2024
Human brain state dynamics are highly reproducible and associated with neural and behavioral features
Lee K, Ji J, Fonteneau C, Berkovitch L, Rahmati M, Pan L, Repovš G, Krystal J, Murray J, Anticevic A. Human brain state dynamics are highly reproducible and associated with neural and behavioral features. PLOS Biology 2024, 22: e3002808. PMID: 39316635, PMCID: PMC11421804, DOI: 10.1371/journal.pbio.3002808.Peer-Reviewed Original ResearchConceptsCo-activation patternsResting-state functional magnetic resonance imagingFunctional magnetic resonance imagingBehavioral featuresNeural variationsMoment-to-moment changesSingle-subject levelBrain state dynamicsEmotion regulationHealthy young adultsBehavioral phenotypesCognitive functionSubstance useNeural activityNeuroimaging markersNeural featuresYoung adultsMagnetic resonance imagingCo-activationResonance imagingCo-variationNeuroimagingIndividualsEmotionsFunctional outcomesMicroglia-mediated neuroimmune suppression in PTSD is associated with anhedonia
Bonomi R, Hillmer A, Woodcock E, Bhatt S, Rusowicz A, Angarita G, Carson R, Davis M, Esterlis I, Nabulsi N, Huang Y, Krystal J, Pietrzak R, Cosgrove K. Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2406005121. PMID: 39172786, PMCID: PMC11363315, DOI: 10.1073/pnas.2406005121.Peer-Reviewed Original ResearchConceptsPTSD groupPrefrontal-limbic circuitsNeuroimmune responseAssociated with anhedoniaPosttraumatic stress disorderPositron emission tomography brain imagingTranslocator protein availabilityBrain immune functionAnhedonic symptomsStress disorderPeripheral immune dysfunctionPTSDGroup differencesSeverity of symptomsPsychiatric diseasesTranslocator proteinBrain imagingAdministration of lipopolysaccharideSymptomsMicroglial markersLPS-induced increaseCompared to controlsImmune functionSickness symptomsAnhedonia
2023
A pilot randomized controlled trial of ketamine in Borderline Personality Disorder
Fineberg S, Choi E, Shapiro-Thompson R, Dhaliwal K, Neustadter E, Sakheim M, Null K, Trujillo-Diaz D, Rondeau J, Pittaro G, Peters J, Corlett P, Krystal J. A pilot randomized controlled trial of ketamine in Borderline Personality Disorder. Neuropsychopharmacology 2023, 48: 991-999. PMID: 36804489, PMCID: PMC10209175, DOI: 10.1038/s41386-023-01540-4.Peer-Reviewed Original ResearchConceptsBorderline personality disorderSecondary outcome measuresOutcome measuresSocio-occupational functioningSuicidal ideationPilot studyTrial of ketaminePersonality disorderInfusion of ketaminePrimary outcome measureEffects of ketamineMidazolam groupAdverse eventsKetamine groupClinical benefitMood symptomsKetamineFDA approvalDrug midazolamInfusionBPD symptomsLarger studyDepressed moodSymptomsChronic mood
2022
Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial
Krystal J, Kane J, Correll C, Walling D, Leoni M, Duvvuri S, Patel S, Chang I, Iredale P, Frohlich L, Versavel S, Perry P, Sanchez R, Renger J. Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial. The Lancet 2022, 400: 2210-2220. PMID: 36528376, DOI: 10.1016/s0140-6736(22)01990-0.Peer-Reviewed Original ResearchConceptsTreatment of schizophreniaPositive allosteric modulatorsAdverse eventsUS sitesAllosteric modulatorsFavorable side effect profileMini International Neuropsychiatric InterviewNovel positive allosteric modulatorReceptor positive allosteric modulatorExtrapyramidal symptom assessmentMultiple ascending dosesCommon adverse eventsPhase 1b trialPlacebo-controlled studySide effect profileInternational Neuropsychiatric InterviewCohort of participantsAscending dosesSafety populationPrimary endpointBlood pressureM4 receptorsTreatment initiationDaily treatmentOral dosesSublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial.
