Model Driven Paediatric European Digital Repository. Call identifier: FP7-ICT Grant agreement no:

Transcript

1 Mdel Driven Paediatric Eurpean Digital Repsitry Call identifier: FP7-ICT Grant agreement n: Thematic Pririty: ICT - ICT : Virtual Physilgical Human Deliverable 3.1 Frm f Infrmed cnsent and study prtcl fr DCM: apprval by the lcal Ethical Cmmittees Due date f delivery: 31 th May 2013 Actual submissin date: 6 th June 2013 Start f the prject: 1 st March 2013 Ending Date: 28 th February 2017 Partner respnsible fr this deliverable: OPBG Versin: 1.2 1

2 Disseminatin Level: Public Dcument Classificatin Title Frm f Infrmed cnsent and study prtcl fr DCM: apprval by the lcal Ethical Cmmittees Deliverable 3.1 Reprting Perid March 2013 February 2014 Authrs OPBG Wrk Package WP3 Data acquisitin and prcessing fr Cardimypathies Security Pu Nature Reprt Keywrd(s) Clinical prtcls, infrmed cnsent, ethical clearance. Dcument Histry Name Remark Versin Date G. Rinelli First Draft th April 2013 G. Rinelli Secnd Draft th May 2013 List f Cntributrs Name Affiliatin S. Martin OPBG N. Bergnzi OPBG A. Taylr UCL List f reviewers Name Affiliatin B. Dallapiccla OPBG Abbreviatins 2

3 Table f Cntents Synpsis f the study (submitted t the Lcal Ethical Cmmittee)... 4 Clinical Prtcl WP3 Data acquisitin and prcessing fr Cardimypathies... 8 Children s Assent Frm Adlescents Assent Frm Parents Guardian cnsent frm Patients ver 18 years ld cnsent frm Case Reprt Frm (CRF) Ethical clearance - May 15th

4 Synpsis f the study (submitted t the Lcal Ethical Cmmittee) SCHEDA RIASSUNTIVA DELLO STUDIO V.3 7 may Titl del prgett: Mdel-Driven Eurpean Paediatric Repsitry- MD PAEDIGREE - WP 3 - Data acquisitin and prcessing fr Cardimypathies 2. Sperimentatre: Gabriele Rinelli 3. Spnsr: OPBG (finanziat dalla Cmmissine Eurpea) 4. Tip di sperimentazine: Nn terapeutica 5. Basi scientifiche e biettivi della ricerca: Mdel-Driven Eurpean Paediatric Repsitry, acrnim MD PAEDIGREE, è un Prgett di Ricerca finanziat dalla Cmmissine Eurpea nell area Virtual Physilgical Human (VPH). MD Paedigree mira a superare l stat dell arte nell ambit della mdellizzazine cmputazinale patient specific di diverse pediatriche (artrite givanile idipatica (JIA), rischi cardivasclare nel paziente bes, malattie neurlgiche e neurmusclari (NND), cardimipatie) ed a tradurre le ultime innvazini in evidenze cliniche, al fine di miglirare la cmprensine delle malattie e sviluppare una piattafrma per la diagnstica e la valutazine di nuve terapie. MD-Paedigree prevede a) l integrazine dell apprcci specific alla varie patlgie cn l analisi di dati bimedici di natura etergenea (derivanti dall analisi clinica, genetica e metagenmica, imaging, emdinamica, sequenziament in temp reale dei parametri musculscheletrici); b) l integrazine e la cndivisine delle diverse infrmazini bimediche utilizzand un sistema VPH adattabile, cmpnibile e affidabile, a supprt di un apprcci terapeutic evidence based. MD-Paedigree è rganizzat in diversi studi (wrk packages). Obiettiv principale del presente studi è frnire dati clinici e relativi alla struttura cardiaca (gemetria, funzinalità) per cstruire un VPH Infstructure dispnibile per clinici e ricercatri, che cnsenta di valutare i predittri dell insufficienza cardiaca in bambini e adlescenti cn cardimipatie (CMD). 4

