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SEXANDGENDER
BIASINTECHNOLOGY ANDARTIFICIAL INTELLIGENCE
WBPbookseries
AbouttheWomen’sBrainProject:TheWomen’sBrainProject(WBP)isaninternationalnonprofitorganizationstudyingsexandgenderdeterminantstobrainandmentalhealth.Foundedin2016,theWBPiscomposedofagroupofscientistshailingfrom variousdisciplines,includingmedicine,neuroscience,psychology,pharmacology,and communication,whoworktogetherwithcaregivers,patientsandtheirrelatives,policymakers,andotherstakeholders.TheWBPaimstoidentifyhowsexandgenderfactors impactdiseases,diagnostics,drugandnoveltechnologiesdevelopment,andtoachieve precisionmedicineforsustainableandinclusivehealthcare. http://www. womensbrainproject.com/.
AbouttheWomen’sBrainProjectBookSeries:Thepurposeoftheseriesisto providecomprehensivereferencesondifferenttopicsinbasic/clinicalresearchbeing conductedontheinfluenceofsexandgenderinbrainandmentalhealthandprecision medicineresearch.
EditorialAdvisoryBoard:
MariaTeresaFerretti,PhD,CofounderandChiefScientificOfficer,Women’sBrain Project,Switzerland;AnnemarieSchumacherDimech,PhD,CofounderandPresident, Women’sBrainProject,Switzerland;ProgramManagerCASPalliativeCare,University ofLucerne,Switzerland;AntonellaSantuccioneChadha,PhD,CEOprobonoand cofounderWomen’sBrainProject,Guntershausen,Switzerland;Vice-PresidentatEuresearch,Switzerland.
SexandGenderDifferencesinAlzheimer’sDisease editedbyMariaTeresaFerretti, AnnemarieSchumacherDimech,andAntonellaSantuccioneChadha,9780128193440.
SexandGenderBiasinTechnologyandArtificialIntelligence:BiomedicineandHealthcare Applications editedbyDavideCirillo,SilvinaCatuara-Solarz,andEmreGuney, 9780128213926.
SEXANDGENDER BIASINTECHNOLOGY ANDARTIFICIAL INTELLIGENCE
BiomedicineandHealthcare Applications
Editedby DAVIDECIRILLO,PHD
SILVINACATUARA-SOLARZ,PHD
EMREGUNEY,PHD
AcademicPressisanimprintofElsevier
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Copyright©2022ElsevierInc.Allrightsreserved.
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ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher (otherthanasmaybenotedherein).
Notices
Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroadenour understanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecomenecessary.
Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusing anyinformation,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethods theyshouldbemindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhomtheyhavea professionalresponsibility.
Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeany liabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceor otherwise,orfromanyuseoroperationofanymethods,products,instructions,orideascontainedinthe materialherein.
ISBN978-0-12-821392-6
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Dedication
WededicatethisbooktoMrsMaraHankMoret.Sheis anangelinvestor/philanthropistandHonoraryPresident oftheWomen’sBrainProject(WBP).Sheholdstwo BachelorofArtsdegreesinpoliticalscienceandsociology fromtheUniversityofSanDiego,California,UnitedStates. Inrecentyears,MaraHankMorethaschosentofocuson herroleasmotherofthreechildren,aged13,11,and8, intheirmostformativeyears.Herphilanthropicworkhas continuedonapersonalbasisandonbehalfofLobnek WealthManagement.Sheliveswithherhusbandand childreninGeneva,Switzerland.
Mara’scontributionandinvolvementforequityand inclusioninmedicineandhealthcarehasinspiredthe workoftheWBPinmultipleways.SincetheinceptionoftheWBP,Marahasalways stronglysupportedtheactivityofthegroupofscientistsworkingtofosterthescientific andethicaldiscussiononsexandgenderbiasinnoveltechnologies.Hervisioninthis fieldhasbeeninstrumentalforourresearchandadvocacyactivityandhasledustosome incredibleachievements,includingtheparticipationofthehumanoidrobot“Sophia”in theInternationalForumonWomen’sBrainandMentalHealthin2019.Togetherwe areexploringnewwaystoimprovethecurrenthealthcaremodelstowardprecision medicineandsustainability.
