the first study in Qatar to systematically classify the biochemical and genetic factors underlying diabetes in children, from birth to age 18 years. The total incidence of diabetes mellitus (all types included) was 39.19 per 100,000 children, and total prevalence was 301.91. Incidence and prevalence were also estimated by subtype and ethnic group. The data from the study will be entered in a national diabetes registry for children in Qatar in support of further studies to inform precision medicine approaches.

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DIAGNOSING AND CHARACTERIZING CHILDHOOD CANCERS Issue: WHO estimates that globally, about 400,000 children and adolescents (aged 0–19 years) develop cancer every year (WHO 2021). Sidra Medicine estimates that the prevalence of childhood cancer in Qatar is about 8 cases per 100,000 population, a proportion similar to regional and global estimates. Leukemias, lymphomas, and brain tumors are the most common types. The risk and clinical evolution of cancer is driven by genetic mutations, resulting in heterogeneity, with an impact on outcomes in the patient and children’s response to treatment.

Tumor management has benefited from a precision management approach.

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Action: Sidra Medicine has a pediatric oncology hub with specialized teams for the diagnosis, care, and support of all children and adolescents with cancer.

Researchers are characterizing pediatric tumors and quantifying immune cells and their function, which can predict the risk of tumor relapse and death. In a recent study, Sidra Medicine quantified antitumor immune responses associated with tumor gene expression and determined that pediatric solid tumors could be divided into six different subtypes, according to their immunological parameters (Sherif et al. 2022). The researchers used an immune signature called the Immunologic Constant of Rejection – which was developed at Sidra Medicine – to accurately predict the risk of death in patients with certain aggressive tumors, such as a subtype of neuroblastoma, which is particularly aggressive in children. The study suggested that immune markers

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associated with an unfavorable prognosis could be explored as targets for novel immunotherapeutic approaches.

In 2021, Sidra Medicine launched a pediatric cancer biobank of tumor and normal tissue samples as a precision medicine pilot project for genetic and epigenetic profiling research. The project envisages several areas of study: analysis of the immune phenotype and oncogenic heterogeneity of tumors; development of non-invasive diagnostics and targeted personalized therapies; and genome oncology profiling, including DNA and RNA extraction, next-generation sequencing, and variant annotation. Personal cancer genome reports and cancer predisposition sequencing reports are generated within two to three weeks for clinicians. Genomic oncology profiling is expedited for study participants with aggressive tumors or relapse, to ensure timely diagnosis and appropriate treatment.

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Impact: The biorepository will be used by researchers as a platform for developing personalized cancer therapies and tools for pediatric patients.

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DIAGNOSING AND TREATING BREAST CANCER Issue: The clinical and molecular heterogeneity of breast cancer has led to the classification of different subtypes, all with different disease courses and prognoses. Breast cancer presents at a younger age in Qatar compared to the Western world (Najjar and Easson 2010), and our studies have shown that the risk profiles and prognoses differ across population groups in Qatar (Roelands et al. 2021). With the growing application of genomics in oncology, it has become possible to identify individuals with the different types of breast cancers and offer them personalized genetic counseling, strategies to reduce their cancer risk, and targeted therapy to improve their outcomes. WHO (2020) reported there were 1,260 cancer cases in Qatar, the most common being breast cancer (15.1 percent), colorectal cancer (11.3 percent), leukemia (6.8 percent), non-Hodgkin’s lymphoma (6.1 percent), prostate cancer (5.8 percent), and lung cancer (5.8 percent). QF is supporting a number of precision medicine projects to identify biomarkers for predicting and diagnosing breast cancer and genetic, immunological, and therapeutic targets for treatment.

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Action: QGP and QBB in partnership with the National Center for Cancer Care and Research (NCCCR) at HMC conducted a pilot study using wholegenome sequencing to identify QBB cohort participants with pathogenic BRCA1 and BRCA2 genes (QBB Annual Report 2022–2023). BRCA mutations are known to increase the risk of developing breast cancer by as much as 87 percent (Kuchenbaecker et al. 2017). A total of 6,000 genomes were analyzed, resulting in the identification of 20 study participants with BRCA genes. The at-risk women and men were enrolled in a five-year cohort study – established by MOPH, QF, and local and international collaborators – for follow-up care and research purposes.

An oncologist and a genetics counselor from NCCCR are providing follow-up care and support, as per HMC guidelines, and genetic testing is provided for families of the cohort study participants. The care pathway developed through the cohort study is being applied to other actionable mutations.

Prediction and early detection of breast cancer, coupled with appropriate selection of therapeutic regimens, are essential for patients’ survival. In 2023 QF awarded an internal research grant to QBRI for the purpose of using genomics, transcriptomics, proteomics, metabolomics, and immunophenotyping analyses to identify diagnostic and prognostic biomarkers and to advance precision medicine in clinical practice.

In 2021, QBRI evaluated the involvement of cancer testis antigen in lactate dehydrogenase C (LDHC) in regulating tumor stability and whether it could be targeted for tumor cellular fitness (Naik and Decock 2022). LDHC is a specific

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marker discovered by the researchers at QBRI (Thomas et al. 2020). The evaluation found that suppressing LDHC could increase the presence of giant cells, nuclear aberrations, DNA damage, and apoptosis. Based on these promising findings, QBRI is developing and validating tools to target LDHC and reduce its negative effects using complexes of cellpenetrating peptides and LDHC-silencing molecules in two- and three-dimensional models for breast cancer in the laboratory.

Although advances in cancer detection and therapies have significantly reduced breast cancer death rates, significant numbers of patients still develop resistance to therapies and almost all patients who develop metastatic disease face very poor clinical outcomes. QBRI leads an interdisciplinary research program in collaboration with HMC and the King Hussein Cancer Center in Jordan that is exploring two main objectives within breast cancer research. The first objective is to identify genetic determinants of familial breast cancer that is not linked to BRCA1 or BRCA2, and the second is to identify novel biomarkers for disease diagnosis and prognosis, as well as prediction of the response to therapy, using multi-omics (genomics, transcriptomics, proteomics, metabolomics, and others). The ultimate goal of the program is to identify novel biomarkers for breast cancer that contribute to the improvement of patient survival in Qatar and the Middle East region.

QBRI is also engaged in a number of transcriptomic studies to identify disease biomarkers as novel genetic and therapeutic targets, which have resulted in a number of publications in 2023. Some of the studies are highlighted here (see the bibliography at the end of the report for full publication details).

and miRNA profiling on tumor samples, the investigators in this study identified RNA and miRNA regulatory networks as functions of breast cancer molecular subtype, tumor grade, and age and ethnicity of the patient (Elango et al. 2023). They also identified RNA and miRNA signatures predictive of worse and better relapse-free survival.

QBRI employed functional screen data from CRISPR-Cas9, a technology that allows editing of the genome, to identify a number of therapeutic targets for each breast cancer molecular subtype, although specific therapy targeting several of these genes is not available on the market.

Impact: Our work provides a framework for future development and testing of novel diagnostic and prognostic biomarkers and genetic and molecular therapeutic targets for breast cancer.

These markers have the potential to improve patient care and outcomes in Qatar, the Middle East and globally.

In another study, investigators at HBKU’s Translational Cancer and Immunity Center (TCIC) and QBRI employed computational algorithms to study the composition of estrogen-positive and triple-negative breast cancer subtypes from a total of 49,899 single cells, publicly available transcriptomic data, and identified gene sets in molecular subtypes (Vishnubalaji and Alajez 2023).

They integrated single-cell transcriptomics with CRISPR-Cas9 functional screen data to identify 13 potential therapeutic targets.