Citrome L, Preskorn SH, Lauriello J, Krystal JH, Kakar R, Finman J, De Vivo M, Yocca FD, Risinger R, Rajachandran L. Sublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial. The Journal Of Clinical Psychiatry 2022, 83 PMID: 36198061, DOI: 10.4088/jcp.22m14447.Peer-Reviewed Original ResearchConceptsAcute agitationHours postdoseSchizoaffective disorderTotal scorePrimary efficacy endpointPlacebo-controlled studyAdrenergic receptor agonistFifth Edition criteriaNegative Syndrome ScaleDexmedetomidine groupOral hypoesthesiaStudy medicationDry mouthEfficacy endpointOrthostatic hypotensionRandomized PlaceboAdverse eventsReceptor agonistEdition criteriaDexmedetomidineMean changePEC scoresPlaceboSyndrome ScaleUS sitesA comparison of methods to harmonize cortical thickness measurements across scanners and sites
Sun D, Rakesh G, Haswell CC, Logue M, Baird CL, O'Leary EN, Cotton AS, Xie H, Tamburrino M, Chen T, Dennis EL, Jahanshad N, Salminen LE, Thomopoulos SI, Rashid F, Ching CRK, Koch SBJ, Frijling JL, Nawijn L, van Zuiden M, Zhu X, Suarez-Jimenez B, Sierk A, Walter H, Manthey A, Stevens JS, Fani N, van Rooij SJH, Stein M, Bomyea J, Koerte IK, Choi K, van der Werff SJA, Vermeiren RRJM, Herzog J, Lebois LAM, Baker JT, Olson EA, Straube T, Korgaonkar MS, Andrew E, Zhu Y, Li G, Ipser J, Hudson AR, Peverill M, Sambrook K, Gordon E, Baugh L, Forster G, Simons RM, Simons JS, Magnotta V, Maron-Katz A, du Plessis S, Disner SG, Davenport N, Grupe DW, Nitschke JB, deRoon-Cassini TA, Fitzgerald JM, Krystal JH, Levy I, Olff M, Veltman DJ, Wang L, Neria Y, De Bellis MD, Jovanovic T, Daniels JK, Shenton M, van de Wee NJA, Schmahl C, Kaufman ML, Rosso IM, Sponheim SR, Hofmann DB, Bryant RA, Fercho KA, Stein DJ, Mueller SC, Hosseini B, Phan KL, McLaughlin KA, Davidson RJ, Larson CL, May G, Nelson SM, Abdallah CG, Gomaa H, Etkin A, Seedat S, Harpaz-Rotem I, Liberzon I, van Erp TGM, Quidé Y, Wang X, Thompson PM, Morey RA. A comparison of methods to harmonize cortical thickness measurements across scanners and sites. NeuroImage 2022, 261: 119509. PMID: 35917919, PMCID: PMC9648725, DOI: 10.1016/j.neuroimage.2022.119509.Peer-Reviewed Original ResearchClinical and Financial Outcomes Associated With a Workplace Mental Health Program Before and During the COVID-19 Pandemic
Bondar J, Morrow C, Gueorguieva R, Brown M, Hawrilenko M, Krystal JH, Corlett PR, Chekroud AM. Clinical and Financial Outcomes Associated With a Workplace Mental Health Program Before and During the COVID-19 Pandemic. JAMA Network Open 2022, 5: e2216349. PMID: 35679044, PMCID: PMC9185188, DOI: 10.1001/jamanetworkopen.2022.16349.Peer-Reviewed Original ResearchConceptsMental health programsHealth programsCohort studyLarge clinical effect sizesPatient Health Questionnaire-9Common mental health conditionsSheehan Disability ScaleClinical effect sizeMental health conditionsMental health symptomsCost of treatmentGeneralized anxiety disorderMental health difficultiesMental health benefitsWorkplace wellness programsCare navigationClinical improvementPrimary outcomeClinical benefitQuestionnaire-9Disability ScaleMedication managementLeast moderate anxietyMixed-effects regressionPerson psychotherapyRemodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium
Sun D, Rakesh G, Clarke-Rubright EK, Haswell CC, Logue MW, O'Leary EN, Cotton AS, Xie H, Dennis EL, Jahanshad N, Salminen LE, Thomopoulos SI, Rashid FM, Ching CRK, Koch SBJ, Frijling JL, Nawijn L, van Zuiden M, Zhu X, Suarez-Jimenez B, Sierk A, Walter H, Manthey A, Stevens JS, Fani N, van Rooij SJH, Stein MB, Bomyea J, Koerte I, Choi K, van der Werff SJA, Vermeiren RRJM, Herzog JI, Lebois LAM, Baker JT, Ressler KJ, Olson EA, Straube T, Korgaonkar MS, Andrew E, Zhu Y, Li G, Ipser J, Hudson AR, Peverill M, Sambrook K, Gordon E, Baugh LA, Forster G, Simons RM, Simons JS, Magnotta VA, Maron-Katz A, du Plessis S, Disner SG, Davenport ND, Grupe D, Nitschke JB, deRoon-Cassini TA, Fitzgerald J, Krystal JH, Levy I, Olff M, Veltman DJ, Wang L, Neria Y, De Bellis MD, Jovanovic T, Daniels JK, Shenton ME, van de Wee NJA, Schmahl C, Kaufman ML, Rosso IM, Sponheim SR, Hofmann DB, Bryant RA, Fercho KA, Stein DJ, Mueller SC, Phan KL, McLaughlin KA, Davidson RJ, Larson C, May G, Nelson SM, Abdallah CG, Gomaa H, Etkin A, Seedat S, Harpaz-Rotem I, Liberzon I, Wang X, Thompson PM, Morey RA. Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium. Biological Psychiatry Cognitive Neuroscience And Neuroimaging 2022, 7: 935-948. PMID: 35307575, PMCID: PMC9835553, DOI: 10.1016/j.bpsc.2022.02.008.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderCortical thicknessStructural covarianceComorbid depressionControl subjectsLarge effect sizesStress disorderEffect sizeTrauma-exposed control subjectsCase-control differencesCortical surface areaInflammatory processClinical dataResting-state functional connectivity networksPositive pairwise correlationsCortical differencesCortical regionsCortical neuroanatomyStress hormonesFunctional connectivity networksPTSD casesSmall effect sizesGroup differencesStructural networkStructural connectome
2021
Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups
Clausen AN, Fercho KA, Monsour M, Disner S, Salminen L, Haswell CC, Rubright EC, Watts AA, Buckley MN, Maron-Katz A, Sierk A, Manthey A, Suarez-Jimenez B, Olatunji BO, Averill CL, Hofmann D, Veltman DJ, Olson EA, Li G, Forster GL, Walter H, Fitzgerald J, Théberge J, Simons JS, Bomyea JA, Frijling JL, Krystal JH, Baker JT, Phan KL, Ressler K, Han LKM, Nawijn L, Lebois LAM, Schmaal L, Densmore M, Shenton ME, van Zuiden M, Stein M, Fani N, Simons RM, Neufeld RWJ, Lanius R, van Rooij S, Koch SBJ, Bonomo S, Jovanovic T, deRoon-Cassini T, Ely TD, Magnotta VA, He X, Abdallah CG, Etkin A, Schmahl C, Larson C, Rosso IM, Blackford JU, Stevens JS, Daniels JK, Herzog J, Kaufman ML, Olff M, Davidson RJ, Sponheim SR, Mueller SC, Straube T, Zhu X, Neria Y, Baugh LA, Cole JH, Thompson PM, Morey RA. Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups. Brain And Behavior 2021, 12: e2413. PMID: 34907666, PMCID: PMC8785613, DOI: 10.1002/brb3.2413.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderEffects of PTSDBrain-PADBrain ageMale controlsOld maleStress disorderAge-related brain changesStructural magnetic resonance imagingBrain structural magnetic resonance imagingOlder age groupsMagnetic resonance imagingChronological ageSubset of controlsContext of PTSDControl subjectsBrain changesBrain agingFuture longitudinal researchTreatment approachesLinear mixed effects modelsAdult subjectsResonance imagingAge groupsPTSD assessmentDynamic structural equation modeling of the relationship between alcohol habit and drinking variability