MariaTeresaFerretti
AnnemarieSchumacherDimech AntonellaSantuccioneChadha
0.Introduction:Therelevanceofsexandgenderinprecisionmedicineandthe roleoftechnologiesandartificialintelligence1
SilvinaCatuara-Solarz,DavideCirillo,andEmreGuney
1.Sexandgenderinbiomedicalresearchandmedicine1
2.TheroleoftechnologiesandAItounderstandsexandgenderdifferencesinhealth4
3.Organizationandscopeofthisbook6
1.Implicationsofsex-specificdifferencesonclinicalstudiesofhuman health
JanetPiñero,Frances-CatherineQuevenco,LauraI.Furlong,andEmreGuney
2.Geneticandphysiologicaldifferencesanddifferentialmanifestation ofdiseasesbetweensexes13
3.Preclinicalandclinicalstudydesign:Ahistoricalperspective16 4.Socioeconomicandsocioethicalconsiderations22 5.Discussionandconclusions25
2.Sexandgenderinequalityinprecisionmedicine:Socioeconomic determinantsofhealth35 NatalyBuslón,SandraRacionero-Plaza,andAtiaCortes
1.Introduction
2.Precisionmedicineandinequalities38 3.Futuredirections48
3.Biasandfairnessinmachinelearningandartificialintelligence57
DavideCirilloandMaríaJoseRementeria
1.Introduction 57
2.Acomplexlandscapeofintersectingbiases58
3.Taxonomiesofbias60
4.Fromideationtodeployment:ThelifecycleofAIdevelopment63
5.Biasmetrics 65
6.Conclusions
4.BigDatainhealthcarefromasexandgenderperspective77
LaiaSubiratsandGemmaPiella
1.Introduction 77
2.BigDatainhealthcareandwellbeing:Asexandgenderperspective79
3.Challengesandopportunities87
4.Conclusions 90 5.Briefsummary 90 Acknowledgments 91 References 91
5.Biasesindigitalhealthmeasures95
SimonaMellino,CzueeMorey,andColinRohner
1.Introduction 95
2.Historyanddevelopmentofdigitalmeasures99
3.Biasesandtheirconsequencesfordigitalmeasures102
4.Outlookandrecommendations108 Acknowledgments109
6.Sexandgenderbiasinnaturallanguageprocessing113
DavideCirillo,HilaGonen,EnricoSantus,AlfonsoValencia,MartaR.Costa-jussà, andMartaVillegas
1.Introduction 113
2.NLPtoday:Breakthroughsandnewchallenges114
3.NLPforbiomedicineandhealth118
4.Acaseinstudy:Chatbotsformentalhealth120
5.Sexandgenderbiasinthetrainingcorpora122
6.Debiasingmethods122
7.Discussion 125 Acknowledgments126
7.Sexdifferencesininvasiveandnoninvasiveneurotechnologies133
LauraDubreuil-Vall,TracyL.Laabs,HarrisA.Eyre,ErinSmith,andSilvinaCatuara-Solarz
1.Introduction 133
2.Sexdifferencesinnoninvasiveneurotechnologies135
3.Sexdifferencesininvasiveneurotechnologies146 4.Ethicalconsiderations152
5.Conclusions
8.Howgenderisintertwinedwithrobotsandaffectivetechnologies:Ashort
1.Introduction
2.Robots
3.Robotsforhealthcareandwellbeing165 4.Sexandgenderaspects166 5.Affectivetechnologies168 6.Discussion/conclusion171
SECTION3Towardprecisiontechnology
9.AunifiedframeworkformanagingsexandgenderbiasinAImodelsfor healthcare179
RobertoConfalonieri,FedericoLucchesi,GiovanniMaffei,andSilvinaCatuara-Solarz
1.Introduction
2.Aframeworktomanagesexandgenderbiasesinbiomedicalresearchand healthcare
3.Biasidentification183 4.Biasexplanation186
5.Distinctionbetweendesirableandundesirablebias192
6.Biasmitigation 194
7.Biasexploitation:Useofdesirablebiasforprecisionmedicine198
8.Summaryandconclusions201 Acknowledgments202
10.Privacyissuesinhealthcareandtheirmitigationthroughprivacypreserving technologies205
LadinaCaduff,GianlucaDiana,CorneliaKutterer,andSpyridonPapasotiriou
1.Introduction 205 2.ResponsibleuseofdataandAIinhealthcare208
3.EmbeddingprivacyinAI210
4.Epilogue 215
5.Conclusion 216 Acknowledgments216 References 217
11.Societalandethicalimpactoftechnologiesforhealthandbiomedicine219
AtiaCortes,NatalyBuslón,andLilianaArroyo
1.Introduction 220 2.AnethicalframeworkforAIinhealthcareandbiomedicine226
3.Conclusions 235 References 236
Conclusion:Towardsex-andgender-stratifiedprecisionmedicine239
EmreGuney,DavideCirillo,andSilvinaCatuara-Solarz
Endorsements
Precisionmedicinepromisesimprovedpreventiveandtherapeutichealthcareacrossthe lifespan.Toachievethispromise,researchersneedtounderstandsexandgender,how theseinteract,andhowthesefactorsintersectwithothersocialdeterminantsofhealth, suchasrace/ethnicity,socioeconomicstatus,accesstocare,etc.Thisforward-looking volumeprovidesmeta-analysesofsexandgenderinbigdata,artificialintelligence,digitalbiomarkers,assistivetechnologies,nanomedicine,chatbotsformentalhealth,and more.Theauthorspushthefieldforwardbycriticallyassessingcutting-edgeliterature topavethewayforAIthatcontributesethicallyandsustainablytopredictive,preventive, personalized,andparticipatorybiomedicalresearchandclinicalpractice.Theytacklehistoricalbiasineffortstocreatenewsystemsthatworkforeveryoneglobally.It’samust readforanyoneworkinginthisarea;thematerialspresentedhereshouldbeintegrated intomedicalschoolcurricula.
