intrODuCtiOn

Our understanding of the genetic basis of many diseaseshas grown exponentially over the last decade. this is dueto a shift in the emphasis of research to include clinicalscopes, as well as the advancement of technologies thatpermit higher-resolution investigation of the human ge-nome. “precision medicine” is an approach to both re-search and clinical medicine that “profiles” individualpatients based on multiple factors. it considers the biolog-ical characteristics and environmental exposures uniqueto each patient. Clinically, it encompasses the use ofmarkers to discriminate between disease categories andto monitor drug efficacy/toxicity, targeted therapies anddose-adjustment methods [1].

in 2015, Barack Obama launched a uSA-basedcohort program that aims to include over one millionAmericans, entitled the “precision Medicine initiative”(pMi) [2]. through this national data sharing initiative,it is thought that discoveries in biomarkers, disease clas-sifications and risk factors might be expedited. A similarcohort program in lebanon and the greater Middle eastand north Africa (MenA) region might prove to be anecessity, firstly to investigate endemic diseases notfound in other parts of the world (which would needsample sizes of thousands to analyze with statistical sig-nificance), to test the validity of international disease find-ings in this unique population.

Although the Arab population is diverse in many ways,there are several social and cultural factors that exert aunique influence over the genetic profile of the people inthe Middle east [3]. for example, consanguinity, pregnan-cy at an advanced parental age, high birth rates, and thelack of public health infrastructures that incorporate andemphasize the genetic basis of medicine are features com-

Lebanese Medical Journal 2018 • Volume 66 (1) 35

MISE AU POINT / IN-DEPTH REVIEWPRECiSion GEnETiC AnD GEnoMiC RESEARCH in LEBAnon HoW CAn WE MovE FoRWARD?http://www.lebanesemedicaljournal.org/articles/66-1/review1.pdf

Michael DAGher1*, nadeem BilAni1*, nathalie K. zGheiB2**

Dagher M, Bilani n, zgheib nK. precision genetic andgenomic research in lebanon: how can we move forward?J Med liban 2018 ; 66 (1) : 35-40.

Dagher M, Bilani n, zgheib nK. recherche de précision engénétique et génomique au liban : état des lieux et perspec-tives d’avenir. J Med liban 2018 ; 66 (1) : 35-40.

ABSTRACT • Purpose : Precision or personalized medi-cine continue to gain prominence in clinical practice andresearch settings. This paper investigates the genetic andgenomic research in Lebanon to comment on its strengthsand provide suggestions for future growth. Methods : Weperformed a literature search for any genetic or genomicpublications produced by Lebanese institutions between2010 and 2015. We evaluated the quality and number ofresearch papers, noting trends in study design, technolo-gy used, sample sizes and collaboration status. Results :One hundred and sixty-one articles were surveyed, butonly ninety-two were found to be pertinent and included inthe study. The majority of research used cross-sectionalor case-control study designs. Appraisal of these articlesshowed a growing trend in the use of high-throughputtechnologies and a capacity for large sample sizes inde-pendent of the collaboration status. Conclusion : Thisstudy suggests that Lebanon is making fine steps towardsimplementing precision genetic and genomic research.This might be facilitated through further funding, training,and collaboration.

Keywords : precision medicine; personalized medicine;Lebanon; genetics; genomics

RÉSUMÉ • Objectif: La médecine de précision et la médecinepersonnalisée ne cessent de gagner de l’importance autant enclinique que dans la recherche. Cet article traite de la recherchegénétique et génomique au Liban et de ses avantages, ainsi quedes avancées futures proposées dans ce domaine. Méthodes :Nous avons réalisé une recherche méthodique des études géné-tiques et génomiques publiées entre 2010 et 2015 par les institu-tions libanaises. Nous avons évalué le nombre et la qualité deces recherches, prenant en considération le type d’étude, la tech-nologie utilisée, la taille des échantillons et la collaboration entreles chercheurs. Résultats: Cent soixante et un articles ont étéexaminés dont 92 cadraient avec notre étude. Dans la majoritédes recherches, des modèles d’études transversales ou de cas-témoins ont été adoptés. Par ailleurs, nous avons noté une ten-dance croissante à utiliser des technologies à haut débit ainsiqu’une capacité à obtenir des échantillons de grande taille, indé-pendamment du statut de collaboration entre les différents cher-cheurs. Conclusion: Cette étude suggère que le Liban pro-gresse dans la mise en place de la recherche génétique et géno-mique. Cependant, de meilleurs financements, des stages deformation et des collaborations internationales pourraient faciliterd’autant plus le progrès dans ce domaine.