5 Si intende quindi cgliere le più imprtanti caratteristiche del sistema cardivasclare, inclus cure, arterie e circlazine periferica, per predire la prgressine delle cardimipatie e pianificare eventuali interventi quali trapiant di cure l impiant di dispsitivi di assistenza ventriclare. I dati che verrann frniti su base investigativa, racclta di immagini, mnitraggi della pressine, sservazine clinica ed esercizi fisici verrann usati per cstruire questi mdelli e validarli, cnfrntandne la capacità predittiva cn la situazine attuale del paziente. Raccgliend tutte le frammentarie infrmazini ttenute dai differenti percrsi diagnstici e generand un mdell funzinale del cure di un bambin, il nstr mdell sarà in grad di ffrire ai cardilgi il miglir strument per la terapia dei pazienti. 6. Tip di Studi: Multicentric Centri partecipanti: Centri clinici per racclta ed analisi dati: OPBG - Respnsabile Fabrizi De Benedetti University Cllege Lndn Great Ormnd Strett Hspital - Respnsabile Andrew Taylr Jhns Hpkins University Stati Uniti Respnsabile Allen Everett BMR Genmics Padva Respnsabile Barbara Siminati Centri tecnlgici per analisi dati annimizzati e cstruzine mdelli: Institut Natinal de Recherche en Infrmatique et en Autmatique Francia Respnsabile Xavier Pennec Siemens repubblica tedesca Respnsabile Michael Suehling 7. Tiplgia dei sggetti: Patlgia: Cardimipativa Dilatativa (CMD) Sess: 50% femmine, 50% maschi Età: 2-18 anni 8. Numer di sggetti da includere (nel cas di sperimentazine multicentriche, indicare anche il lr numer cmplessiv): Ttali: 180 OPBG: Criteri di inclusine: Bambini e adlescenti (età 2-18 anni) affetti cn diagnsi di Cardimipativa Dilatativa (CMD) primaria secndaria cn fisilgia biventriclare, evidenza di disfunzine ventriclare (EF<50%) e dilatazine del ventricl sinistr (>2 DS) Cnsens del genitri/tutre, assens dell adlescente 5

6 10. Criteri di esclusine: Pazienti cn una più delle seguenti caratteristiche: fisilgia di cure univentriclare, evidenza di aritmie significative, Cr plmnale, ipertensine artrerisa essenziale severa, patlgie del pericardi. 11. Disegn sperimentale: Lngitudinale sservazinale prspettic 12. Cnsiderazini statistiche: L scp principale del Prgett riguarda la creazine di un repsitry di dati utile per la creazine di mdelli bimeccanici e di wrkflws. Per questi scpi nn sn previste analisi statistiche inferenziali né l applicazine di criteri frmali per la definizine della dimensine del campine dell studi. Sarann effettuate tuttavia analisi descrittive dei dati in frma assluta e nrmalizzata. Per garantire la qualità e l usabilità dei dati racclti verrann applicate le seguenti prcedure: data pre-prcessing: validazine, discretizzazine, rimzine dei valri nulli & utlier, che sarà eseguit cn il sistema Data Curatr & Validatr - DCV, sviluppat nel crs del precedente prgett An integrated platfrm fr Eurpean paediatrics based n a Gridenabled netwrk f leading clinical centres (Health-e-Child); mapping: i descrittri ttenuti sarann mappati cn dizinari standard di dati (ad esempi utilizzand i data sets sviluppati nel sistema del prgett epsos, i cdici diagnstici ICD-10, LOINC...); nrmalizzazine: i dati numerici riginali sarann nrmalizzati per generare i valri z; dati di riferiment: i valri nrmali secnd le crrenti linee guida sarann aggiunti al data set; calcl di nuve variabili: verrann calclate nuve variabili a partire dai valri di altri campi (ad esempi il Bdy Mass Index dal rapprt pes/altezza); descrizine dei dati: - analisi descrittive standard verrann eseguite per le variabili categriche e per quelle cntinue; - i valri delle single variabili verrann utilizzati per calclare un rank che permetta la classificazine dell specific pattern nel data base generale (case-based retrieval applicatin); - sarà effettuat il clustering dei pattern utilizzand algritmi statistici e di visualizzazine; per i dati di imaging sarann estratte dalle immagini le caratteristiche visive che descrivn le regini dell immagine stessa (lcal image cntent); queste infrmazini sarann aggregate ad altre di differente frmat all scp di differenziare i dati anrmali da quelli nrmali; 6