LondaSchiebinger,PhD
JohnL.HindsProfessorofHistoryofScience,StanfordUniversity FoundingDirector,GenderedInnovationsinScience,Health&Medicine,Engineering, andEnvironment
Healthsciencesandespeciallymedicinehavebeen,andstillare,anandrocentricfield.In thelastthirtyyears,numeroussexandgenderbiaseshavebeenidentifiedinthediagnosisandtreatmentofdiseasesandinpreventionstrategies.Moreovertheinvisibilityof womenandthelackofascienceofsexandgenderdifferences,includinggenetics,morbidity,pharmacokineticsanddifferentialmortality,havebeenlargelyconfirmed.Inthis scenario,aparadigmshiftisrequiredtorealizePersonalizedMedicine,whichisbasedon diagnosticandtherapeuticdecisionstakingintoaccountindividualdifferences,notonly thebiologicalonesbutalsolifeandworkconditions,environmentalexposures,andgenderstereotypesinhealthcarepractice,withnewessentialresources,suchasArtificial Intelligence,nanotechnology,andgenomics.ThebookthatIhavethehonortopreface constitutesadeepandcourageousreflectiononhowtoanalyzeandavoidsexandgenderbiaseswiththehelpofnewtechnologies,inresearchandmedicalassistance,andthe ethicalandlegalimplicationsoftheirapplications.Theriskstoavoidareanalyzed,butit alsoexpressesthehopethatthenewprecisionmedicine,withthehelpofArtificial Intelligence,willbuildascienceofsexandgenderdifferences,forabetterequalityof opportunitiesinthehealthofallhumanbeings.
CarmeValls-Llobet,MD
Promoterofmedicinewithagenderperspective
DirectoroftheWomen,HealthandQualityofLifeProgramattheCenterforHealth AnalysisandPrograms(CAPS)
Authorofthebook InvisibleWomenforMedicine,Ed.CapitanSwing
Timely,provocativeinsightsintowayswemustaddressthelongignoredcontributionsof sexandgenderdifferencesinscientificdiscoveryandtranslationintopersonalizedhealth care.Beforewecanpromotebetterhealthforallpeople,wemustintentionallyaskthe rightquestionstoavoidover-generalizationsthatdonotapplyatanindividuallevel.This extraordinarybookhelpsdojustthat.Itprovidesamuch-neededamountofexpert knowledgefromdiversedisciplinessothatwecanbetteraddressdifferencesaswell assimilaritiesinwomenandmen’sbrains.Convincingly,theserichchaptersprovide valuableinsightsintohowmachinelearningandartificialintelligencecannowbeharnessedtobetterinformprecisionmedicine.Suchinformationisessentialtocreatearadicallynewapproachtoimprovegenderequalitywithbetteroverallhealthandwellbeing forall.
SandraBondChapman,PhD FounderandChiefDirector,CenterforBrainHealth
DeeWylyDistinguishedUniversityProfessor
SchoolofBehavioralandBrainSciencesatTheUniversityofTexasatDallas
Thisissuchanimportantbookforeveryonefromstudentsacrossallsectorsthattouch healthcarethroughtopolicymakers,industry,cliniciansandhealthservices.Wecannot repeatthesexandgenderbiasandneglectinunderstandingsexandgenderdifferences weseeinhealthandmedicalresearchandhealthcareinthedevelopmentoftechnology andartificialintelligence.Thebiasandneglectcompromisesqualityandsafetyinhealth caretodayandinturnimpactsthesustainabilityofgloballystrainedhealthcaresystems. Systematicallyeliminatingsexandgenderbiasinhealthcareandhenceintechnology andAIinhealthandmedicineisacriticalsteptowardprecisionmedicine;wecan’t possiblyhaveintegrityinprecisionmedicinewithoutincorporatingthiscriticalvariable.
ZoeWainer,MD,PhD
HeadofPublicHealthandMedicalDirectorforBupaAustraliaandNewZealand ChairoftheBoardofDentalHealthServicesVictoria(DHSV)
Contributors
LilianaArroyo
DepartmentofSociety,PoliticsandSustainability(ESADE).Ramo ´ nLlullUniversity,Barcelona, Spain
NatalyBuslo ´ n
BarcelonaSupercomputingCenter(BSC);Bioinfo4Women(B4W);LifeSciences—SocialLink AnalyticsLifeSciencesGroup,Barcelona,Spain
LadinaCaduff
MicrosoftSwitzerland,Zurich,Switzerland
SilvinaCatuara-Solarz Women’sBrainProject,Guntershausen,Switzerland
DavideCirillo
LifeSciencesDepartment,BarcelonaSupercomputingCenter,Barcelona,Spain
RobertoConfalonieri
FreeUniversityofBozen-Bolzano,FacultyofComputerScience,Bozen-Bolzano,Italy
AtiaCortes
BarcelonaSupercomputingCenter(BSC);Bioinfo4Women(B4W);LifeSciences—SocialLink AnalyticsLifeSciencesGroup,Barcelona,Spain
MartaR.Costa-jussa ` ComputerScienceDepartment,PolytechnicUniversityofCatalonia,Barcelona,Spain
GianlucaDiana
MicrosoftBrussels,Brussels,Belgium
LauraDubreuil-Vall
MassachusettsGeneralHospital,HarvardMedicalSchool,Boston,MA,UnitedStates
HarrisA.Eyre