Mots-clés : médecine de précision; médecine personnali-sée; Liban; génétique; génomique

1 American university of Beirut faculty of Medicine (AuBfM), lebanon.

2 Department of pharmacology and toxicology, AuBfM.* these authors had equal contribution and are hence considered

co-first authors.**Corresponding author : Nathalie K. Zgheib, MD.

e-mail: nk16@aub.edu.lb

mon to many MenA countries [4]. As such, it comes asno surprise to find that countries in the region have elevat-ed rates of congenital disorders that account for a substan-tial proportion of infant deaths [5,6]. with a consanguini-ty rate between 12.5 to 42% [7] and at least 600 childrenborn with congenital heart defects every year [8], leba-non is no exception to this pattern.

the uniqueness of this target population has been rec-ognized, and the initial steps towards addressing its spe-cific needs have been taken. in 2003, the Center for ArabGenomic Studies (CAGS) was founded with the aim toincrease research, clinical genetic implementation andpublic awareness surrounding the genetics of the Arabworld [9]. Shortly after its conception, the CAGS estab-lished the Catalogue of transmission Genetics in Arabs(CtGA), a database documenting hundreds of genes andtheir associated disease traits from several Arab coun-tries [3]. As initiatives such as the CtGA provide MenAcountries with unprecedented access to information thatis specific to the Arab population, it is important thatacademic institutions in the region develop their re-search design and methods in order to make full use ofthe growing amount of data available to them. this is thekey to successful growth and the implementation of pre-cision medicine in the region.

As the Middle east slowly begins to embrace preci-sion medicine, an important question arises: are coun-tries, such as lebanon, currently equipped and ready tonavigate this shift? this paper is an evaluation of leb-anese genetic and genomic papers published in the lastsix years (2010 to 2015). it aims to explore and betterunderstand the quality and quantity of lebanese re-search. this is with the ambition of providing a clearerpicture of how that research can expand in the future andaccommodate the implementation of advancing preci-sion medicine practices.

MethODS

Literature searchthe literature search was carried out using MeDlineand retrieved genetics and genetics-related papers pub-lished by lebanese institutions. the Medical Subjectheadings (MeSh) terms that were used to construct thesearch were Pharmacogenetics, Genetics, Genomics, andGenetic Predisposition to Disease. to ensure that all ofthe retrieved publications originated from lebanon, twodifferent search techniques were employed separatelyand the results from each combined.

in the first search, only articles containing the wordsLebanon or Lebanese in their title in conjunction with thepreviously mentioned search criterion were selected. Anautomatic filter was used to limit the search results to ar-ticles published between the years 2010 and 2015. thesecond search technique was identical to the first exceptthat the names of the major institutions conducting med-ical research replaced Lebanon or Lebanese in the title.these were: Abou Joude hospital, American university of

Beirut, Balamand university, Beirut Arab university,Blego-lebanese Center for infertility, Centre hospitalierdu nord, Chronic Care Center, Chtoura hospital, Daher elBashek Governmental hospital, farhat hospital, ham-moud Medical Center, hôpital Sacré-Cœur, hôtel-Dieu defrance, labib Medical Center, lebanese American uni-versity, lebanese Atomic energy Commission, lebaneseuniversity, Makassed hospital, Mediterranean universityof Beirut, Monla hospital, Mount lebanon hospital,national tuberculosis Center, notre Dame des Secours,rafic hariri hospital, rizk hospital, Saint George hos-pital, Saint-Joseph university and Secours populaire liba-nais. in addition, the institutions’ names were searched forin the article abstracts.

the results of both searches were combined and thenreviewed article by article. papers at least coauthored bylebanese research institutions relating genetics/ genomicsto human disease entities in the lebanese population wereincluded in the analysis. Articles were excluded if theywere literature reviews, basic science studies (includingstudies that used animal models), or if they explored thegenome of micro-organisms. Duplicate studies were alsoexcluded to ensure that each study was only representedonce.

Evaluation metricsBasic information, including primary institutional affil-iation, year of publication, sample size, study design,and both inter- and intranational collaborators, were re-ported for each article. in addition, type of research(genetic, pharmacogenetic, genomic, or pharmacoge-nomic), whether or not the study used high-throughputtechnology (microarrays or next generation sequencing[nGS]), and disease/attribute studied were also docu-mented.

the content of the articles was assessed and classifiedusing a “translational Continuum” for genetic medicine.this classification divides research into one of four tiers(t1-t4) [10]. t1 research relates to discoveries that mightgenerate a “candidate health application”. t2 researchinvestigates how this might culminate in new “evidence-based practice guidelines”. t3 describes research thatexplores how guidelines might be implemented intohealth practice. finally, t4 considers how this might im-pact the population as a whole.