Triple-negative breast cancer is resistant to neoadjuvant chemotherapy. QBRI has identified the transcriptional landscape associated with resistance at a single-cell level by analyzing transcriptomic data from more than 5,000 single cells (Vishnubalaji et al. 2021). In the same study, investigators reported identifying three gene signatures predictive of response to neoadjuvant therapy that can be used as prognostic markers and therapeutic targets.

Using comprehensive transcriptomic RNA

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OMOUMA MOTHER-CHILD COHORT Issue: Qatar has very high rates of pregnancy-related complications, including gestational diabetes (21 percent), gestational hypertension (18.4 percent), preterm birth (10 percent), low birth weight (6.9 percent), and pre-eclampsia (3.7 percent) (HMC 2019). Pregnancy health outcomes are influenced by multiple lifestyle, molecular, and cellular processes.

Recent studies have revealed high levels of heterogeneity and the multifactorial nature of pregnancy-related complications.

Action: Sidra Medicine is the only private tertiary hospital in Qatar providing complex care for women and children, with physicians covering 30 subspecialties. In addition to its role as the national genomics center for highvolume sequencing, Sidra Medicine conducts research in precision health, mainly for rare diseases, pediatric leukemia, mitochondrial disorders, and autism. Integrative multi-omics technologies at Sidra Medicine include immune simulation and blood transcriptomics, proteomics, metabolomics, epigenomics, and metagenomics. Researchers and clinicians apply integrative bioinformatics tools to explore in depth the complex molecular interactions impacting the health of women, children, and adolescents.

Omouma is a precision medicine pilot project established at Sidra Medicine in 2021 to investigate the maternal, genetic, social, environmental, and lifestyle factors that affect pregnancy outcomes and infant health (Kumar et al. 2021). A total of 1,000 pregnant mothers receiving antenatal care in their first trimester at Sidra Medicine have been enrolled to date; multiple assessments on the cohort samples are being conducted to identify predictive biomarkers. Omouma also aims to determine how early childhood determinants impact the health outcomes of infants, children, and adolescents in Qatar’s geographically and genetically diverse population. Pregnant women are followed up every trimester until delivery

and later, with their babies, for one year post delivery. Using the biological samples collected, the investigators aim to identify molecular mechanisms of pregnancy complications – such as gestational diabetes, gestational hypertension, preeclampsia, stillbirth, and prematurity – and biomarkers that predict pregnancy outcomes.

The work is paving the way for personalized care, and the biobank of samples will be used in future research, including the study of microbial profiling, vaginal immune response, blood transcriptomics, epigenomics, and metabolomics.

Impact: The Omouma project study is still under way, with impact yet to be determined.

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PLASMA EYE DROPS FOR CONGENITAL PLASMINOGEN DEFICIENCY Issue: A 10-month-old baby admitted to Sidra Medicine was diagnosed with congenital plasminogen deficiency, an extremely rare genetic disorder, which makes the eyes fill up with inflamed, ’’wood-like’’ growths of the conjunctiva (Sidra Medicine Research Annual Report 2021).

Action: A multidisciplinary team at Sidra Medicine (with specialists in hematology, ophthalmology, pathology, blood bank, and advanced cell therapy) produced plasma eye drops for this condition – for the first time in the world.

2.3 TREATMENT OF RARE HEREDITARY DISEASES Sidra Medicine’s Research Institute has launched several initiatives to target the diagnosis and treatment of children with rare genetic disorders. Key among these is the long-standing Mendelian Program, which acts as an umbrella protocol for research using whole-genome sequencing and other omics. The program is open to any child suspected of having a monogenic condition and to members of the child’s family; to date, it has enrolled more than 500 families representing a wide range of disease conditions. As evidenced by the growing literature from Qatar, the Mendelian Program has made significant strides in gene dicovery. Importantly, novel genes and variants discovered in pediatric disorders are tested functionally using cellular and zebrafish models, increasing the confidence in their causality as well as illuminating possible pathways for intervention and treatment.

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To expand the reach of this successful approach to more patients, the Research Institute recently launched the Precision Medicine for All grant, the first national initiative to fund research studies enrolling patients in clinicalresearch protocols. This grant is a mechanism for community funds to be directed towards research, enabling young patients, particularly those with genetic, rare, or hard-to-diagnose conditions, to access diagnostic and therapeutic services at Sidra Medicine, including wholegenome sequencing, zebrafish modeling, and immunophenotyping.

Impact: After a year of using the eye drops, the baby was successfully treated; and several other patients have benefited from this treatment to date. Congenital plasminogen deficiency is a rare disease, but there are multiple patients in Qatar’s small population, due to consanguinity.

More recently, with the completion of Qatar’s first fully accredited Good Manufacturing Practice facility, Sidra Medicine has developed clinical algorithms for therapeutic discoveries for rare diseases and is liaising with industry and pharma to begin clinical trials for rare conditions affecting its patient populations.

These are described in more detail:

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GENE REPLACEMENT THERAPY FOR SPINAL MUSCULAR ATROPHY

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Issue: In a joint effort, HMC and Sidra Medicine treated 11 patients aged 2–22 months diagnosed with spinal muscular atrophy (SMA) between 2019 and 2021 (Ali et al. 2021). SMA is an inherited autosomal recessive neuromuscular disorder that is usually fatal in infants. It is characterized by progressive muscle weakness and wasting from infancy, resulting from the loss of motor neurons in the spinal cord. The incidence of SMA is up to 40fold higher in the Middle East than in the Western world due to high consanguinity (Al-Rajeh et al. 1992).

Action: Diagnosis of SMA was confirmed by genetic testing to identify two homozygous SMN1 deletions. The multidisciplinary teams treated children using Zolgensma (onasemnogene abeparvovec), a gene therapy manufactured by Novartis and approved by the United States Food and Drug Administration (FDA) in 2019. All but one of the patients receiving the therapy showed improvements in terms of their reduced need for a ventilator to aid breathing and fewer hospital stays, among other outcomes.

Impact: Following the publication in 2021 of the evidence of the efficacy of this treatment in Qatar, Sidra Medicine was appointed as the lead treatment center in the Middle East and North Africa region to administer Zolgensma.

Novartis’s Managed Access Program works with selected partner hospitals to offer gene therapies to babies suffering from rare and life-threatening neurological genetic diseases in settings where treatment and medication are unavailable.

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USE OF ABATACEPT IN THE PERSONALIZED TREATMENT OF TWO SIBLINGS WITH SEVERE AUTOIMMUNE DISEASE

Issue: Sidra Medicine sequenced the genomes of two siblings with severe autoimmune disease who were not responding to traditional immunosuppressive therapies (Merico et al. 2021). The siblings were found to have mutations in the lipopolysaccharide-responsive beigelike anchor protein gene (LRBA).

Action: Sidra Medicine’s previous work demonstrated that the LRBA gene was an important regulator of CTLA4, an immune-inhibitory molecule.

Abatacept, a CTLA4 mimic, was shown in the laboratory to compensate for the defective LRBA. The hospital treated the patients with abatacept, which resulted in substantive improvements in their clinical condition, including reduced inflammation, fewer gut symptoms, and significant weight gain (Qatar Foundation 2021).

In administering the treatment, Sidra Medicine followed the hospital protocol for the use of new discovery medicines.

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Impact: Mutations such as those found in the two siblings are likely to reoccur, given the levels of consanguinity in Qatar. For these rare conditions, Sidra Medicine has established a management model of care to facilitate the use of new therapeutic discoveries. Parents admitted to the hospital are given the option to consent to the use of available novel treatment options as a standard part of care. Children are automatically sequenced to look for mutations and provide personalized care.