Neuroscience-InspiredPolicyInitiative,OrganisationforEconomicCo-Operationand Development(OECD),PRODEOInstituteandMeadowsMentalHealthPolicyInstitute,Paris, France;InstituteforMentalandPhysicalHealthandClinicalTranslation(IMPACT),Deakin University,Geelong,VIC,Australia
LauraI.Furlong
ResearchProgrammeonBiomedicalInformatics,HospitaldelMarResearchInstitute(IMIM) andPompeuFabraUniversity(UPF);MedbioinformaticsSolutionsS.L.,Barcelona,Spain
HilaGonen
PaulG.AllenSchoolofComputerScience&Engineering,UniversityofWashington,Seattle, WA,UnitedStates
EmreGuney
ResearchProgrammeonBiomedicalInformatics,HospitaldelMarResearchInstitute(IMIM) andPompeuFabraUniversity(UPF);DiscoveryandDataScience(DDS)Unit,STALICLA R&DSL,Barcelona,Spain
CorneliaKutterer
MicrosoftBrussels,Brussels,Belgium
TracyL.Laabs
WyssCenterforBioandNeuroengineering,Geneva;Women’sBrainProject,Guntershausen, Switzerland
FedericoLucchesi
KoaHealth(FormerTelefonicaInnovationAlpha)B.V.,ResearchandDevelopment,Barcelona, Spain
GiovanniMaffei
KoaHealth(FormerTelefonicaInnovationAlpha)B.V.,ResearchandDevelopment,Barcelona, Spain
NikolaosMavridis
MassachusettsInstituteofTechnology,Cambridge,MA,UnitedStates
SimonaMellino
Women’sBrainProject,Guntershausen,Switzerland
CzueeMorey
Women’sBrainProject,Guntershausen,Switzerland
SpyridonPapasotiriou
Women’sBrainProject,Guntershausen,Switzerland
GemmaPiella
DepartmentofInformationandCommunicationsTechnologies,PompeuFabraUniversity, Barcelona,Spain
JanetPin ˜ ero
ResearchProgrammeonBiomedicalInformatics,HospitaldelMarResearchInstitute(IMIM) andPompeuFabraUniversity(UPF);MedbioinformaticsSolutionsS.L.,Barcelona,Spain
Frances-CatherineQuevenco
Women’sBrainProject,Guntershausen;InstituteforRegenerativeMedicine(IREM), UniversityofZurich,Zurich;RocheDiagnosticsInternational,Rotkreuz,Switzerland
SandraRacionero-Plaza
UniversitatdeBarcelona(UB),Barcelona,Spain
Marı´aJoseRementeria
LifeSciencesDepartment,BarcelonaSupercomputingCenter,Barcelona,Spain
ColinRohner
Women’sBrainProject,Guntershausen,Switzerland
EnricoSantus
DecisionScience&AdvancedAnalyticsforMA,PV&RADivision,Bayer,Whippany, NJ,UnitedStates
ErinSmith
Neuroscience-InspiredPolicyInitiative,OrganisationforEconomicCo-Operationand Development(OECD),PRODEOInstituteandMeadowsMentalHealthPolicyInstitute,Paris, France;SchoolofMedicine,StanfordUniversity,PaloAlto,CA,UnitedStates
LaiaSubirats
Eurecat,TechnologyCentreofCatalonia;ADaSLab,OpenUniversityofCatalonia,Barcelona, Spain
AlfonsoValencia
LifeSciencesDepartment,BarcelonaSupercomputingCenter;ICREA—Institucio ´ Catalanade RecercaiEstudisAvanc ¸ats,Barcelona,Spain
MartaVillegas
LifeSciencesDepartment,BarcelonaSupercomputingCenter,Barcelona,Spain
EditorBiographies
DavideCirillo,PhD, istheHeadoftheMachineLearningforBiomedicalResearch UnitattheLifeSciencesDepartmentoftheBarcelonaSupercomputingCenter(BSC). HeisascientificadvisortotheWomen’sBrainProjectandamemberoftheBSCBioinfo4Womeninitiativesince2018.HereceivedhisMScdegreeinpharmaceuticalbiotechnologyfrom“LaSapienza”UniversityofRome,Italy.Hismastersresearchonthe predictionofimmunoglobulinstructurewasconductedunderthesupervisionofProf. AnnaTramontano.Afterthat,hejoinedtheGeneFunctionandEvolutiongroupled byProf.GianGaetanoTartagliaattheCenterforGenomicRegulation(CRG)ofBarcelona,Spain,toundertakehisdoctoralstudies.HisPhDthesisonthepredictionofproteinandnucleicacidinteractionswasawardedtheExtraordinaryPrizeoftheDoctoral SchoolinBiomedicinefromtheUniversitatPompeuFabra(UPF)ofBarcelona,Spain. AfterhisPhD,hejoinedtheComputationalBiologygroupatBSCasaJuandelaCierva postdoctoralresearcherunderthesupervisionofProf.AlfonsoValencia.In2019,hewas awardedaJoseCastillejoMobilityGranttoundertakeaninternshipatIBMResearch Zurich.Hisresearchfocusesoncomputationalmethodsforprecisionmedicinewitha specialemphasisonmachinelearning,networkscience,andethicsofartificial intelligence.
SilvinaCatuara-Solarz,PhD, isaDataScienceManagerattheAccentureBarcelona InnovationCenter,whereshesupportsorganizationsfromboththepublicandprivate sectorsintheimplementationoftechnologiesandanalyticsforhealthcareandlifesciences.SheisaProjectEvaluatorandMentorofDigitalHealthandMedtechstart-ups attheEuropeanInstituteofInnovationandTechnologyHealth(EITHealth)andamentorattheEuropeanInnovationCouncil(EIC).Inaddition,sheisaselectedmemberof theWorldHealthOrganization’sDigitalHealthRosterofExpertsandScientificAdvisor attheWomen’sBrainProjectaswellasanAtlanticFellowforEquityinBrainHealthat theGlobalBrainHealthInstitute.