Articles that focused on interventions were also catego-rized according to the “health impact pyramid” [11]. thispublic health framework consists of a 5-stage pyramidoutlining the scope and reach of an intervention. from topto bottom, these are: “Counseling and education”, “Clini-cal interventions”, “long-lasting protective interven-tions”, “Changing the context to make individuals’ defaultdecisions healthy”, and “Socioeconomic factors”. inter-ventions classified into the basal levels of the pyramid canbenefit the largest number of people. the public healthpyramid only classifies interventional studies so for pa-pers dealing with susceptibility to disease, no furtheraction was taken.

36 Lebanese Medical Journal 2018 • Volume 66 (1) M. DAGHER et al – Precision genetic & genomic research in Lebanon

reSultS

Literature searchthe literature search yielded a total of 161 genetic/genomic articles published between 2010 and 2015,addressing a multitude of subjects. After manual exclu-sion of duplicates and papers outside the scope of thisstudy, 92 remained [table i]. this equates to an averageof 15 articles a year. A total of 29 institutions, includinguniversities and hospitals, have been involved in thisresearch. the most studied diseases were cancer (n = 11,12.0%), cardiovascular diseases (n = 11, 12.0%) and dia-betes (n = 8, 8.70%). the other studies (n = 62, 67.3%)explored a range of other topics. these included en-

demic diseases – such as sickle cell anemia, familialMediterranean fever (fMf) and thalassemia – and globalpathologies, such as asthma. infectious diseases, includ-ing influenza and tuberculosis, were also studied. therewere also a number of population surveys exploring drugmetabolism, ancestry, and the genetic typing of humanleukocyte antigen (hlA), and various microorganisms.

Type of researchSeventy-eight articles were genetic studies (84.8%), nine(9.8%) were genomic, and five (5.4%) were pharmaco-genetic. no pharmacogenomic papers were published.the majority of studies employed a cross-sectional design(n = 70, 76.1%). Case-control studies were the second most

M. DAGHER et al – Precision genetic & genomic research in Lebanon Lebanese Medical Journal 2018 • Volume 66 (1) 37

Table IsummaRy of aRticles’ descRiptions and metRics by yeaR

year2010 2011 2012 2013 2014 2015

Total

Total Number of articles 11 17 25 12 16 11 92

cancer 0 1 1 3 3 3 11

Disease cardiovascular 2 2 4 0 1 2 11

Studied diabetes 1 1 4 1 1 0 8

other 8 13 16 8 11 6 62

genetic 10 14 23 11 13 7 78

area of genomic 1 0 2 0 3 3 9

Research pharmacogenetic 0 3 0 1 0 1 5

pharmacogenomic 0 0 0 0 0 0 0

Studycross-sectional 11 13 21 7 10 8 70

Designcase-control 0 2 4 5 5 2 18

other 0 2 0 0 1 1 4

Type ofsusceptibility 10 14 21 11 15 10 81

Researchintervention 0 1 1 0 0 0 2

epidemiology 1 2 3 1 1 1 9

Research t1 11 17 23 12 16 11 90

Tier t2 0 0 2 0 0 0 2

Division of lebanon primary 11 (100%) 15 (88%) 17 (68%) 11 (92%) 14 (88%) 8 (73%) 76 (83%)

authorship lebanon secondary 0 (0%) 2 (12%) 8 (32%) 1 (8%) 2 (13%) 3 (27%) 16 (17%)

lebanon 1o 5 11 11 3 7 4 41

Collaborationinternational lebanon 2o 0 2 8 1 2 3 16

Statustotal 5 13 19 4 9 7 57

national 2 1 1 1 4 2 11

none 4 3 5 7 3 2 24

Total Sample Size (median sample size) 45139 (230) 7216 (140) 87063 (233) 13695 (199) 16754 (148) 1499 (144) 171366 (164)

High-Throughput 0 (0%) 1 (6%) 2 (8%) 2 (17%) 4 (25%) 3 (27%) 12 (13%)

common (n =18, 19.6%) followed by case reports (n = 3,3.3%) and retrospective cohort studies (n = 1, 1.1%). eighty-one (88.0%) were susceptibility studies, nine (9.8%) wereepidemiological studies and only two (2.2%) were inter-vention studies. Both intervention studies were classifiedas “clinical interventions”, the highest level of the publichealth pyramid previously discussed.

According to the translational Continuum, most of thestudies fell into tier 1 (n = 90, 97.8%), and only two arti-cles (2.2%) could be classified as tier 2. there were notier 3 or tier 4 articles.