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A collaboration between Weill Cornell Medicine-Qatar, and Sidra Medicine led experts to use precision medicine to identify and treat a sick child using innovative methods and advanced technology. The child in question was admitted to Sidra Medicine with severe infections, muscular hypotonia, and anhidrosis, all of which prevented the child from thriving. Genome sequencing revealed a novel mutation in the Orai1 gene, known to be involved in the activation of immune cells. Initially, it was unclear whether this mutation was pathogenic, and because most pathogenetic variants are associated with a low risk of disease (Forrest et al. 2022) it was clear that experts needed to investigate this further. The teams from Weill Cornell Medicine-Qatar and Sidra Medicine did so by developing cellular models

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to replicate the mutation found in the child and study its functional implications. These studies showed that the mutated Orai1 channel could not traffic properly to the cell membrane and was not functional. As this channel is required for immune cell function, this explains the primary immunodeficiency observed clinically. Based on that information which proved the pathogenesis of the mutation, the child was prioritized for a bone marrow transplant and has since received the treatment. This case is important as it shows the ability to supplement genomics analyses with functional data using cellular models to define the pathogenesis and inform clinical treatment, which is a direct application of personalized medicine in the clinical setting in Qatar (Yu et al. 2021).

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2.4 PHARMACOGENOMICS EFFORTS Most treatment protocols currently in use in Qatar are modeled after United States and European clinical trials in the absence of specific, population-characteristic data on pharmacogenomic profiles. Expanding access

to optimal therapeutic options for patients and reducing adverse drug reactions for Qataris require a better understanding of how specific genetic variations can affect individual responses to certain medications.

ONGOING STUDIES IN PHARMACOGENOMICS QF has been supporting the following ongoing studies on pharmacogenomics (for full publication details, see the bibliography at the end of the report): A population study of clinically actionable genetic variation affecting drug responses from the Middle East Genetic variants play an important role in individual responses to a specific medication.

QF is leading the coordination of adopting pharmacogenomics in Qatari healthcare settings for common complex diseases, including cancer and cardiovascular conditions. This is in parallel to its work of conducting research to understand population-specific genetic variations in

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drug metabolism genes. These activities under the pharmacogenomics program at QF seek to enable targeted treatment and dosing for individuals who are fast or slow metabolizers of a prescribed drug. The program is also identifying individuals at risk for adverse reactions.

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Whole-genome sequencing can identify clinically actionable variants affecting patients’ responses to treatment. Using genomes from the QBB population cohort, the partners in this first comprehensive study – HBKU, Sidra Medicine, HMC, QGP,

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Quantitative Genomics Laboratories in Barcelona, and the University of Liverpool – characterized clinically actionable genotypes and diplotypes and their phenotypic effects on efficacy, dosing, and risk of adverse events for several medications (Jitesh et al. 2022).

The study demonstrated that 1,320 variants in 703 genes were different in Qataris when compared to population groups in other parts of the world, and these variants affected Qatari patients responses to 299 drugs.

More specifically, 615 of the variants had higher frequencies in the Qatari population, requiring further work to determine clinical significance for precision medicine.

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INFLUENCE OF PHARMACOGENETICS ON CLINICAL OUTCOMES OF QATARI PATIENTS: TREATMENT OF BREAST CANCER WITH ANTHRACYCLINE/ CYCLOPHOSPHAMIDE-BASED CHEMOTHERAPY Anthracyclines, including doxorubicin, epirubicin, daunorubicin, and idarubicin, are commonly used in chemotherapy regimens for breast cancer. However, anthracyclines are also associated with adverse events that significantly limit their use in patients. NCCCR and QF are collaborating on an evaluation of an anthracycline cyclophosphamidebased chemotherapy. The protocol has been submitted to the Medical Research Council.

PERSONALIZATION OF CLOPIDOGREL ANTIPLATELET THERAPY IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION IN QATAR Clopidogrel is a widely used antiplatelet agent for a variety of atherothrombotic diseases.

However, there are concerns about its reduced efficacy in people unable to convert clopidogrel to its active metabolite. Studies have shown that patients possessing genetic variants of the CYP2C19 gene may be at increased risk of adverse cardiovascular events due to impaired clopidogrel efficacy. A recent study by Qatar University and HMC estimated that the prevalence of the CYP2C19*2 gene, the most common loss of function variant, ranged from

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1.7 percent to 35 percent in the Middle East and North Africa region (Ali and Elewa 2019).

A pilot project on personalization of the clopidogrel antiplatelet therapy in patients undergoing percutaneous coronary intervention is under way in Qatar; 300 patients are enrolled to date. A larger project will be partially funded by QF; the project proposal has been submitted to the Medical Research Council.

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PERSONALIZED WARFARIN PHARMACOGENETIC GENOTYPEGUIDED DOSING: CLINICAL IMPLEMENTATION IN PATIENTS WITH HEART VALVE REPLACEMENT IN QATAR Several CYP2C9 gene polymorphisms are associated with decreased activity of the CYP2C9 enzyme that slows the body’s metabolism of warfarin. The drug remains active in the body for a longer period of time, leading to warfarin toxicity. QF and HMC are collaborating on a study to evaluate clinical implementation of pharmacogenetic genotype-guided dosing of warfarin in patients with heart valve replacement. The pilot study is under way, and patients are receiving genotype-guided dosing therapy.

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EVALUATION OF THE USE OF ANTIPSYCHOTICS IN MIDDLE EASTERN POPULATIONS TO ASSESS PRESCRIPTION PATTERNS HBKU, HMC, and Sidra Medicine conducted a cross-sectional study of Qatari patients who received antipsychotic prescriptions from major healthcare providers in Qatar between June 2018 and May 2020 (Bastaki et al. 2021).

Among the 35,938 antipsychotic prescriptions dispensed, second-generation antipsychotics were the most highly prescribed (59 percent), followed by first-generation antipsychotics (13 percent). Most of the prescriptions (69 percent) indicated that the antipsychotics were for off-label use in treating conditions like sleeping disorders, benign paroxysmal positional vertigo, and irritable bowel syndrome. The study concluded that integrating these data with pharmacogenomic and clinical outcome data would be helpful in personalized decision-making and precision medicine in Qatar and beyond.

PRE-EMPTIVE PHARMACOGENETIC TESTING FOR STATIN PERSONALIZED PRESCRIPTION: POTENTIAL IN THE PREVENTION OF STATINRELATED MYOPATHY Statins are a cornerstone of treatment and prevention of atherosclerotic cardiovascular disease. However, genetic polymorphism can significantly affect statin efficacy, and in 10 percent of patients it led to organ toxicity or myopathy (Kitzmiller et al. 2016).

Dose-response relationships have been demonstrated repeatedly for both statin efficacy and toxicity. Taking this research further, HMC and QF are collaborating on a study to evaluate preemptive genetic testing in statin personalized prescription. The protocol has been submitted to the Medical Research Council.

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CREATING A ROBUST HEALTHCARE SYSTEM The data derived from QF-supported work in clinical settings – including integration of data sets, disease cohorts, and the disease-specific tools being developed from the pilot studies – are an important element for Qatar’s transition

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to a precision medicine-based healthcare system and its successful rollout. Chapter 3 looks at how QF is contributing to training the workforce who will run the precision health system.