Dr.Catuara-Solarzhasabackgroundintranslationalneurosciencewithexpertisein neurodevelopmental,neurodegenerative,andpsychiatricdisorders.AfterearningaPhD inBiomedicinebythePompeuFabraUniversitythatshedevelopedattheCentrefor GenomicRegulation(CRG),theHospitaldelMarResearchInstitute(IMIM)(Barcelona,Spain)andtheUniversityofCaliforniaIrvine(Irvine,UnitedStates),sheworked ontargetidentificationfordrugdevelopmentatJanssenPharmaceutica(Beerse,Belgium).DrivenbyherinterestsinmergingTechnologyandHealth,shethenjoined theHealthMoonshotatTelefonicaInnovationAlpha(Barcelona,Spain)asStrategy
Managerwhereshewasinvolvedwiththedevelopmentofevidence-baseddigitalmental healthsolutionsandtheirefficacyassessment.
Hermaininterestsareinvolvedwiththedevelopmentofscalableandfairdigital healthtechnologiesforbrainandmentalhealth.
EmreGuney,PhD, hasmorethan15yearsofexperienceincomputationaldataanalysis withanemphasisontranslationalsystemsmedicine,diseasebioinformatics,andnetwork pharmacology.HeistheCTOandHeadofDiscoveryandDataScienceUnitatSTALICLA,aclinicalstagebiopharmaceuticalcompanyleadingomics-basedprecisionmedicinedrugdevelopmentforpatientswithneurodevelopmentaldisordersthrough endophenotypingandartificialintelligence.Hespentseveralyearsasapostdoctoral scholaratHarvardMedicalSchoolandNortheasternUniversityintheUnitedStates, wherehepioneeredthedevelopmentofinsilicodrugefficacyscreeningusingcomputationalmodelingofintegrativemultiomicsdata.HewasaninvestigatorinEU-funded consortiaprojectsfordrugtoxicityandefficacymodelingduringhisappointmentsatthe ResearchProgrammeinBiomedicalInformaticsattheHospitaldelMarResearchInstitute(IMIM)inSpainandintheDepartmentofPharmacology&PersonalisedMedicine atMaastrichtUniversityintheNetherlands.Heisanalumnusofthe“FromScienceto Business”programofESADEBusiness&LawSchoolinBarcelona.Hehasatrackrecord ofscientificinnovation,withmorethan40peer-reviewedpublicationsandhas authored/co-authored2patents.
Acknowledgments
Thisbookistheresultofthecollectiveeffortbyalltheauthors,reviewers,editorialstaff, andnumerouscollaboratorswithwhomwehavebeenworkingtogetherandexchanging viewsinthepastyears.Wethankearnestlyallofthemfortheirhardworkandinvolvement,whichstartedduringtheCOVID-19pandemicwithmanyassociatedchallenges.
Weexpressourprofoundappreciationtomanyleadingorganizationsthathavesupportedusandalsopromoteddisseminationandopendiscussionoftherelevanttopicof thebook,includingbutnotlimitedtotheBioinfo4WomenprogramoftheBarcelona SupercomputingCenter,the“laCaixa”Foundation—PalauMacayainBarcelona,All Women,theBcNFemTechprojectbyAyuntamientodeBarcelona,BarcelonaActiva, EndesaandFundacio ´ Formacio ´ iTreball,theWyssResearchInstituteforBiomedical EngineeringinGeneva,andtheEuropeanAcademyofNeurology(EAN).Wealso thankMicrosoftforprovidingcomplimentaryaccesstotheTeamsplatform.
SpecialthankstoallthemembersandadvisorsoftheWomen’sBrainProject(WBP) whofosteredtheproject,believedinus,andhelpedintherevisionofthechapters.We arealsoindebtedtoanumberofcollaborators,acrossvariousfields,whohaveshared WBP’sjourneyandjoinedWBP’svision.Theideaofworkingonsexandgenderdifferencesinartificialintelligenceandnoveltechnologiesisaboldandinnovativeonethat WBPhasdevelopedthankstothecollaborationwithanumberofsupporterstowhom weareprofoundlyindebt.First,wethankDr.NicolettaIacobacciforhavinginspiredthis workalreadyin2016.BydoingresearchwithDr.NikolaosMavridis,Dr.Alfonso Valencia,Dr.AlbertoFerrari,Dr.EnricoSantus,andDr.NicolaMarino,WBPhas developedauniqueunderstandingofthistopic.Whiledevelopingthisbookproject, agreatimpulsecamefromtheHackathononWomen’sBrainandMentalHealthheld byWBPin2020;weheartilythankalltheparticipants,mentors,andorganizers— SamanthaPaoletti,PieraMarongiu,VirginiaSchumacher,LauraFurlong,LaiaSubirats, DavideCirillo,NikolaosMavridis,SimonaMellino,GuidoPutignano,AndreaTognon, NicolettaIacobacci,SilvieCuperus—manyofwhomareauthorsandeditorsofthis book.ThanksalsotoDr.IoannisTarnanas,CEOofAltoida,forsharingourpassion towardlookingintosexdifferencesindigitalbiomarkers.Wearegratefulto Dr.TracyLaabsforthecontinuoussupportandcollaboration,whichhasinspiredmany ofourprojects.Wealsothankthepatientsandpatientorganizations(suchasADI,EFNA, andWomen’sParkinsonProject)fortheirinputandpositivefeedback,whichhasmotivatedustocontinueonthispathofinnovation,forthebenefitofpeoplelivingwith brainandmentaldiseases.