Authorship and collaboration statusSeventy-six (82.6%) studies had a lebanese primaryauthor, while 16 (17.4%) had a non-lebanese primaryauthor. the majority of articles published between 2010and 2015 were collaborative (n = 68; 73.9%), and mostof these collaborations were with international institu-tions (n = 57, 62.0%) versus other lebanese institutions(n = 11, 12.0%). Of the papers with international collab-orations, 41 (72.0%) had primary authors affiliated witha lebanese academic institution, as opposed to 16(28.1%) where the primary author was affiliated with anon-lebanese academic institution.

Sample size the sample sizes ranged from 1 to 65402, with a mediansample size of 164. the median sample size of an articleper year was lowest in 2011 (n = 140) and highest in 2012(n = 233). the median sample size for papers that did nothave any international collaboration (n = 35) was 176 asopposed to 165 for those with a lebanese primary author(n = 41), and 104 for those with a lebanese secondaryauthor (n = 16).

Accordingly, there was not much variability in samplesize with respect to the collaboration status of the papersdespite the presence of some outliers (figure 1). Onlyone of these outliers, a 2012 article with a sample size of65402, had a lebanese primary author. All others werenon-collaborative and ranged between two extremes: acase report with a sample size of 1 (2011) and a cross-sectional study with 39745 participants (2010).

TechnologyBetween 2010 and 2015, there has been a progressiveincrease in the number of studies that employ high-throughput technologies, from 0% in 2010 to nearly 30%(n = 3) in 2015 (figure 2). interestingly, there was nosignificant difference in percentage of high-throughputstudies with regards to the collaboration status of thepapers (figure 3).

DiSCuSSiOn

this study only examined published articles. this maynot be fully indicative of how lebanese physiciansemploy precision medicine in their clinical practice, suchas with molecular diagnostic testing. however, the results

of this paper have shown that genetic/genomic research inlebanon has a number of strengths. for instance, leba-nese studies have been able to recruit large sample sizeswithout needing to be collaborative, with one non-collab-orative study collecting data on nearly 40,000 cases. never-theless, this strength might still be enhanced through col-laboration. Many international disease-based consortiaexist in other parts of the world. they enable the recruit-ment of large sample sizes as well as the sharing of exper-tise. A similar MenA-based cohort program might yieldthese same benefits. this is especially essential when re-searchers are investigating rare or endemic diseases notfound in other parts of the world.

38 Lebanese Medical Journal 2018 • Volume 66 (1) M. DAGHER et al – Precision genetic & genomic research in Lebanon

Figure 1. Total sample size of studies by their correspondinginternational collaboration status

a..International collaboration in which the corresponding author wasaffiliated with a Lebanese institution.

b..International collaboration in which the corresponding author wasnot affiliated with a Lebanese institution.

* The y-axis scale was log transformed to better visualize the broadrange of sample sizes.

Figure 2. Percentage of research that employed high-throughputtechnology by year

Non-Collaborative

100

80

60

40

20

0

Hig

h-T

ho

ug

hp

ut

(%)

International Collaboration Status

2010 2011 2012 2013 2014 2015

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27.2725.0016.67

8.005.88

100000

10000

1000

100

10

1

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am

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e (

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Lebanon SecondarybLebanon Primarya

what must also be commended is the year-by-yearincrease in the use of high-throughput technology in leb-anon. there is still capacity for improvement, as current-ly less than 50% of articles published every year use thistechnology. high-throughput techniques include micro-arrays and nGS. they allow researchers to collect andanalyze vast quantities of information without compro-mising quality. researchers can thus holistically investi-gate different omics systems and their inter-relatedness(seeing the “big picture”). nevertheless, it is important tonote that “high-throughput” should not be equated with“precision” research. this technology was simply used asa marker to comment on the ability and power of researchventures.

One weakness of lebanese research, however, is thelack of diversity in study design and an almost completefocus on research that falls in early tiers of the transla-tional continuum. More cohort studies and randomizedcontrol trials are needed to support causal relationships.the later tiers in the translational continuum define stud-ies that investigate how empirical data can be implement-ed into clinical and public health practice. these aretherefore also essential, and need more emphasis. never-theless, lebanon performs well compared to other Me-nA countries. One marker of how far precision genetic/genomic research has progressed is the extent to which itincludes not only susceptibility studies but also interven-tional ones. interventional studies are classified in the

higher tiers of the aforementioned “continuum of transla-tion”. One previous study examined MenA precisiongenetic/genomic research in breast cancer and diabetespublished between the years 2000-2015. lebanon wasamong the only seven countries in the region that pro-duced interventional research. unsurprisingly, the othersix countries had the highest research and developmentexpenditures when measured as a percentage of totalGDp [12,13]. Data for this measure was not found forlebanon.