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Transforming the the Future Future of of Healthcare Healthcare in in Qatar Qatar Transforming

2.5 QF MILESTONES: DELIVERING ON THE PROMISE OF PRECISION HEALTH IN QATAR

•

• •

Launched Qatar Genome Program with Her Highness Sheikha Moza bint Nasser

• • •

2014

•

Created Qatar Genome Program Research Consortium First landmark study of the Qatari population appeared on the cover of Genome Research, an international, peer-reviewed journal Released MoPH Design, Ethical Review, and Conduct of Genomic Research in Qatar Guidance Published a study on successful construction of the Qatar Reference Genome (Fakhro et al. 2016)

•

Established partnerships with Genomics England and the Global Biobank Meta-Analysis Initiative for joint work

• • •

2019

Identified actionable pathogenic and likely pathogenic variants in healthy Qatari adults through a whole-genome sequencing study using QBB cohort samples Created a pediatric cancer biobank and began research to develop non-invasive diagnostics and targeted, personalized therapies for children Developed plasma eye drops to successfully treat a child with congenital plasminogen deficiency Designed the Omouma cohort study at Sidra Medicine to identify predictive biomarkers for adverse pregnancy and child health outcomes

• •

2022

2021

2016

•

Confirmed through a population study the genetic differences in drug efficacy, dosing, and adverse reactions among Qataris, when compared to other population groups Demonstrated through analysis of polygenic risk scores for common cancers the significant differences between the six ancestry groups in Qatar Extended precision medicine support to PHCC Smart Health Check and Wellness Clinics Sidra Medicine appointed as the lead treatment center in the Middle East and North Africa by Novartis to administer Zolgensma for spinal muscular atrophy

2023 2015 •

2012 •

•

Established Pathway Towards Precision Medicine grant scheme Created the Mendelian Program at Sidra Medicine, Qatar’s most successful gene-discovery protocol for rare diseases

Created Qatar Biobank with MoPH and HMC

2020

2018

• •

• •

Developed the Q-chip, a low-cost, genotyping microarray tool for specific use with the Qatar population Established the Qatari Birth Cohort Study to evaluate how genomics and other factors affect children’s health in early childhood and later in life

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Validated eye-tracking tool for diagnosing autism spectrum disorder

• • • • •

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Published new evidence on biomarkers for autism and MODY prevalence in diabetes patients, and RNA and mRNA regulatory networks in breast cancer characteristics (Elashi et al. 2022; Elango et al. 2023) Received Juvenile Diabetes Research Award for Sidra Medicine to develop an autoimmune antibody and genetic screening model for children in Qatar and the Middle East Integrated pharmacogenomic testing in the healthcare system to guide warfarin and clopidogrel treatment decisions Provided genomics and precision medicine internships to 41 students in grades 11 and 12 and led orientation workshops for secondary-school biology teachers QPHI led workshops for biology teachers from 50 public schools to increase teachers' knowledge of precision medicine.

QPHI released Genome Heroes, a bilingual Arabic-English mobile phone application for children aged 6 to 12 that promotes learning about genomics in a fun, educational way Genomic wellness and lifestyle reports have been delivered to more than 100 patients through the Wellness Clinic within PHCC

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CHAPTER 3 Equipping the Precision Health Workforce of the Future

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have been developed or are in the pipeline, including university courses up to the PhD level, orientation programs, and dialogue platforms, to develop the next generation of professionals and leaders in science. These academic programs are underpinned by our experience of research, development, and innovation.

TERTIARY INSTITUTIONS QF has invested in graduate-level training of healthcare professionals in genomics and other omics-based technologies. HBKU offers MSc and PhD programs in genomics

CHAPTER 3 EQUIPPING THE PRECISION HEALTH WORKFORCE OF THE FUTURE In Qatar, precision medicine interventions are new and largely unfamiliar to many clinical providers. Healthcare professionals are updating their skill set to respond to the additional workload of integrating genomics and precision medicine into patient care.

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and precision medicine that are based on reputable programs developed in Canada, Europe, and the United States. The aim is to train researchers, who can provide new insights for translating the study of genomics into clinical practice. Each program has a maximum capacity for 10 graduate students, and the programs are tailored in consideration of their diverse backgrounds. Specifically, 30 percent of students should be Qatari, to create a critical mass to work in the genomics and precision medicine field locally, and 20 percent should be residents or foreigners.

To that end, curricula in the schools and universities in QF’s ecosystem are evolving to help people understand the value of precision health, and to ultimately enable healthcare professionals to confidently treat life-threatening diseases and complex genetic disorders. We are contributing to building a multidisciplinary workforce with the capacities and skills to drive the sustainable rollout of precision medicine in Qatar.

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HBKU provides core training in precision medicine under an MoU with Sidra Medicine.

All HBKU students and faculty have access to advanced technological platforms at the level of sequencing or other bioinformatic tools.

Many of the scientists at Sidra Medicine are also adjunct faculty at CHLS-HBKU. For the past two years, many of HBKU’s graduate students have pursued their PhD projects under the co-supervision of Sidra Medicine and HBKU faculty.

In 2022, the first 10 to 12 students enrolled in these programs graduated and received their doctorates in genomics and precision medicine. Some of them are now working in hospitals such as Sidra Medicine and HMC or as research assistants in laboratories in QF’s Education City. Since 2020, 25 to 30 students have enrolled in the programs, including nurses enrolled in the MSc program.

Transforming the Future of Healthcare in Qatar

Weill Cornell Medicine-Qatar Qatar is contributing to building biomedical research and human capacity. Students in Qatar graduate with the same Doctor of Medicine (MD) degree as do students in the United States. Students in the fourth year of the MD program are required to do a six-month research internship, in which they may choose precision medicine, bench science, or clinical or translational research.

Weill Cornell Medicine-Qatar is also contributing to building capacity in precision medicine at the local level. Its Research Department has a team dedicated to training the local workforce to understand precision medicine and research as part of its Research Exposure Program, which includes a 10-month training course followed by application in a science or clinical lab, among other options.

The clinical applications are done at HMC, PHCC, and Sidra Medicine. The program was specifically designed for Qatari nationals and long-term residents who will stay in Qatar and support the health ecosystem. Most of the trainees are employed by Weill Cornell Medicine-Qatar, HMC, or Sidra Medicine once they complete the program.

As Qatar transitions to a precision healthcare system, practicing clinicians are benefiting from continuing education opportunities, such as the Research Exposure Program and various symposia on precision medicine organized for them by QF. Clinicians in the Research Exposure Program receive a minimal stipend while they take time off from their regular jobs to attend the training.

Genetic counselors are critical to the success of precision care, particularly as Qatar is already implementing precision medicine technologies such as genome sequencing, premarital testing, and cancer screening.

Qatar University has a MSc in genetic counseling program that trains professionals on how to advise patients and their families in a sensitive manner about genetic testing, patient test results, and the implications of such results. Qatar University is increasingly providing support to clinicians who wish to learn more about genetics.

CHLS-HBKU is collaborating with MoPH and two other HBKU institutions – the College of Law and the College of Public Policy – to develop a MSc program that addresses the ethical concerns of patient care, including patient data safety and privacy issues.

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TABLE 1: TERTIARY EDUCATION PROGRAMS

INSTITUTION

PROGRAM

FOCUS

MSc and PhD in Biological and Biomedical Sciences

Multidisciplinary programs in Applied Biological and Biomedical Sciences for clinical, computational, and translational life sciences research that are important for precision medicine in clinical services. The courses include bioinformatics, advanced cell and molecular biology, epigenetics, molecular and cellular immunology, research methodology and ethics, statistics, and stem cell biology.

MSc and PhD in Genomics and Precision Medicine

Multidisciplinary programs in Genomics and Precision Medicine, with a focus on four main precision medicine pillars: clinical aspects, technology, omics, and bioethics.

MSc in Exercise Science

Joint degree by HBKU and the Arnold School of Public Health at the University of South Carolina (United States), applying genomics and transcriptomics technology to personalized fitness development and scientific advancement, within regenerative care and sports-related injuries. This degree addresses the complex relationships between exercise participation, physical activity, and human health.

MDA in Health Management

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This program offers students an understanding of the principles and technologies in health management analytics, including courses on AI and Machine Learning in Healthcare and Research Methods and Ethics in Health and Genomics.