7 sarann effettuate simulazini basate su tecniche di data-mining, utilizzand il sistema ΑΙΤΙΟΝ (Scalable Platfrm fr Interactive Data Mining), sviluppat ed utilizzat durante il precedente prgett An integrated platfrm fr Eurpean paediatrics based n a Gridenabled netwrk f leading clinical centres (Health-e-Child). 13. Durata dell studi (cmprendente: perid di arrulament, eventuale perid di wash-ut, perid di trattament, fllw up, per il singl sggett e per tutt il campine in studi). Perid di arrulament: 16 mesi Perid di fllw up: 16 mesi 14. Prspett degli esami strumentali e di labratri (in aggiunta a quelli nrmalmente eseguiti per la patlgia in questine). Esami di labratri: - Su campini di sangue: Esami genetici- panel di geni (per il dettali vedi ptcll), su un campine di sangue nn prelevat appsitamente ma residu rispett al preliev che il paziente effettuerebbe cmunque per i cntrlli legati alla sua malattia. Per gli scpi di questa ricerca nn sn quindi necessari prelievi ematici aggiuntivi. Imaging: - RMN cardiaca 15. Fattibilità dell studi I sggetti (n=90) da includere nell studi sarann identificati tra quelli che attualmente sn seguiti press la nstra struttura assistenziale cn una diagnsi di cardimipatia dilatativa (circa 100/ann arrulabili afferenti al centr). La valutazine dei pazienti sarà eseguita press le strutture assistenziali del DMCCP (DH cardilgia, DH scmpens, Ambulatri di Fllw-up cardilgic). Le tre unità perative cinvlte (DH Cardilgia, Medicina dell Sprt, e Cardidiagnstica) dispngn di tutte le strutture e le strumentazini necessarie alla valutazine clinica e diagnstica necessaria all svlgiment dell studi cn la sla eccezine degli RX trace e delle RMN, che sarann eseguite dal Dipartiment di Diagnstica per Immagini. 7

8 Clinical Prtcl WP3 Data acquisitin and prcessing fr Cardimypathies TITLE Mdel-Driven Eurpean Paediatric Repsitry- MD PAEDIGREE WP 3 - Data acquisitin and prcessing fr Cardimypathies Prtcl n: Versin: 5 May 7th, 2013 CONFIDENTIAL 8

9 Prtcl n.: Title: Data acquisitin and prcessing fr Cardimypathies Acrnym: MD-Paedigree WP 3 Multicentric/Mncentric Study Multicentric Principal Investigatr/Crdinatr Prf. Brun Dallapiccla Spnsr: Eurpean Cmmissin thrugh the Bambin Gesù Children Hspital Persn respnsible f the study Persn respnsible fr OPBG Dr. Gabriele Rinelli Dr. Gabriele Rinelli Data Management/Statistical analysis: Prtcl apprved and signed by: Principal Investigatr: Prf. Brun Dallapiccla Respnsible Wrk Package: Dr. Gabriele Rinelli Respnsible Unit: Dr. Gabriele Rinelli. 9

10 Acrnym List AEs EC CRF GCP ICH IRB/IEC NSAEs SAEs SOPs Adverse Events Ethical Cmmittee Case Reprt Frm Gd Clinical Practice Internatinal Cnference n Harmnisatin Institutinal Review Bard/Independent Ethics Cmmittee Nn Serius Adverse Events Serius Adverse Events Standard Operating Prcedures.. 10

11 INDEX 1 INTRODUCTION 1.1 BACKGROUND OF THE MD-PAEDIGREE PROJECT 1.2 BACKGROUND OF THE DATA ACQUISITION AND PROCESSING FOR CARDIOMYOPATHIES STUDY 2 AIMS OF THE STUDY 2.1 MAIN GOAL 2.2 PRIMARY END-POINT 2.3 SECONDARY END-POINTS 3 STUDY DESCRIPTION 3.1 STUDY DESIGN 3.2 SUBJECTS SELECTION 4 WITHDRAWAL FROM THE STUDY 5 STUDY PLANNING 5.1EFFICACY PARAMETER 5.2 EXPERIMENTAL DESIGN 5.3 DATA PROTECTION 6 SECURITY EVALUATION 6.1 DEFINITIONS 7 SAMPLE DIMENSION AND STATISTIC METHODOLOGY 7.1 STATISTIC DESIGN 11