WeareparticularlygratefultoDr.LondaSchiebinger,Dr.CarmeValls-Llobet, Dr.SandraBondChapman,andDr.ZoeWainerforauthoringtheendorsementsofthis book.Theirsupportonthisprojectisacontinuoussourceofmotivationforus.OurgratitudeextendstotheElsevierEditorsandManagers,MelanieTucker,SaraPianavilla, JoslynChaiprasert-Paguio,andKameshRamajogi,whoenvisionedthebookand accompaniedusonthisjourneyandwhohavebeenassistingusineverystep.We acknowledgealltheauthorsandeditorswhohaveworkedprobonothroughoutthe creationofthisbookdonatinganyfinancialrewardtotheWBPorganization.
Finally,ourheartfeltthankstoourfamiliesforsupportingourlongworkinghours, thestress,andtheworries,butalsoforpartakinginourexcitementandpride.
DavideCirillo,PhD
SilvinaCatuara-Solarz,PhD
EmreGuney,PhD
MariaTeresaFerretti,PhD
AnnemarieSchumacherDimech,PhD
AntonellaSantuccioneChadha,MD,PhD
TheWomen’sBrainProject
SimonaMellino,MariaTeresaFerretti,andAntonellaSantuccioneChadha
Women’sBrainProject,Guntershausen,Switzerland
1.ThebirthoftheWomen’sBrainProject
TheWomen’sBrainProject(WBP)isanonprofitorganization,foundedinSwitzerland andofficiallyregisteredin2017withaglobalreach.Composedlargelybyscientists,but alsoincludingpatients,caregivers,medicaldoctors,engineers,statisticians,andartists,the associationhasthemaingoaltostudysexandgenderdeterminantsofhealthasthegatewaytoprecisionmedicine,withaspecialemphasisonbrainandmentaldisorders.
WBPstemsfromtheacknowledgmentofapressingneedforshiftingfromaCaucasianmale-centricapproachinmedicinetowardamoreinclusiveone,basedontherecognitionthatdiseasescanpresentdifferencesbetweenmalesandfemalesinseveral domains:epidemiology,clinicalmanifestations,diseaseprogression,prognosis,response totreatmentandcare,amongothers [1].Theunderstandingofsuchdifferenceshasbeen greatlyaidedbythecollectionofbigdataandtechnologicaladvances.Theuseofartificial intelligence(AI)inbiomedicineandhealthcarehasthepotentialtomitigateinequalities byaccountingforsexandgenderdifferencesindiseaseasthegatewaytoprecisionmedicine,toachievemoreaccuratediagnosisandtreatment.Despitetheseadvances,thisline ofresearchremainsanicheandspecializedarea,andWBPaimstogenerateevidenceon theimpactofsuchdifferencesindiseasesandadvocatingforsexandgenderfactorsconsiderationsasanecessaryandimperativesteptomovetowardprecisionmedicine.
AtthetimeofWBP’sfoundationin2016,littledataandminimaldiscussionexisted ontheroleofsexandgender,particularlyinmentalandbrainhealth.Forinstance,inthe fieldofAlzheimer’sdisease,thefactthatmorewomenthanmenwerelivingwiththe diseasewasseldomrecognized,beingdismissedbymostscientistsasnotrelevantforclinicalresearch.Thesexoftheanimalsusedinexperimentalmodelswasoftennotreported, thesameappliedinclinicalresearch:thesexandthegenderoftheindividualsinvolvedin clinicaldevelopmentwasoftennotdescribednorspecificallyanalyzedondisease’scharacteristics.Theburdenofcaregiversonthefemalepopulationwasnotrecognizedor addressedbyspecificpolicyactions.
Asafirststep,theWBPteamdecidedtoanalyzethisphenomenonbydivingintothe availablescientificliteratureonAlzheimer’sdiseasetocollectinformationonthestateof theartandproviderecommendationsforfuturestudies.Theresultofthiscollaborative work,whichincludedaninternationalteamofscientists,highlightedseveral,potentially clinicallyrelevantdifferencesofthediseaseinmenandwomensuchasfastercognitive
declineinwomendiagnosedwithmildcognitiveimpairmentascomparedtomen [2]. SuchfindingsaddedtoourunderstandingofsexdifferencesinAlzheimer,beyondthe frequencyofthediseasebeinghigherinwomen;importantly,thepaperidentified numerousgapsintheglobalknowledge,whichneededtobeaddressed.Theseresults pavedthewaytofurtherstudiesintothisdirectionopeningthescientificdebateon theimportanceofsexandgenderdifferencesinAlzheimer’sdisease(whichisthefocus ofthefirstbookofthisseries)andbeyond.
Thebookseries,incollaborationwithElsevier,hasbeenenvisionedtocollectand organizethegrowing,availableevidenceinthetopicsofgendermedicineandprecision medicineinastructuredmannerusingamultidisciplinaryapproach.
Sincethen,thescientificcommunityhasgraduallybeguntorecognizesexandgender differenceanalysisasthegatewaytoprecisionmedicine,highlightingtheimportanceof patientheterogeneityandcharacteristicsrelatedtodiseasesriskfactors,diagnosis,progression,treatment,preventionstrategy,andcare.Thisisofhighclinicalrelevance,especiallyinneurologyandpsychiatry,whicharedisciplineswhereoneofthehighestmedical unmetneedsremains.Thepossibilityofdevelopingmoreprecisepreventativestrategies, diagnostictools,andeventreatments,basedontheunderstandingofpatientsubgroups andtheirindividualneeds,motivatedthesubsequentworkoftheWBPteam.