BSc in Biological Sciences

Core courses include genetics and molecular biology, biochemistry and biophysics, cell and developmental biology, neuroscience, and computational biology. The course equips graduates with the technical expertise necessary for precision medicine.

Integrated Medical Program

A six-year MD program with core courses on genetics and translational science.

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sciences industry in research and healthcare systems has many benefits, including the possibility for patients of accessing leadingedge medications.

In 2015, QF launched a summer internship program for university students who wish to learn about the latest science in genomics and its relevance to health care. This two-week internship is aimed at cultivating students’ interest in the different aspects of precision medicine as a career. The interns are resident physicians and nurses at HMC, as well as biomedical graduates and pharmacists from Qatari universities.

Beyond healthcare and academia, students have the option to pursue a career in the life sciences industry. QF is collaborating with Roche on two internship programs.

One program gives interns the opportunity to work in Qatar on the specific side effects of chemotherapy in the treatment of breast cancer and other cancers. The second program gives interns an opportunity to work for six months at Roche research facilities in Basel (Switzerland) or San Francisco (United States); it is open to students from HBKU and started at the end of 2023. Involving the life

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EDUCATION OF SECONDARYSCHOOL STUDENTS QF has created several programs for secondary-school students considering genomics and precision medicine as a potential career, including an entry qualifying program for genomic and precision medicine science and research, and personalized internships for students in grade 12.

The Empower Generations Consortium, sponsored by QGP with Qatar University has attracted dozens of students from grades 11 and 12 as interns in the Genomics and Precision Medicine program, advising the students on study and career choices in precision medicine. The qualifying program is organized by the Biomedical Research Center and the College of Health Sciences at Qatar University in collaboration with the Ministry of Education and Higher Education.

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PROGRAMS FOR YOUNG CHILDREN QF, in partnership with the Ministry of Education and Higher Education, has established a range of programs to help young children learn about genomics and to encourage them to become future scientists.

One program, developed with children themselves, is Genome Heroes, an animated series containing stories, edutainment activities, and a game accessible to users worldwide in English and Arabic. The digital version is available for download via the Apple Store and Google Play; a print version is also available. QF also organizes workshops and school field trips to the ‘Journey to the Heart of Life’, an exhibition located within Msheireb Museums’ Bin Jelmood House, in Msheireb Downtown Doha.

3.1 SHAPING GLOBAL DISCUSSIONS Optimizing precision medicine interventions relies on collaboration and the sharing of expertise on best practices and intervention models to address some of the most challenging global health issues. The next chapter further describes QF’s convening role and our engagement with ethical and policy issues through the World Innovation Summit for Health (WISH).

PUBLIC EDUCATION To create public awareness, QF produced multiple resources, including edutainment videos, infographics and a brochure ,, ,, titled Genomics Made Simple, which is accessible on our website. At the DNA exhibition at Bin Jelmood House, in Msheireb Downtown Doha, we held Genome Café workshops in which parents could participate in hands-on experiments with their children.

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CHAPTER 4

Strategic Convening for Policy Advocacy and Global Collaboration

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CHAPTER 4 STRATEGIC CONVENING FOR POLICY ADVOCACY AND GLOBAL COLLABORATION This chapter highlights QF’s convening role in advancing both dialogue and action on precision health, primarily through the World Innovation Summit for Health (WISH). At this policy forum, we bring together global health experts and the latest available evidence and science to foster conversations on the most pressing healthcare issues in the world. This ongoing global collaboration is influencing healthcare policies worldwide, and Qatar is being positioned as an emerging center for innovation in healthcare and knowledge.

4.1 THE WORLD INNOVATION SUMMIT FOR HEALTH WISH serves as a global health policy and advocacy platform. Scientists, entrepreneurs, innovators in healthcare, policy makers, and health ministry representatives from over 100 countries have met at WISH summits since 2013 to identify solutions to major health issues.

Most notably, they explore ways in which innovation can enhance health delivery in Qatar and beyond.

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precision medicine in clinical practice globally.

The report, Precision Medicine: A Global Action Plan for Impact (Dzau et al. 2016), emphasizes the need for stakeholders to collaborate across sectors and countries to create an environment that is conducive to precision medicine in four areas: • • • •

Patient and public engagement Implementation Data ownership, privacy, and sharing Evidence generation

This report provides a blueprint for precision medicine and an action plan that can be used by policymakers worldwide to generate their own action plans.

The Future of Precision Medicine: Healthcare Innovation through Precision Medicine

POLICY DIALOGUE REPORTS As outputs from these summits, WISH has produced several policy dialogue reports that include actionable policy recommendations.

Three reports relevant to the implementation of precision medicine are highlighted below (for details, see the bibliography at the end of this report).

Genomics in the Gulf Region and Islamic Ethics In 2016, WISH produced a report on Genomics in the Gulf Region and Islamic Ethics to spark discussions on ethical and cultural issues in genomics, with particular consideration of the many operational challenges triggered by incidental genomic findings (Ghaly et al.

2016). Religion plays an integral part in the lives of people in this region, influencing their

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values, health beliefs, and practices. The Islamic bioethical perspective addressed in this report provides expert perspectives for policy consideration. The report also covers the status of research in the Gulf region and international discourse on incidental findings.

Precision Medicine: A Global Action Plan for Impact Precision medicine is growing in momentum.

Achievements in scientific research have enabled a better understanding of diseases, with scientists now able to alter treatments or develop new therapies and preventative techniques to combat diseases based on an individual’s genetic and personal characteristics. However, despite recent breakthroughs, significant challenges and barriers remain, with implications for the broad implementation and integration of CHAPTER 1

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In 2020, WISH published The Future of Precision Medicine: Healthcare Innovation through Precision Medicine, which explores factors affecting the continued development of precision medicine, sustained investment, associated risks, and innovations (Qoronfleh 2020). The paper provides key policy considerations for decision-making, i.e., for harmonizing precision medicine actions, and offers key recommendations for fast-tracking implementation. Recommendations include creating community awareness of precision medicine and developing education programs; engaging and empowering patients; developing appropriate infrastructure and information management systems; integrating precision medicine into a standard healthcare system; and ensuring access to care. All these actions have been adopted in Qatar.

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GLOBAL POLICY FORUMS ON GENOMICS Precision Medicine: A Global Action Plan for Impact (Dzau et al. 2016) emphasizes the importance of creating an international network of organizations to help fulfill a unified vision for the application and integration of precision medicine into medical frameworks worldwide. Beyond the WISH platform, QF is engaged in global policy forums on genomics organized by Public Policy Projects in the United Kingdom, and our collaboration with several leading international research institutions has helped position the new evidence on the Qatari and Arab genome within the global discourse. For example, HMC is a member of the organizing committee of the Personalized Medicine Coalition (based in the United States) and Genomic England, both excellent leveraging opportunities.

Locally, QF hosts thematic international scientific conferences to share evidence and foster dialogue, including Sidra Medicine’s flagship Precision Medicine and Functional Genomics Conference (held annually since 2014, the region’s longest running precision medicine conference), Qatar Genome Precision Medicine Symposia (held annually since 2015), the HMC Precision Medicine Conference (in 2021 and 2023), and HBKU’s Conference on Advances in Precision Medicine: Epigenetics and Precision Medicine (in 2021).

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LOOKING AHEAD In this report, we have seen the possibilities of precision medicine and how it can rapidly transform the way that healthcare is delivered to Qataris.

The future of precision medicine in Qatar is very promising. Over the last decade, QF’s foundational investments in biomedical research and precision medicine have yielded measurable results. Notably, new data produced on genetic variations specific to the Qatari population have resulted in a better understanding of the impact of variants on disease susceptibility, prevalence, progression, and responses to therapies. Qataris – especially Qatari children living with previously undiagnosed diseases – now have better chances of survival and more possibilities of leading healthier lives.