12 7.2 MANAGEMENT OF MISSING DATADEVISATIONS WARNING 7.3 SUBJECT SELECTION 8 PROCEDURE AMMINISTRATIVE ED ETICHE 8.1 AUTORIZATIONS 8.2 INFORMED CONSENT 8.3 INSURANCE COVERAGE 8.4 USE OF THE INFORMATION AND DATA PUBBLICATION 8.5 CLINICAL PROTOCOL AMENDMENTS 8.6 DATA MANAGEMENT AND DOCUMENT PRESERVATION 8.7 BUDGET 9 RESEARCHER RESPONSIBILITY 10 ANNEXES 11 REFERENCES 12

13 1 INTRODUCTION 1.1 BACKGROUND OF THE MD-PAEDIGREE PROJECT MD PAEDIGREE Mdel-Driven Eurpean Paediatric Repsitry is a research prject funded by the Eurpean Cmmissin under the Virtual Physilgical and Human Area (VPH) f the ICT Theme f the Seventh Framewrk Prgramme (cntract n ). The prject fresees 7 wrldrenwned clinical centres f excellence pursuing imprved interperability f paediatric bimedical infrmatin, data and knwledge, by develping a set f reusable and adaptable multiscale mdels fr mre predictive, individualised, effective and safer paediatric healthcare. The prject is scientifically and technlgically supprted by ne f the leading industrial actrs in medical applicatins in Eurpe, and perating in cnjunctin with highly qualified SMEs and sme f the mst experienced research partners in the Virtual Phisilgical Human (VPH) cmmunity. MD Paedigree validates and brings t maturity patient specific cmputer based predictive mdels f varius paediatric diseases (cardimypathy, risk f cardivascular disease in bese children and adlescents, Juvenile Idipathic Arthritis (JIA) and neurlgical and neurmuscular diseases (NND), thus increasing their ptential acceptance in the clinical and bimedical research envirnment by making them readily available nt nly in the frm f sustainable mdels and simulatins, but als as newly defined wrkflws fr persnalised predictive medicine at the pint f care. MD Paedigree aims t advance the state f the art f patient specific cmputatinal mdelling f different paediatric diseases and translate the latest advances int clinics t imprve disease understanding, therapy utcme, and prvide an infstructure platfrm fr assessing new therapies at the pint f care. MD Paedigree s gals therefre are t integrate and share highly hetergeneus bimedical infrmatin, data and knwledge, using best, jintly develp reusable, adaptable and cmpsable multi scale VPH wrkflw mdels and t supprt evidence based translatinal medicine at the pint f care practices frm the bimedical semantic Web. Illness in infants, children, and adlescents are a large and under appreciated public health prblem. Because paediatric patients nw have a much lnger life expectancy, the burden and csts are substantial fr families and sciety. Fr instance, recent studies have shwn that the number f adult patients with cngenital heart disease is already similar t that f the paediatric ppulatin and will cntinue t grw. It can therefre be stated that in the lnger term the VPH scientific apprach requires a fundamental research investment in paediatrics, where the cnceptual revlutin which is underway, transfrming the nature f healthcare frm reactive t preventive, can best be applied, mving twards an apprach based n persnalised, predictive, preventive, and participatry (P4) medicine, increasingly fcused n wellness. MD Paedigree represents a majr step twards persnalised paediatric e Health, based n datadriven mdels, patient specific simulatins and a sustainable data and mdel repsitry. The prject can in fact impact the way healthcare is practiced in the future. MD Paedigree s impact n dealing with very cncrete and exemplary clinical cases is demnstrated thrugh the fllwing applicatins in the diseases scenaris. MD Paedigree encmpasses cmplete services fr strage, similarity search, utcme analysis, risk stratificatin, and persnalised decisin supprt in paediatrics within its innvative mdel driven data and wrkflw based mdels repsitry, 13