COnCluSiOn

Medical institutions around the world are striving tointegrate precision medicine into their daily practice.high quality research is essential to ensure the success ofthese healthcare facilities in this endeavor. we haveshown that lebanon has already made an impressivestart on providing this vital research. every year, moreand more high-throughput technology is being used toefficiently generate larger-scale data about the lebanesepopulation. in addition, lebanese studies have managedto achieve substantial sample sizes without the need forheavy reliance on international collaboration.

this study provides a number of recommendations forpotential future growth. Most importantly, the breadth andreach of the research must be expanded. the overwhelm-ing majority of current research can be classified undertier 1 of the translational research continuum, but empha-sis could be placed on pushing the boundary to moreadvanced tiers. Secondly, as discussed earlier, nationalfunding seems to be correlated with more advanced re-search. the national Council for Scientific research is apublic institution that awards grants to projects in leb-anon. in 2016, 82 ventures were financed through desig-nated funds totaling 1438.6 million lBp for that year [14].this enterprise should be celebrated and supported fur-ther. in addition, continuous training of researchers isessential to ensure that they are confident in their use ofthe most up-to-date precision practices. this will allowlebanese research to remain on par with that of the vari-ous other countries making great strides in precisiongenetic/genomic research. finally, as discussed above,although significant sample sizes have been generatedwithout international collaboration, partnership with othercountries would allow us to better examine diseases en-demic to the Middle east.

referenCeS

1. Marquet p, longeray ph, Barlesi f et al. translationalresearch: precision medicine, personalized medicine, tar-geted therapies: marketing or science? therapie 2015; 70(1): 1-19.

2. hudson K, lifton r, patrick-lake B et al. the precisionMedicine initiative Cohort program – Building a re-search foundation for 21st Century Medicine. 2015,precision Medicine initiative (pMi).

3. tadmouri GO, Al Ali Mt, Ali SAh, Al Khaja n. CtGA:

M. DAGHER et al – Precision genetic & genomic research in Lebanon Lebanese Medical Journal 2018 • Volume 66 (1) 39

Figure 3. Percentage of research articles using high-throughputtechnology by corresponding international collaboration status

a..International collaboration in which the corresponding author wasaffiliated with a Lebanese institution.

b..International collaboration in which the corresponding author wasnot affiliated with a Lebanese institution.

100

80

60

40

20

0

Art

icle

s (

%)

International Collaboration Status

96

47

4

93 96

Noyes

Non-Collaborative Lebanon SecondarybLebanon Primarya

the database for genetic disorders in Arab populations.nucleic Acids res 2006; 34 (Database issue): D602-D606.

4. tadmouri G, Al Ali M, Al Khaja n. Genetic Disorders inthe Arab world: united Arab emirates. Centre for ArabGenomic Studies, Dubai, uAe, 2004.

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6. hamamy h, Alwan A. hereditary disorders in theeastern Mediterranean region. Bull world health Organ1994; 72 (1): 145-54.

7. tadmouri GO, nair p, Obeid t, Al Ali Mt, Al Khaja n,hamamy hA. Consanguinity and reproductive healthamong Arabs. reproductive health 2009; 6 (1): 17.

8. Children’s heart Center (supported by the Brave heartfund). [cited 2016 november]; Available from: http: //www.aubmc.org/patientcare/spe_cli_pro_ser/Pages/chc.aspx.

9. About CAGS. [cited 2016 november]. Available from:http://www.cags.org.ae/about-us.aspx.

10. Khoury MJ, Gwinn M, yoon pw, Dowling n, Moore CA,

Bradley l. the continuum of translation research ingenomic medicine: how can we accelerate the appropri-ate integration of human genome discoveries into health-care and disease prevention? Genetics in Medicine 2007;9 (10): 665-74.

11. Khoury MJ, iademarco Mf, riley wt. precision publichealth for the era of precision medicine. AmericanJournal of preventative Medicine 2016; 50 (3): 398-401.

12. Jahan S. human development report 2015: work forhuman development. unDp: new york, ny, uSA,2015.

13. Bilani n, Dagher M, zgheib nK. precision genetic andgenomic medicine in the Middle east and north Africaregion: Are we there yet? public health Genomics 2017;20: 149-57.

14. national Council for Scientific research, lebanon.funding of 82 research projects, 54 new DoctoralScholarships, and 84 renewed Doctoral Scholarships.newsletter of the national Council for Scientific research,lebanon 2016, issue 184.

40 Lebanese Medical Journal 2018 • Volume 66 (1) M. DAGHER et al – Precision genetic & genomic research in Lebanon