DeMartini KS, Gueorguieva R, Taylor JR, Krishnan-Sarin S, Pearlson G, Krystal JH, O'Malley SS. Dynamic structural equation modeling of the relationship between alcohol habit and drinking variability. Drug And Alcohol Dependence 2021, 233: 109202. PMID: 35151022, PMCID: PMC10046111, DOI: 10.1016/j.drugalcdep.2021.109202.Peer-Reviewed Original ResearchPrevalence and Trends in Suicidal Behavior Among US Military Veterans During the COVID-19 Pandemic
Nichter B, Hill ML, Na PJ, Kline AC, Norman SB, Krystal JH, Southwick SM, Pietrzak RH. Prevalence and Trends in Suicidal Behavior Among US Military Veterans During the COVID-19 Pandemic. JAMA Psychiatry 2021, 78: 1218-1227. PMID: 34431973, PMCID: PMC8387942, DOI: 10.1001/jamapsychiatry.2021.2332.Peer-Reviewed Original ResearchConceptsUS military veteransCOVID-19 infectionCohort studySuicidal behaviorPast-year suicide ideationRisk factorsMilitary veteransPopulation-based prospective cohort studyCOVID-19 pandemicSuicide ideationSuicide attemptsProspective cohort studyLifetime posttraumatic stress disorderStrong risk factorCOVID-19 public health emergencyLow social supportPosttraumatic stress disorderPublic health emergencyAlcohol use disorder severityUS veteransNational HealthMAIN OUTCOMESuicide attempt historyVeterans StudyCOVID-19-related variablesImaging brain cortisol regulation in PTSD with a target for 11β-hydroxysteroid dehydrogenase type 1
Bhatt S, Hillmer AT, Rusowicz A, Nabulsi N, Matuskey D, Angarita GA, Najafzadeh S, Kapinos M, Southwick SM, Krystal JH, Carson RE, Huang Y, Cosgrove KP. Imaging brain cortisol regulation in PTSD with a target for 11β-hydroxysteroid dehydrogenase type 1. Journal Of Clinical Investigation 2021, 131: e150452. PMID: 34651587, PMCID: PMC8516462, DOI: 10.1172/jci150452.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderPositron emission tomographyVolume of distributionDehydrogenase type 1Trauma-exposed controlsPTSD groupTranslocator proteinType 1Veterans Affairs (VA) National CenterOverall PTSD severityBrain glucocorticoidBrain immuneMethodsSixteen individualsPeripheral cortisolMicroglial markersImmune suppressionTranslational Science AwardsCortisol levelsNIH National CenterTC groupCortisol regulationEmission tomographyStress disorderLower PTSD symptomsPTSD symptomsDopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia
Abi-Dargham A, Javitch JA, Slifstein M, Anticevic A, Calkins ME, Cho YT, Fonteneau C, Gil R, Girgis R, Gur RE, Gur RC, Grinband J, Kantrowitz J, Kohler C, Krystal J, Murray J, Ranganathan M, Santamauro N, Van Snellenberg J, Tamayo Z, Wolf D, D’Souza D, Srihari V, Gueorguieva R, Patel P, Forselius-Bielen K, Lu J, Butler A, Fram G, Afriyie-Agyemang Y, Selloni A, Cadavid L, Gomez-Luna S, Gupta A, Radhakrishnan R, Rashid A, Aker R, Abrahim P, Nia A, Surti T, Kegeles L, Carlson M, Goldberg T, Gangwisch J, Benedict E, Govil P, Brazis S, Mayer M, de la Garrigue N, Fallon N, Baumvoll T, Abeykoon S, Perlman G, Bobchin K, Elliott M, Schmidt L, Rush S, Port A, Heffernan Z, Laney N, Kantor J, Hohing T, Gray D, Lieberman J. Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia. Schizophrenia Bulletin 2021, 48: 199-210. PMID: 34423843, PMCID: PMC8781338, DOI: 10.1093/schbul/sbab095.Peer-Reviewed Original ResearchConceptsCortical dopamine neurotransmissionPositive allosteric modulationImportant therapeutic targetPF-06412562Dopaminergic receptorsD1R stimulationDA levelsTolerable dosesLevel of stimulationDopamine neurotransmissionReceptor stimulationTherapeutic targetPartial agonistCognitive deficitsBiased agonismFull agonismTarget engagementAllosteric modulationNew drugsStimulationPoor bioavailabilitySchizophreniaOptimal stimulationDrugsExpression levelsIndividual Differences in the Associations Between Risk Factors for Alcohol Use Disorder and Alcohol Use-Related Outcomes
Haeny AM, Gueorguieva R, Jackson A, Morean ME, Krishnan-Sarin S, DeMartini KS, Pearlson GD, Anticevic A, Krystal JH, O’Malley S. Individual Differences in the Associations Between Risk Factors for Alcohol Use Disorder and Alcohol Use-Related Outcomes. Psychology Of Addictive Behaviors 2021, 35: 501-513. PMID: 34110841, PMCID: PMC9211405, DOI: 10.1037/adb0000733.Peer-Reviewed Original ResearchMapping data‐driven individualized neurobehavioral phenotypes in heavy alcohol drinkers
DeMartini KS, Gueorguieva R, Pearlson G, Krishnan‐Sarin S, Anticevic A, Ji LJ, Krystal JH, O’Malley S. Mapping data‐driven individualized neurobehavioral phenotypes in heavy alcohol drinkers. Alcohol Clinical And Experimental Research 2021, 45: 841-853. PMID: 33605439, DOI: 10.1111/acer.14580.Peer-Reviewed Original ResearchConceptsConfirmatory factor analysisIncentive salienceNeurofunctional domainsAlcohol use disorderExecutive functionLatent factorsPhysical neglectSelf-report measuresChildhood emotional abuseUse disordersChildhood physical neglectEarly life stressSignificant predictorsMultiple significant predictorsMultiple causes modelCurrent AUDNegative emotionalityAddiction developmentEmotional abuseChildhood neglectFactor structureDrinking frequencySalienceCause modelFactor analysis
2020
Transcriptomic organization of the human brain in post-traumatic stress disorder
Girgenti MJ, Wang J, Ji D, Cruz DA, Stein M, Gelernter J, Young K, Huber B, Williamson D, Friedman M, Krystal J, Zhao H, Duman R. Transcriptomic organization of the human brain in post-traumatic stress disorder. Nature Neuroscience 2020, 24: 24-33. PMID: 33349712, DOI: 10.1038/s41593-020-00748-7.Peer-Reviewed Original ResearchMeSH KeywordsAdultAutopsyBrain ChemistryCohort StudiesDepressive Disorder, MajorFemaleGene Expression RegulationGene Regulatory NetworksGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansInterneuronsMaleMiddle AgedNerve Tissue ProteinsSex CharacteristicsStress Disorders, Post-TraumaticTranscriptomeYoung AdultConceptsGenome-wide association studiesSignificant gene networksDifferential gene expressionSystems-level evidenceSignificant genetic liabilityMajor depressive disorder cohortGene networksTranscriptomic organizationTranscriptomic landscapeDownregulated setsGenomic networksGene expressionAssociation studiesMolecular determinantsExtensive remodelingGenotype dataSexual dimorphismSignificant divergenceMolecular profileNetwork analysisELFN1TranscriptsDimorphismPostmortem tissueDivergenceTransdiagnostic, Connectome-Based Prediction of Memory Constructs Across Psychiatric Disorders