QF’s contribution to genomics and the rollout of precision medicine in healthcare settings has been catalytic. We have leveraged rapidly evolving technology, tools, and systems, and we have made significant investments in infrastructure, capacity building, and AI, with sustainability at the heart of everything we do.

In recent years, QF has focused on defining repeatable pathways for the wide-scale adoption of precision medicine. We are working in collaboration with MoPH, under their leadership, to implement key precision medicine interventions in public health care settings, particularly for chronic diseases, cardiometabolic diseases, and familial cancers. Precision medicine is now a reality in Qatar, and we are proud to have accompanied our nation on this journey.

Health has been a priority for QF since its inception in 1995. We are now at a critical stage in our journey to merge technology with social and human care. Precision health is an opportunity for us to lead not only in scientific discovery, but also in the delivery of personalized services. QF has long been a pioneer in health research, education, and community engagement.

Precision health is the natural next step for us to empower and enable healthy and vibrant communities.

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Chemaitelly, H., et al. (2021). Efficacy of Natural Immunity against SARS-CoV-2 Reinfection with the Beta Variant. New England Journal of Medicine, 385(27), 2585–2586. https://doi.org/10.1056/ nejmc2110300.

Diboun, I., et al. (2022). The Prevalence and Genetic Spectrum of Familial Hypercholesterolemia in Qatar Based on Whole Genome Sequencing of 14,000 Subjects. Frontiers in Genetics, 13, 927504. https:// doi.org/10.3389/fgene.2022.927504.

Dzau, V., et al. (2016). Precision Medicine: A Global Action Plan for Impact. WISH Forum Report. https:// wish.org.qa/reports/precision-medicine-a-globalaction-plan-for-impact/.

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CONCLUSION

Ahmed, L. H. M., Butler, A. E., Dargham, S. R., Latif, A., Robay, A., Chidiac, O. M., Jayyousi, A., Al Suwaidi, J., Crystal, R. G., Atkin, S. L., & Abi Khalil, C. (2020).

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Spatial mapping of cancer tissues by OMICS technologies. Biochimica et Biophysica Acta Reviews on Cancer, 1877(1) Ahmed W.S., Philip A.M., Biswas K.H.(2022).

Corrigendum: Decreased interfacial dynamics caused by the N501Y mutation in the SARS-CoV-2 S1 spike:ACE2 complex(Front. Mol. Biosci., (2022), 9, (846996), 10.3389/fmolb.2022.846996).Frontiers in Molecular Biosciences,9.

Aigha, I. I., & Abdelalim, E. M. (2023). P53 Inhibition in Pancreatic Progenitors Enhances the Differentiation of Human Pluripotent Stem Cells into Pancreatic β-Cells. Stem Cell Reviews and Reports. https://doi.org/10.1007/s12015-023-10509-1 Aigha, I. I., Memon, B., Elsayed, A. K., & Abdelalim, E. M. (2018). Differentiation of human pluripotent stem cells into two distinct NKX6.1 populations of pancreatic progenitors. Stem Cell Research & Therapy, 9(1), 83. https://doi.org/10.1186/s13287018-0834-0 Akbar S., Raza A., Mohsin R., Kanbour A., Qadri S., Parray A., Zar Gul A.R., Philip A., Vijayakumar S., Merhi M., Hydrose S., Inchakalody V.P., Al-Abdulla R., Abualainin W., Sirriya S.A., Al-Bozom I., Uddin S., Khan O.M., Mohamed Ibrahim M.I., Al Homsi U., Dermime S.(2023). Circulating exosomal immunooncological checkpoints and cytokines are potential biomarkers to monitor tumor response to antiPD-1/PD-L1 therapy in non-small cell lung cancer patients.Frontiers in Immunology,13.

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Al-Khadairi, G., Naik, A., Thomas, R., Al-Sulaiti, B., Rizly, S., & Decock, J. (2019). PRAME promotes epithelial-to-mesenchymal transition in triple negative breast cancer. Journal of Translational Medicine, 17(1), 9. https://doi.org/10.1186/s12967018-1757-3

Al-Khelaifi F., Diboun I., Donati F., Botrè F., Alsayrafi M., Georgakopoulos C., Yousri N.A., Suhre K., Elrayess M.A. (2018). Metabolomics profiling of xenobiotics in elite athletes: Relevance to supplement consumption. Journal of the International Society of Sports Nutrition, 15(1)

Ali, M. H. M., Rakib, F., Al-Saad, K., Al-Saady, R., & Goormaghtigh, E. (2019). An Innovative Platform Merging Elemental Analysis and Ftir Imaging for Breast Tissue Analysis. Scientific Reports, 9(1), Article 1. https://doi.org/10.1038/s 41598-019-46056-4

Alkhateeb, A. M., Aburahma, S. K., Habbab, W., & Thompson, I. R. (2016). Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability. Metabolic Brain Disease, 31(4), 901–907. https://doi.org/10.1007/ s11011-016-9827-9

Al-Khelaifi F., Donati F., Botrè F., Latiff A., Abraham D., Hingorani A., Georgakopoulos C., Suhre K., Yousri N.A., Elrayess M.A. (2019). Metabolic profiling of elite athletes with different cardiovascular demand.

Scandinavian Journal of Medicine and Science in Sports, 29(7)

Ali, M. H. M., Toor, S. M., Rakib, F., Mall, R., Ullah, E., Mroue, K., Kolatkar, P. R., Al-Saad, K., & Elkord, E. (2019). Investigation of the Effect of PD-L1 Blockade on Triple Negative Breast Cancer Cells Using Fourier Transform Infrared Spectroscopy. Vaccines, 7(3), Article 3. https://doi.org/10.3390/vaccines7030109

Alkhateeb, A. M., Habbab, W., Aburahma, S. K., & Thompson, I. R. (2017). PTBP1: A candidate gene for intellectual disability. Meta Gene, 13, 57–62. https:// doi.org/10.1016/j.mgene.2017.05.002

Ali, M. Z., Farid, A., Ahmad, S., Muzammal, M., Mohaini, M. A., Alsalman, A. J., Al Hawaj, M. A., Alhashem, Y. N., Alsaleh, A. A., Almusalami, E. M., Maryam, M., & Khan, M. A. (2022). In Silico Analysis Identified Putative Pathogenic Missense nsSNPs in Human SLITRK1 Gene. Genes, 13(4), 672. https://doi. org/10.3390/genes13040672 Al Thani, A., Fthenou, E., Paparrodopoulos, S., Al Marri, A., Shi, Z., Qafoud, F., & Afifi, N. (2019). Qatar biobank cohort study: Study design and first results. American Journal of Epidemiology, 188(8), 1420–1433. https://doi. org/10.1093/aje/kwz08 Ali R., Aouida M., Sulaiman A.A., Madhusudan S., Ramotar D.(2022). Can Cisplatin Therapy Be Improved? Pathways That Can Be Targeted.

International Journal of Molecular Sciences,23(13) Ali Z, Elewa H. The Effect of CYP2C19 and Nongenetic Factors on Clopidogrel Responsiveness in the MENA Region: A Systematic Review. Clin Appl Thromb Hemost.

2019 Jan-Dec;25:1076029619875520. doi: 10.1177/1076029619875520. PMID: 31512486; PMCID: PMC6829969.

Alkailani M.I., Aittaleb M., Tissir F.(2022). WNT signaling at the intersection between neurogenesis and brain tumorigenesis.Frontiers in Molecular Neuroscience,15.

Alkailani M.I., Gibbings D.(2023). The Regulation and Immune Signature of Retrotransposons in Cancer.