14 leveraging n service and knwledge utilities. It fsters the state f the art f patient specific cmputatinal mdelling f the selected diseases and translates the latest advances int clinics t imprve disease understanding and prvide a platfrm fr testing new therapies at the pint f care. In fact, MD Paedigree demnstrates hw a dedicated VPH repsitry can prvide full accessibility t existing and further develping knwledge in paediatrics t all interested bimedical researchers precisely thrugh linking data with mdels, thus prving the large scale benefits f having bth the data and mdels readily available at the pint f care. The data cllectin perfrmed within Health e Child and Sim e Child prjects (already funded by the Eurpean Cmmissin in previus calls fr prpsals) is still available t the MD-Paedigree cnsrtium thanks t the cntinuity in the ehealth platfrm which is shared by all three prjects. In additin, the new patients recruitment t be perfrmed within MD Paedigree cnsists f: Pathlgy N f patients/time Cardimypathies CVD risk in bese children Juvenile Idipathic Arthritis (JIA) 180 children, by mnth 33: 90 patients (amng which 30 girls) fr each clinical centre. 180 patients, by mnth 36: 90 patients (amng which 30 girls) fr each clinical centre. Altgether 200 patients by mnth 28. Genetic and meta genmic: 180 patients with cardimipathies, 180 with CVD risk in besity, 200 with JIA, and 100 unaffected subjects (cntrl grup). Cerebral Palsy: 50 patients fr each clinical centre fr prbabilistic mdelling, as well as 600 retrspective patients frm KU Leuven and OPBG. NND Spinal Muscular Atrphy (SMA) 20 ambulant patients (severity grade type 3); 10 patients fr each centre fr biphysical mdeling; 10 patients amng the 3a subgrup (symptms f weakness appearing befre age 3 years); 10 patients amng the 3b subgrup (weakness appearing after the age f 3 years. Duchenne Muscular Dystrphy (DMD) Clinical data will be cllected by OPBG, KU Leuven and VUA frm 20 ambulant genetically cnfirmed DMD Patients. 10 patients with an age ranging between 5 and 6 years, additinal 10 patients with an age ranging between 7 and 8 years. 14

15 1.2 BACKGROUND OF THE DATA ACQUISITION AND PROCESSING FOR CARDIOMYOPATHIES STUDY In paediatric cardivascular disease, predicting hw patients will respnd t treatments (peratins, catheter interventins, pharmaclgy), which treatments t use, and when t treat can be difficult t define due t small patient numbers and limited utcme data. When children present with new nset heart failure, there are five pssible utcmes: full recvery, dilated cardimypathy (DCM) requiring drug therapy, DCM requiring transplantatin r mechanical supprt, anther diagnsis (ther frms f cardimypathy, metablic disease) r death. At presentatin, hwever, it is very difficult t predict which grup any patient will end up in. Data suggests that gd systlic functin and yunger age are gd prgnstic indicatrs fr survival [Andrews RE et al., 2008]18, but better prgnsticatrs are necessary. FP7 ICT MD Paedigree Part B 7. Over the last decade, there has been a huge investment int infrmatin technlgy and cmputer mdelling t build mdels f the heart that are able t gather any kind f clinical infrmatin and prduce realistic representatins f the cardivascular system. Mdelling f patient biinfrmatic data may prvide better insight int prgnsis f cardimypathies, which wuld help in patient management and in telling families hw their child will prgress. Wuld he/she recver cmpletely r wuld he/she require heart transplant? These mdels have nw reached high levels f reprducibility, pening new avenues fr mre efficient, safer, and cst effective patient management. Hwever, their cmprehensive validatin is still limited. 2 AIMS OF STUDY 2.1 MAIN GOAL Main bjective f the data acquisitin and prcessing fr cardimypathies study is t evaluate predictrs f cardiac failure in children and adlescents with cardimypathy (CMD) and, by ding s, t prvide clinical, and cardiac structural, gemetrical and functinal data t build a VPH Infstructure data repsitry, t be readily available t clinicians and researchers n CMD in the yuth. MD Paedigree will re use the mdels develped in Health e Child and Sim e Child (research prjects funded by the Eurpean Cmmissin in previus calls fr prpsals, and participated by several MD- Paedigree prject partners) and extend them t cardimypathies. The bjective is t capture the main features f the cardivascular system, including the heart, arteries and peripheral circulatin, t predict cardimypathy prgressin an plan therapies like heart transplant and ventricular assist devices. Investigative data prvided by imaging, pressure mnitring, clinical bservatins and exercise will be used t build these mdels and t validate them, by cmparing mdel predictin with actual utcme. By merging all scattered infrmatin btained frm different diagnstic tls in clinical practice, and btaining a generative mdel f heart functin in children, ur mdel will prvide cardilgists the tls t deliver patients the best pssible medical care. 15