Barron DS, Gao S, Dadashkarimi J, Greene AS, Spann MN, Noble S, Lake EMR, Krystal JH, Constable RT, Scheinost D. Transdiagnostic, Connectome-Based Prediction of Memory Constructs Across Psychiatric Disorders. Cerebral Cortex 2020, 31: 2523-2533. PMID: 33345271, PMCID: PMC8023861, DOI: 10.1093/cercor/bhaa371.Peer-Reviewed Original ResearchConceptsMacroscale brain networksIndividual differencesBrain networksMemory deficitsFunctional connectivityAttention deficit hyper-activity disorderTask-based functional MRI dataLong-term memoryWhole-brain functional connectivityDiagnostic groupsWhole-brain patternsDefault mode networkFunctional MRI dataHuman Connectome ProjectPsychiatric disordersMemory constructsMemory performanceTransdiagnostic sampleBrain correlatesMode networkFunctional connectomeConnectome ProjectLimbic networkHealthy participantsMemoryThe Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk
Spiegelman D, Lovato LC, Khudyakov P, Wilkens TL, Adebamowo CA, Adebamowo SN, Appel LJ, Beulens JW, Coughlin JW, Dragsted LO, Edenberg HJ, Eriksen JN, Estruch R, Grobbee DE, Gulayin PE, Irazola V, Krystal JH, Lazo M, Murray MM, Rimm EB, Schrieks IC, Williamson JD, Mukamal KJ. The Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk. European Journal Of Preventive Cardiology 2020, 27: 1967-1982. PMID: 32250171, PMCID: PMC7541556, DOI: 10.1177/2047487320912376.Peer-Reviewed Original ResearchConceptsModerate alcohol consumptionCardiovascular Health TrialAlcohol consumptionHealth trialsCardiovascular diseaseModerate alcoholNon-fatal ischemic strokeNon-fatal myocardial infarctionPrimary composite endpointCongestive heart failureCoronary heart diseaseModerate alcohol consumersAdults 50 yearsPublic health guidelinesAlcohol use disorderPreferred alcoholic beverageCardiometabolic effectsCardiometabolic riskCarotid revascularizationIschemic strokeSecondary outcomesComposite endpointHeart failurePrimary outcomeMyocardial infarctionMobilizing an institutional supportive response for healthcare workers and other staff in the context of COVID-19: The Yale experience
Krystal JH, Alvarado J, Ball SA, Fortunati FG, Hu M, Ivy ME, Kapo J, Olson KD, Rohrbaugh RM, Sinha R, Tebes JK, Vender RJ, Yonkers KA, Mayes LC. Mobilizing an institutional supportive response for healthcare workers and other staff in the context of COVID-19: The Yale experience. General Hospital Psychiatry 2020, 68: 12-18. PMID: 33254081, PMCID: PMC7680059, DOI: 10.1016/j.genhosppsych.2020.11.005.Peer-Reviewed Original ResearchCortical Transcriptomic Alterations in Association With Appetitive Neuropeptides and Body Mass Index in Posttraumatic Stress Disorder
Stone LA, Girgenti MJ, Wang J, Ji D, Zhao H, Krystal JH, Duman R. Cortical Transcriptomic Alterations in Association With Appetitive Neuropeptides and Body Mass Index in Posttraumatic Stress Disorder. The International Journal Of Neuropsychopharmacology 2020, 24: 118-129. PMID: 32951025, PMCID: PMC8611677, DOI: 10.1093/ijnp/pyaa072.Peer-Reviewed Original ResearchConceptsUpstream regulatorGene co-expression network analysisCo-expression network analysisFunctional genomic studiesPutative upstream regulatorsIngenuity Pathway Analysis softwarePathway Analysis softwarePathway annotationGenomic studiesTranscriptomic modulesTranscriptomic dataTranscriptomic alterationsGene expression