Atthesametime,itbecameclearthatsexandgenderdifferencesexistedinvirtually anydisorderofthebrainandourbody.Incontrastwithotherdisciplines,sexandgender differencesinthebrainwereseldomlydiscussedandoftenstigmatized.Indeed,reportsof sexdifferencesinbrainanatomyorfunctionhaveoftenbeenmisreadinthepastandmisusedtojustifysexistdiscriminationsandpreconcepts.Yet,whilerefusingallsortofdiscriminationbasedonscientificevidence,theWBPteamremainsconvincedofthe importanceofstudyingandunderstandingsexandgendercharacteristicsinbrainand mentalhealthforthebenefitofmillionsofmenandwomen(patientsandtheirfamilies) whodeservedbettertreatment.
2.TheWomen’sBrainProjectway—Aholisticapproachtoa complextopic
Confidentoftheimportanceofsexandgendercharacteristicsanalysisfortheachievementofprecisionmedicine,WBPinitiatedanunprecedentedinitiativetogeneratescientificevidenceandraiseawarenessonthetopicwithallthestakeholdersinvolvedfrom scientists,drugdevelopers,policymakers,andthelaypublic.Theoverarchinggoalhas beentopromotechangeintreatmentsolutionsbasedonasex-andgender-specific approachinmedicineandhealthcareingeneral.
Fromamostlydementia-focusedgroup,WBP’sworkhasgrowntoincludeother diseaseareas,suchasmigraine,Parkinson’sdisease,depression,anxiety,neuroimmunologicaldiseases,maternalhealth,andmorerecentlyCOVID-19 [3,4].Also,thescopeof
theworkhasextended,beyondclinicalresearch.Assexandgenderdifferencescan impactdiseasesatdifferentlevels,thepotentialsolutionsrequireamultidisciplinary approach.Sexdifferencesalreadyexistincellsandwillneedtobetakenintoconsiderationinpreclinicalmodelsofthedisease,butthisisalsotruefornewAI-basedhealthcare solutions,whichwillmostlikelyrepresentthefutureanswertounmetmedicalneeds suchasneurologicalandpsychiatricconditions.Theorganization,therefore,decided totakeaholisticapproach,tacklingtheissueat360degrees,frombasicsciencetodigital biomarkers.
Withanetworkofcollaboratorsspanningacrossfourcontinents,theWBPsetoutto establishexpertiseandinnovationinthefield.Theteamcurrentlyactsacrossfourpillars, allofwhichareimportantinthecontextofsexandgendermedicine:
1. Basicscience:Fundamentalsex-differenceshavebeendescribedinanatomy,molecular pathways,andpharmacology,alsoinanimalandcellularmodelsaswellasinpathophysiologyofhumandiseases.Forinstance,Mogiletal.demonstratedthatinanimal modelsofneuropathicpain(adiseaseoverwhelminglyaffectingwomen),microglia mediatepaininmales,butnotinfemalemice [5].
Thisresulthighlightstheimportanceofincludingandanalyzingbothsexesin experiments.Includingsexconsiderationsinbasicscienceisneededtoimprove reproducibilityofresults,aswellastranslatabilityoftheresultinhumans.
2. Clinicaltrials:AccordingtotheGAOreport [6],8outof10withdrawndrugscaused severesideeffectsinwomenratherthaninmen.Acarefulconsiderationofsafetyprofilesofdrugsduringdrugdevelopment,aswellassex-adjustedscalestoestablishefficacy,isdeemedtodramaticallyimprovedrugtestingprocessandmakemedicine sustainable.
3. Policy:Gender-relatedaspectsthataffecthealthandillnessneedtobecarefullyconsideredandaddressed.ThishasbecomeveryclearduringtheCOVID-19crisis;while womenappeartobebiologicallylessvulnerabletothevirus,becausetheyrepresent themajorityofthehealthworkforceandcaregivers,theyareexposedtoinfectedindividualsathigherrates,andthismighthaveimplicationsfortheirhealthintheyearsto comeaswellasindiseasespreadinggiventheroletheyplaywithinfamiliesandcommunities.Womenarealsooverrepresentedinmostofthegroupsthathavebeenparticularlyimpactedbythepsychologicalandsocioeconomicconsequencesofthe pandemic [7].
4. Noveltechnologies:Digitalbiomarkersandpredictivealgorithmspromisetodramaticallychangethelandscapeofmedicine,greatlyimprovingandstreamlininghealth management,fromriskfactorsmonitoringtodiagnosisandtreatment.However,bias isahiddenissueofmostdatabasesusedtogeneratealgorithms;assuch,thefieldneeds tointerrogateitselfonwhethergenderbiasesmightaffecttheefficiencyofAItoolsfor health.Atthesametime,sex-specificcharacteristicsmightbeleveragedtoimprove theefficiencyofsuchdigitaltools [8]
3.Becominganinternationalopinionleader
ThegoaloftheWBPistopositionsexandgenderdifferencesasthegatewaytoprecision medicine.Tothisend,theorganizationhasgainedvaluableexpertise,positioningitselfas aglobalthought-leaderinthefield.Inparalleltostandardresearchactivities,theWBP generatesawarenessanddiscussionintheacademicworld(includingconferences,workshops,opinionpieces,lecturesatacademicinstitutions,books),inthelaypublic(with frequentappearancesinthepress,TED-xtalks,andnarrativebooks)aswellaswithpolicymakers(WBPiscurrentlyleadingthefirstworld-wideregulatoryroundtabletodiscusswomen’shealthandprecisionmedicine).Itsflagshipevent,theInternationalForum onWomen’sBrainandMentalHealth,isauniqueandhighlyengagingoccasionfora multidisciplinarydiscussiononthetopic.WBPhaspioneerednovelapproachestopromoteaglobaldiscussion,includingfeaturingthehumanoidrobotSofiaatitsInternational Forumin2019,thelaunchofthefirstHackathononthetopic,andthestudyofsexdifferencesindigitalbiomarkersincollaborationwithcompaniessuchasAltoida.