16 2.2 PRIMARY END POINT The primary end pint f the study is the successful cllectin f clinical, labratry and diagnstic data t be subsequently mdelled and simulated by the IT experts. The primary end pint envisages: Enrlment f 180 DCM patients: Enrlment f 180 patients, at baseline, with clinical, labratry and diagnstic tl analysis achieved frm mnth 4 t mnth 20, including echcardigraphic, MRI and exercise test parameters. Re-evaluatin f all patients: All 180 patients enrlled during D3.2 re-evaluated at fllw up (mnth 21 t 36) t evaluate changes in clinical, labratry and cardiac gemetry and functinal parameters. 3 STUDY DESCRIPTION 3.1 STUDY DESIGN The data acquisitin and prcessing fr cardimypathies study is a 33-mnth bservatinal lngitudinal chrt study. The study will be perfrmed in tw chrts f CMD children (ttal N=180). Ninety patients (apprximately 45 girls) fr each clinical Centre will be cnsecutively enrlled. Patients will be evaluated at the baseline (mnth 4 t mnth 20) and re-evaluated between mnth 21 and mnth 36. The study will include clinical evaluatin, labratry testing, genetic testing, and diagnstic testing including functinal class assessment tests (6-minute walk test and cardipulmnary test), as well as imaging mdalities (echcardigraphy and cardiac MRI). Study prtcl details are described belw. SUBJECTS SELECTION Inclusin Criteria: Study chrt will include children and adlescents (age 2-11 and years ld) f bth genders with established diagnsis f acute r chrnic DCM (including bth primary and secndary DCMs). In details inclusin criteria fr the present analysis will be: presence f biventricular heart physilgy, LV ejectin fractin <50% and/r fractinal shrtening <25%, diagnsed by echcardigram, and increased left ventricular end-diastlic diameter >2 standard deviatins frm the expected nrmal limit. Patients will be enrlled in the tw clinical study centers (Ospedale Pediatric Bambin Gesù, University Cllege Lndn). Exclusin Criteria: Patients will be excluded frm the study, in the presence f ne r mre f the fllwing: systemic hypertensin (>95 th percentile fr age and height), persistent high rate supraventricular arrhythmias, pericardial disease (including restrictive and cnstrictive pericarditis), univentricular heart physilgy, cr pulmnale. 16

17 STUDY DESCRIPTION Patients will underg clinical evaluatin, labratry testing, genetic testing, and diagnstic testing. All data will be cllected at baseline and at ne fllw-up visit which will take place after 16 mnths (± 2 weeks), with the exclusin f genetic testing, which will be perfrmed nly nce during the study in a subgrup f selected patients (see exclusin criteria in the genetic testing paragraph fr details). The study will include clinical evaluatin, labratry testing, genetic testing, and diagnstic testing, including functinal class assessment tests (6-minute walk test and cardipulmnary test) as well as imaging mdalities (echcardigraphy and/r cardiac MRI). Study prtcl details are described belw. CLINICAL EVALUATION PROTOCOL Clinical evaluatin will be perfrmed at baseline and during the fllw-up visit it will include past medical histry interview, clinical evaluatin, standard diagnstic testing (X-rays and ECG) and labratry testing. Clinical prtcl details are specified belw. Medical histry interview and clinical symptms - ONSET: acute r chrnic presentatin (Y/N categrical variable) IF CHRONIC: time frm nset f the disease (mnths, cntinuus variable) IF ACUTE: reasn fr referral t cardilgist (e.g. cardimegaly at Chest RX and/r arrhythmias at ECG) (descriptive variable). - SYMPTOMS: cugh (Y/N categrical variable), pr feeding (Y/N categrical variable), irritability (Y/N categrical variable), pallr (Y/N categrical variable), sweating (Y/N categrical variable). - COMORBIDITIES: neurlgical (Y/N categrical variable) muscular disrder (Y/N categrical variable) renal disease (Y/N categrical variable). In all cases, knwn factrs f mycardial damage will be evaluated. In details the three majr causes knwn in paediatric ppulatin with DCMP: viral mycarditis, autimmunity and genetic predispsitin. - DEMOGRAPHICS: age (years, mths) ethnic rigin (categrical variable) previus hspitalizatin (Y/N categrical variable, if yes als include number f episdes and dates when available). 17