Cancers,15(17) CHAPTER 1

CHAPTER 2

Al-Khawaga, S., AlRayahi, J., Khan, F., Saraswathi, S., Hasnah, R., Haris, B., Mohammed, I., Abdelalim, E. M., & Hussain, K. (2019). A SLC16A1 Mutation in an Infant With Ketoacidosis and Neuroimaging Assessment: Expanding the Clinical Spectrum of MCT1 Deficiency. Frontiers in Pediatrics, 7. https:// doi.org/10.3389/fped.2019.00299 Al-Khawaga, S., Memon, B., Butler, A. E., Taheri, S., Abou-Samra, A. B., & Abdelalim, E. M. (2018).

Pathways governing development of stem cell-derived pancreatic β cells: Lessons from embryogenesis. Biological Reviews, 93(1), 364–389. https://doi.org/10.1111/brv.12349 Al-Khawaga, S., Mohammed, I., Saraswathi, S., Haris, B., Hasnah, R., Saeed, A., Almabrazi, H., Syed, N., Jithesh, P., El Awwa, A., Khalifa, A., AlKhalaf, F., Petrovski, G., Abdelalim, E. M., & Hussain, K. (2019). The clinical and genetic characteristics of permanent neonatal diabetes (PNDM) in the state of Qatar. Molecular Genetics & Genomic Medicine, 7(10), e00753. https://doi.org/10.1002/mgg3.753 Al-Khelaifi F., Diboun I., Donati F., Botrè F., Abraham D., Hingorani A., Albagha O., Georgakopoulos C., Suhre K., Yousri N.A., Elrayess M.A. (2019). Metabolic GWAS of elite athletes reveals novel geneticallyinfluenced metabolites associated with athletic performance. Scientific Reports, 9(1) Al-Khelaifi F., Diboun I., Donati F., Botrè F., Alsayrafi M., Georgakopoulos C., Suhre K., Yousri N.A., Elrayess M.A. (2018). A pilot study comparing the metabolic profiles of elite-level athletes from different sporting disciplines. Sports Medicine Open, 4(1) CHAPTER 3

CHAPTER 4

CONCLUSION

Al-Khelaifi F., Yousri N.A., Diboun I., Semenova E.A., Kostryukova E.S., Kulemin N.A., Borisov O.V., Andryushchenko L.B., Larin A.K., Generozov E.V., Miyamoto-Mikami E., Murakami H., Zempo H., Miyachi M., Takaragawa M., Kumagai H., Naito H., Fuku N., Abraham D., Hingorani A., Donati F., Botrè F., Georgakopoulos C., Suhre K., Ahmetov I.I., Albagha O., Elrayess M.A. (2020). Genome-Wide Association Study Reveals a Novel Association Between MYBPC3 Gene Polymorphism, Endurance Athlete Status, Aerobic Capacity and Steroid Metabolism. Frontiers in Genetics, 11 Alkowari, M., Espino-Guarch, M., Daas, S., Abdelrahman, D., Hasan, W., Krishnamoorthy, N., Sathappan, A., Sheehan, P., Panhuys, N., The Qatar Genome Program Research Consortium, & Estivill, X. (2022). Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients. International Journal of Molecular Sciences, 23(6), 3369. https://doi.org/10.3390/ ijms23063369 Al-Mansoori L., Al-Jaber H., Madani A.Y., Mazloum N.A., Agouni A., Ramanjaneya M., Abou-Samra A.-B., Elrayess M.A. (2020). Suppression of GATA-3 increases adipogenesis, reduces inflammation and improves insulin sensitivity in 3T3L-1 preadipocytes.

Cellular Signalling, 75 Al-Maslamani N.A., Oldershaw R., Tew S., Curran J., D’Hooghe P., Yamamoto K., Horn H.F.(2022).

Chondrocyte De-Differentiation: Biophysical Cues to Nuclear Alterations.Cells,11(24) Almomani R., Marchi M., Sopacua M., Lindsey P., Salvi E., de Koning B., Santoro S., Magri S., Smeets H.J.M., Boneschi F.M., Malik R.R., Ziegler D., Hoeijmakers J.G.J., Bönhof G., Dib-Hajj S., Waxman S.G., Merkies I.S.J., Lauria G., Faber C.G., Gerrits M.M., on behalf on the PROPANE Study Group (2020). Evaluation of molecular inversion probe versus TruSeq® custom methods for targeted nextgeneration sequencing. PLoS ONE, 15(45178) BIBLIOGRAPHY

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Stem cell library screen identified ruxolitinib as regulator of osteoblastic differentiation of human skeletal stem cells. Stem Cell Research & Therapy, 9(1), 319. https://doi.org/10.1186/s13287-018-1068-x AlMuraikhi, N., Ali, D., Vishnubalaji, R., Manikandan, M., Atteya, M., Siyal, A., Alfayez, M., Aldahmash, A., Kassem, M., & Alajez, N. M. (2019). Notch Signaling Inhibition by LY411575 Attenuates Osteoblast Differentiation and Decreased Ectopic Bone Formation Capacity of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells International, 2019, 3041262. https://doi.org/10.1155/2019/3041262 AlMuraikhi, N., Almasoud, N., Binhamdan, S., Younis, G., Ali, D., Manikandan, M., Vishnubalaji, R., Atteya, M., Siyal, A., Alfayez, M., Aldahmash, A., Kassem, M., & Alajez, N. M. (2019). Hedgehog Signaling Inhibition by Smoothened Antagonist BMS-833923 Reduces Osteoblast Differentiation and Ectopic Bone Formation of Human Skeletal (Mesenchymal) Stem Cells. Stem Cells International, 2019, 3435901. https://doi.org/10.1155/2019/3435901

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Prognostic tools and candidate drugs based on plasma proteomics of patients with severe COVID-19 complications. Nature Communications, 13(1), Article 1. https://doi.org/10.1038/s 41467-022-28639-4 Alonso N., Albagha O.M.E., Azfer A., Larraz-Prieto B., Berg K., Riches P.L., Ostanek B., Kocjan T., Marc J., Langdahl B.L., Ralston S.H.(2023). Genomewide association study identifies genetic variants which predict the response of bone mineral density to teriparatide therapy.Annals of the Rheumatic Diseases,82(7) Al-Qaissi A., Papageorgiou M., Deshmukh H., Madden L.A., Rigby A., Kilpatrick E.S., Atkin S.L., Sathyapalan T. (2019). Effects of acute insulin-induced hypoglycaemia on endothelial microparticles in adults with and without type 2 diabetes. Diabetes, Obesity and Metabolism, 21(3) Alrashoudi, R. H., Crane, I. J., Wilson, H. M., AlAlwan, M., & Alajez, N. M. (2018). Gene expression data analysis identifies multiple deregulated pathways in patients with asthma. Bioscience Reports, 38(6), BSR20180548. https://doi. org/10.1042/BSR20180548 Alsaloum M., Estacion M., Almomani R., Gerrits M.M., Bönhof G.J., Ziegler D., Malik R., Ferdousi M., Lauria G., Merkies I.S.J., Faber C.G., Dib-Hajj S., Waxman S.G., on behalf of the Propane Study Group (2019). A gain-of-function sodium channel 2-subunit mutation in painful diabetic neuropathy. Molecular Pain, 15 Alsamman AM, Almabrazi H, Zayed H. WholeGenome Sequencing of 100 Genomes Identifies a Distinctive Genetic Susceptibility Profile of Qatari Patients with Hypertension. J Pers Med. 2022 Apr 29;12(5):722. doi: 10.3390/jpm12050722. PMID: 35629146; PMCID: PMC9144388.