Importantly,initsgrowth,theWBPhasrecognizedthatcurrentmedicalpractice (basedonaonesizefitsalldesignedforanaveragenonexistingpersona)canworkwith manypatients,butitwillfailwithmanyothers.Mostofthecurrenttreatmentsforbrain disordersarebasedontrialanderror,withpatientsthatgothroughlengthycyclesof unsuccessfultreatments,untiltherightoneisfound.Inmanycases,acureisnotavailable, suchasforAlzheimer’sdisease.Inadditiontothehumandamagecausedbysuchstateof affairs,suchashallowapproachcanresultindrugsbeingadministeredandreimbursed evenintheabsenceofclinicaleffectrenderinghealthcaresystemsunsustainable.Inthis regard,wehaveoftenseendrugsbeingwithdrawnfromthemarketbecauseofmajor severesideeffectsinthefemalepopulationorbeingpausedasinthecaseofadverseevents intheCOVID-19vaccinestrategy.Inthiscontext,thecallofWBPhasbecome,inthe lastyear,toadvocateforaprecisionmedicinemovementtotransformhealthcaresystems andmedicalpracticestowardsustainability.Foritseffortsinthisfield,theCEOofWBP, Dr.AntonellaSantuccioneChadhawhoisalsooneoftheWBPfounders,hasbeen electedasWomanoftheYearinSwitzerlandandalsoreceivedtheItalianPrize“MedicinaItalia.”Importantly,shealsoledtheorganizationtowardreceivingtheWorldSustainabilityAwardin2020,andin2021,shewasrecognizedamongSwisswomenwho fosteredinnovationglobally.
WiththeCOVID-19pandemic,thetopicofprecisionmedicineandsexandgender differenceshasfinallyhitthespotlight.WBPhasbeenamongthefirsttohighlightsex differencesinSars-CoV2effects,aswellasimportantgenderimbalancesandrisksfor womeninthepandemic.Thevaccineapprovalhasexposedanumberofissuesrelated tosexandgenderdifferences(insafetyaswellasitsuseinpregnancy),whichneedtobe addressed.Theteamiscurrentlyworkingtoraiseawarenessontheseissuesandpromote ad-hocpolicychangesindrugdevelopment.
4.Thefuture:Women
’sBrainProjectcalltoaction
Movingforward,andalsobasedonthelessonslearntduringthepandemic,WBP’scallto actionistoreconsiderthewaywedevelopdrugsandothersolutionsforhealth,towarda sustainablemodelbasedonAI-poweredprecisionmedicine.InWBP’svision,thiscanbe achievedbytheconcertedactionofresearchers,patients,caregivers,drugdevelopers,and policymakers.Tothisend,theWBPiscurrentlyworkingontheestablishmentofthe firstsex-andgender-basedprecisionmedicineinstituteinSwitzerland.
References
[1]Mauvais-JarvisF,BaireyMerzN,BarnesPJ,BrintonRD,CarreroJJ,DeMeoDL,etal.Sexandgender: modifiersofhealth,disease,andmedicine.Lancet2020;396:565–82. https://doi.org/10.1016/S01406736(20)31561-0
[2]FerrettiMT,IulitaMF,CavedoE,ChiesaPA,DimechAS,ChadhaAS,etal.SexdifferencesinAlzheimerdisease—thegatewaytoprecisionmedicine.NatRevNeurol2018;14:457–69. https://doi.org/ 10.1038/s41582-018-0032-9
[3]SantusE,MarinoN,CirilloD,ChersoniE,MontagudA,SantuccioneChadhaA,ValenciaA,Hughes K,LindvallC.Artificialintelligence-aidedprecisionmedicineforCOVID-19:strategicareasofresearch anddevelopment.JMedInternetRes2021;23(3). https://doi.org/10.2196/22453 ,e22453.
[4]FerrariA,SantusE,CirilloD,etal.SimulatingSARS-CoV-2epidemicsbyregion-specificvariablesand modelingcontacttracingappcontainment.NpjDigitMed2021;4:1–9. https://doi.org/10.1038/ s41746-020-00374-4
[5]SorgeRE,MapplebeckJCS,RosenS,BeggsS,TavesS,AlexanderJK,etal.Differentimmunecells mediatemechanicalpainhypersensitivityinmaleandfemalemice.NatNeurosci2015;18:1081–3. https://doi.org/10.1038/nn.4053.
[6]Drugsafety:mostdrugswithdrawninrecentyearshadgreaterhealthrisksforwomen;n.d. https:// www.gao.gov/products/gao-01-286r.[Accessed10May2021].
[7] Deloitte.Uncoveringthehiddeniceberg:whythehumanimpactofCOVID-19couldbeathirdcrisis; 2020.
[8]CoravosA,KhozinS,MandlKD.Developingandadoptingsafeandeffectivedigitalbiomarkersto improvepatientoutcomes.NpjDigitMed2019;2:1–5. https://doi.org/10.1038/s41746-019-0090-4