18 - TREATMENT: nging treatments (type [categrical variable] and dsage [cntinuus variable]) treatments taken and stpped within 3 mnths befre type [categrical variable] CLINICAL EXAMINATION: Clinical parameters will be cllected. In details: - Symptms severity (System will be applied t assess patients thrughut the entire study perid): NYHA r Rss classificatin as apprpriate [categrical variable], accrding t the fllwing tables: Table 1. NYHA Class. Used fr patients lder than 6 years [Rsenthal et al, Jurnal f Heart and Lung transplantatin, 2004] Class I Class II Class III Class IV Patients with cardiac disease but withut resulting limitatin f physical activity. Ordinary physical activities des nt acute undue fatigue, palpitatin, dyspnea, anginal pain. Patients with cardiac disease with slight limitatin f physical activity. They are cmfrtable at rest. Ordinary physical activities results in fatigue, palpitatin, dyspnea, anginal pain. Patients with cardiac disease resulting in marked limitatin f physical activity. They are cmfrtable at rest. Less than rdinary physical activities results in fatigue, palpitatin, dyspnea, anginal pain. Patients with cardiac disease resulting in inability t carry n any physical activity withut discmfrt. Symptms are present at rest. If any physical activity is undertaken, discmfrt is increased. Table 2. Rss Classificatin. [Rss et al, American Jurnal f Cardilgy, 1987] Class I Class II Class III Patients with cardiac disease but withut resulting limitatin f physical activity. N limitatin r symptms, during feeding. Mild tachypnea r diaphresis with feeding in infants. Dyspnea n exertin in lder children. N grwth failure. Marked tachypnea r diaphresis with feeds r n exertin. Prlnged feeding times. Grwth failure frm cngestive heart failure. 18

19 Class IV Tachypnea, retractins, grunting r diaphresis at rest. Assess stage severity, accrding t Guidelines (n the basis f the histry, symptms and ventricular functin). - Physical examinatin including: Presence f enfrced S3,S4, S2 (Y/N categrical variable) Murmurs: Mitral (Y/N categrical variable, if yes als add grading) Tricuspid ((Y/N categrical variable, if yes als add grading) Liver enlargement and tenderness (Y/N categrical variable, if yes als add grading) Presence f pulmnary rales (Y/N categrical variable). - CLINICAL PARAMETERS INCLUDING: Systlic (SBP) and diastlic bld pressure (DBP) will be measured, using apprpriate cuff sizes, three times while the subjects are seated after resting fr 5 minutes. Measurements will be averaged fr the analysis, accrding t the Furth reprt n the Diagnsis, Evaluatin, and Treatment f High Bld Pressure in Children and Adlescents (t the nearest mm f Hg, cntinuus variable) Weight (in Kg, t the nearest 50g [cntinuus variable]) Height (in m, t the nearest 0.5cm [cntinuus variable]) Heart rate (bpm, [cntinuus variable]) Respiratry rate (bpm, [cntinuus variable]) Saturatin (% [cntinuus variable]). LABORATORY TESTING: - Perfrm baseline labratry bld samplings fr: Haematlgy: red bld cell cunt, haemglbin haematcrit mean cell vlume white bld cell cunt differential white bld cell cunt platelet cunt bichemistry: sdium ptassium chlride creatinine ttal prteins albumin alkaline phspatases AST ALT glycemia LDH 19