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CHAPTER 1

CHAPTER 2

Al-Sarraj, Y., Al-Dous, E., Taha, R. Z., Ahram, D., Alshaban, F., Tolfat, M., El-Shanti, H., & Albagha, O. M. E. (2021). Family-Based Genome-Wide Association Study of Autism Spectrum Disorder in Middle Eastern Families. Genes, 12(5), Article 5. https://doi.org/10.3390/genes12050761 Alshaban, F. A., Aldosari, M., Ghazal, I., AlShammari, H., ElHag, S., Thompson, I. R., Bruder, J., Shaath, H., Al-Faraj, F., Tolefat, M., Nasir, A., & Fombonne, E. (2023). Consanguinity as a Risk Factor for Autism. Journal of Autism and Developmental Disorders. https://doi.org/10.1007/s10803-02306137-w Alshaban F, Aldosari M, Al-Shammari H, El-Hag S, Ghazal I, Tolefat M, Ali M, Kamal M, Abdel Aati N, Abeidah M, Saad AH, Dekair L, Al Khasawneh M, Ramsay K, Fombonne E. Prevalence and correlates of autism spectrum disorder in Qatar: a national study. J Child Psychol Psychiatry. 2019 Dec;60(12):1254-1268. doi: 10.1111/jcpp.13066. Epub 2019 May 8. PMID: 31069792; PMCID: PMC6899566.

Alshaban, F., Aldosari, M., El Sayed, Z., Tolefat, M., El Hag, S., Al Shammari, H., Ghazal, I., & Fombonne, E. (2017). Autism spectrum disorder in Qatar: Profiles and correlates of a large clinical sample. Autism & Developmental Language Impairments, 2, 2396941517699215. https://doi. org/10.1177/2396941517699215

Al-Sharshani D., Velayutham D., Samara M., Gazal R., Al Haj Zen A., Ismail M.A., Ahmed M., Nasrallah G., Younes S., Rizk N., Hammuda S., Qoronfleh M.W., Farrell T., Zayed H., Abdulrouf P.V., AlDweik M., Silang J.P.B., Rahhal A., Al-Jurf R., Mahfouz A., Salam A., Al Rifai H., Al-Dewik N.I.(2023).

Association of single nucleotide polymorphisms with dyslipidemia and risk of metabolic disorders in the State of Qatar.Molecular Genetics and Genomic Medicine,11(8) Al-Sheikhly D., Östlundh L., Arayssi T. (2020).

Remediation of learners struggling with communication skills: A systematic review. BMC Medical Education, 20(1)

CHAPTER 4

Al-Sulaiti H., Diboun I., Agha M.V., Mohamed F.F.S., Atkin S., Dömling A.S., Elrayess M.A., Mazloum N.A. (2019). Metabolic signature of obesity-associated insulin resistance and type 2 diabetes. Journal of Translational Medicine, 17(1) Althani A. Qatar biobank and Qatar genome programs road map. J Tissue Sci Eng. 2015; 6: 157 Al-Thani HF, Shurbaji S, Yalcin HC. Zebrafish as a Model for Anticancer Nanomedicine Studies.

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Al-Thani N.M., Schaefer-Ramadan S., Aleksic J., Mohamoud Y.A., Malek J.A. (2022). Identifying novel interactions of the colon-cancer related APC protein with Wnt-pathway nuclear transcription factors.

Cancer Cell International, 22(1)

Al-Shammari, A. R., Bhardwaj, S. K., Musaelyan, K., Srivastava, L. K., & Szele, F. G. (2018).

Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone. Npj Schizophrenia, 4(1), Article 1. https://doi.org/10.1038/s41537-0180057-5

CHAPTER 3

Al Sulaiman, R., Othman, A., El Akouri, K., Fareed, S., AlMulla, H., Sukik, A., Al Mureikhi, M., Shahbeck, N., Ali, R., Al Mesaifri, F., Musa, S., Al Mulla, M., Ibrahim, K., Mohamed, K., Al Nesef, M. A., Ehlayel, M., & Ben Omran, T. (2020). A founder RAB27A variant causes Griscelli syndrome type 2 with phenotypic heterogeneity in Qatari families.

American Journal of Medical Genetics Part A, 182(11), 2570–2580. https://doi.org/10.1002/ ajmg.a.61829

CONCLUSION

Altmaier E., Emeny R.T., Krumsiek J., Lacruz M.E., Lukaschek K., Häfner S., Kastenmüller G., Römisch-Margl W., Prehn C., Mohney R.P., Evans A.M., Milburn M.V., Illig T., Adamski J., Theis F., Suhre K., Ladwig K.-H. (2013). Metabolomic profiles in individuals with negative affectivity and social inhibition: A population-based study of Type D personality. Psychoneuroendocrinology, 38(8) Altmaier E., Fobo G., Heier M., Thorand B., Meisinger C., Römisch-Margl W., Waldenberger M., Gieger C., Illig T., Adamski J., Suhre K., Kastenmüller G. (2014). Metabolomics approach reveals effects of antihypertensives and lipidlowering drugs on the human metabolism.

European Journal of Epidemiology, 29(5) Altmaier E., Menni C., Heier M., Meisinger C., Thorand B., Quell J., Kobl M., Römisch-Margl W., Valdes A.M., Mangino M., Waldenberger M., Strauch K., Illig T., Adamski J., Spector T., Gieger C., Suhre K., Kastenmüller G. (2016). The pharmacogenetic footprint of ACE inhibition: A population-based metabolomics study. PLoS ONE, 11(4)

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Atkin, A. S., Moin, A. S. M., Nandakumar, M., AlQaissi, A., Sathyapalan, T., Atkin, S. L., & Butler, A. E. (2021). Impact of severe hypoglycemia on the heat shock and related protein response. Scientific Reports, 11(1), 17057. https://doi.org/10.1038/ s41598-021-96642-8 Atkin, S. L., Butler, A. E., Hunt, S. C., & Kilpatrick, E. S. (2021). The retinopathy-derived HbA1c threshold of 6.5% for type 2 diabetes also captures the risk of diabetic nephropathy in NHANES. Diabetes, Obesity & Metabolism, 23(9), 2109–2115. https://doi. org/10.1111/dom.14449 Atkin S.L., Katsiki N., Banach M., Mikhailidis D.P., Pirro M., Sahebkar A. (2017). Effect of dipeptidyl peptidase-4 inhibitors on circulating tumor necrosis factor-α concentrations: A systematic review and meta-analysis of controlled trials. Journal of Diabetes and its Complications, 31(9) Atkin S.L., Ramachandran V., Yousri N.A., Benurwar M., Simper S.C., McKinlay R., Adams T.D., NajafiShoushtari S.H., Hunt S.C. (2019). Changes in blood microRNA expression and early metabolic responsiveness 21 days following bariatric surgery.

Frontiers in Endocrinology, 10(JAN)

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Awad, S.F., Dargham, S.R., Toumi, A.A, et al. A diabetes risk score for Qatar utilizing a novel mathematical modeling approach to identify individuals at high risk for diabetes. Sci Rep 11, 1811 (2021). https://doi.org/10.1038/s41598-021-81385-3.

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Atkin, A. S., Moin, A. S. M., Al-Qaissi, A., Sathyapalan, T., Atkin, S. L., & Butler, A. E. (2021). Plasma heat shock protein response to euglycemia in type 2 diabetes. BMJ Open Diabetes Research and Care, 9(1), e002057. https://doi.org/10.1136/ bmjdrc-2020-002057

CHAPTER 3

Augustine, T., Al-Aghbar, M. A., Al-Kowari, M., Espino-Guarch, M., & van Panhuys, N. (2022).

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CONCLUSION

Awad, S. F., Toumi, A. A., Al-Mutawaa, K. A., Alyafei, S. A, et al. Associations of vaccination and of prior infection with positive PCR test results for SARSCoV-2 in airline passengers arriving in Qatar.

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CONCLUSION

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Yet I., Menni C., Shin S.-Y., Mangino M., Soranzo N.,

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