20 creatinin phsphkinase (CPK) EGA Metablic disease screening: Acylcarnitine Aminacidemia Ammnemia acid psphatases IEF sialtransferrin Urine analysis and rganic aciduria BNP dsing 0- - Diagnstic testing: 12-lead ECG cardiac rhythm heart rate (bpm ) PR interval (msec) QRS duratin (msec) uncrrected QT duratin (msec) crrected QT duratin applying the Bazett s frmula (msec) Presence f LVH (by either Sklw-Lyn vltage criteria, r Crnell vltageduratin measurement). Chest Xray fr pulmnary cngestin (yes/n) Hlter ECG 24h (mean heart rate, mean daytime heart rate, mean nighttime heart rate, analysis f arrhythmias: supraventricular ectpic beats (yes/n); number (numeric variable), ventricular ectpic beats (yes/n; number (numeric variable), supraventricular tachyarrhythmia (Yes/n), ventricular tachyarrhythmia (yes/n) ESTIMATION OF FUNCTIONAL CLASS AND CARDIOPULMONARY TEST Six minutes walking test (6MWT): the test will measure the distance that the patient can walk n a flat, hard surface in a perid f 6 minutes. It evaluates the glbal and integrated respnses f all the systems invlved during exercise, including the pulmnary and cardivascular systems, systemic circulatin, peripheral circulatin, bld, neurmuscular units, and muscle metablism. Mst patients d nt achieve maximal exercise capacity during the 6MWT; instead, they chse their wn intensity f exercise and are allwed t stp and rest during the test. Since mst activities f daily living are perfrmed at submaximal levels f exertin, the 6MWT reflects with accuracy the functinal exercise level fr daily physical activities. Parameters recrded during the test: The lnger walked distance (meters) Heart rate at the beginning f the test (rest) and maximal heart rate (bpm) Bld pressure at rest and maximal bld pressure (mmhg) Maximal speed (Km/h) Presence/absence f symptms, arrhythmias and electrcardigraphy findings. Cardipulmnary test (CPX). CPX will be perfrmed t analyze gas exchange at rest, during exercise, and during recvery and yield breath-by-breath (BBB) measures f xygen uptake (VO2), carbn dixide utput (VCO2), and ventilatin (VE). Advanced cmputerized systems will prvide bth simple (direct) and cmplex (integrated) analysis f data. Data will be integrated with standard variables measured during exercise testing, including heart rate, bld pressure, wrk rate, electrcardigraphy 20

21 findings, and symptms, t prvide a cmprehensive assessment f exercise tlerance and exercise respnses. Exercise testing is perfrmed n a treadmill fllwing the Bruce Prtcl. Parameters recrded during the test: Time f exercise (minutes) and wrk rate (METs) Heart rate at the beginning f the test (rest) and maximal heart rate (bpm ) Bld pressure at rest and maximal bld pressure (mmhg) Presence/absence f symptms, arrhythmias and electrcardigraphy findings Maximal xygen uptake (VO2) and maximal carbn dixide utput (VCO2) in L/min and expressed as ml/kg/min and Gas Exchange Rate (VO2/VCO2) Ventilatin (VE) in L/min. GENETIC TESTING Patients will underg specific genetic investigatins as DCM can be primary due t an underlying genetic defect. Genetically based DCM is sub-classified int islated DCM and DCM secndary t multisystemic genetic disrders, mstly muscular dystrphies. Islated primary DCMP is rare in paediatric patients and recently numerus genes causative f familial DCMP have been identified. Hwever, these gene mutatins accunt fr abut 20 t 40% f CMPs. After exclusin f secndary causes and apparent absence f secndary multisystemic disrder, the majrity f these patients are yet underdiagnsed and difficult t characterise. DCMP secndary t muscular dystrphies can be familial and accurate histry and first degree relatives physical examinatin and investigatin might reveal mre than ne affected individual in the same family. In the present study all patients will be evaluated by trained clinical geneticists. Metablic investigatins will be perfrmed including baseline bld tests (as specified in the labratry testing sectin). Apparently islated DCM patients will be clinically evaluated by a neurlgist, and, when indicated, specifically tested t exclude systemic neurmuscular disrders, as Duchenne and Becker muscular dystrphies and Barth syndrme. Clinical assessment will include: family histry based n three generatins, with specific enquiry abut heart failure, sudden death, cnductin disrders, strke, muscular dystrphy and related anmalies, sensrineural deafness, muscle weakness; parental cardivascular assessment, evaluatin f muscle bulk and jint cntractures fr ruling ut multisystemic muscular dystrphies. The fllwing cnditins will be excluded frm genetic study: mycarditis investigated by endmycardial bipsy (viral, bacterial r fungal infectins), nutritinal deficiency (Kwashirkr, pellagra, thiamine deficiency, selenium deficiency), cllagen diseases (rheumatic fever, rheumatid arthritis, systemic lupus erythematsus, dermatmysitis, Kawasaki disease), hematlgic diseases (thalassemia, sickle cell disease, irn deficiency anemia), expsure t carditxic drugs (anthracycline, cyclphsphamide, chlrquine, irn verlad), endcrine disrders (hypthyridism, hyperthyridism, hypparathyridism, phechrmcytma, hypglycemia), and metablic disrders except fr Barth syndrme. Exclusin will include anmalus rigin f left crnary artery frm pulmnary artery. 21