Cheryl Doiron. Winnipeg. Robin Casey. Aneal Khan g p multi system sequelae family experiences, clinical outcomes, health system outcomes);. Cheryl Doiron.
The The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) he Ca Canadian ad d a Inherited he ted d Metabolic etabo b l c Diseases seases Research esea ch Network et o k (CIMDRN) ((C ) Establishing a Multidisciplinary Practice Based Research Network to Improve Health Care and Outcomes for Paediatric Inborn Errors of Metabolism Establishing a Multidisciplinary, Practice‐Based Research Network to Improve Health Care and Outcomes for Paediatric Inborn Errors of Metabolism Khangura SS1, Potter B Khangura Potter B1, Chakraborty P Chakraborty P2, Feigenbaum A Feigenbaum A3, Hernandez M Hernandez M4, Kronick J Kronick J3, Little J Little J1, MacKenzie JJ MacKenzie JJ5, Mitchell J Mitchell J6, Prasad C Prasad C7, Rockman Rockman‐Greenberg Greenberg C C8, Wilson B Wilson B1, on behalf of the Canadian Inherited Metabolic Diseases Network (CIMDRN) on behalf of the Canadian Inherited Metabolic Diseases Network (CIMDRN) 1 University of Ottawa 2 Children’ss Hospital of Eastern Ontario, 3 The Hospital for Sick Children, 4 Newborn Screening Ontario, 5 Queen 1 University of Ottawa, 2 Children Hospital of Eastern Ontario 3 The Hospital for Sick Children 4 Newborn Screening Ontario 5 Queen’ss University, 6 McGill University Health Centre, 7 London Health Sciences Centre, 8 University of Manitoba University 6 McGill University Health Centre 7 London Health Sciences Centre 8 University of Manitoba
Background
Objectives & Priority Research Themes Objectives & Priority Research Themes
Inborn errors of metabolism ((IEM)) Inborn errors of metabolism (IEM)
CIMDRN Objj ti CIMDRN Objectives
• A group of >400 genetic congenital metabolic diseases characterized by g p g g y defects in one or more biochemical pathways defects in one or more biochemical pathways
• With core funding from a CIHR Emerging Team Grant (2012‐2017), we have g g g ( ), established a multidisciplinary practice based research network to develop established a multidisciplinary practice‐based research network to develop an evidence‐informed an evidence informed approach to health care for paediatric approach to health care for paediatric IEM that: IEM that:
• Individually rare (birth prevalence 1:10,000 to 1:1,000,000) I di id lly (bi ( th p l 1 10 000 t 1 1 000 000)) • Clinical manifestations range from risk of acute episodic illness to chronic g p multi system sequelae multi‐system sequelae
• focuses focuses on outcomes from the triple aim perspective (patient and on outcomes from the triple aim perspective (patient and family experiences, clinical outcomes, health system outcomes); family experiences, clinical outcomes, health system outcomes);
• TTreatments are typically burdensome and expensive for patients, families, t t typi lly b d d p i f p ti t f ili and society and are traditionally based on presumed pathophysiology and society, and are traditionally based on presumed pathophysiology rather than on empirical evidence (challenging to assemble evidence in rather than on empirical evidence (challenging to assemble evidence in rare disease context) di t t)
• considers considers and integrates a variety of interventions, patient and integrates a variety of interventions patient characteristics and other factors that may influence outcomes; and h i i d h f h y i fl ; d
• Inter Inter‐dependency of health system‐level interventions and clinical dependency of health system level interventions and clinical interventions at the level of individual patient care: interventions at the level of individual patient care:
Programs to support P the development of and access to interventions
Cli i l i t Clinical interventions ti
Coordination of care delivery care delivery (e g multi disciplinary (e.g., multi‐disciplinary team care regional team care, regional centres) )
Individual patient care: Individual patient care: orphan drugs (e g enzyme orphan drugs (e.g., enzyme replacement therapy), l t th ) medical foods, dietary supplements, organ pp , g replacement, stem cell replacement, stem cell therapies therapies
Biological research to inform treatment; ; diagnostic technologies & diagnostic technologies & facilities
Calgary Robin Casey Robin Casey Aneal Khan
Vancouver S l i S kl Sylvia Stockler Hilary Vallance Hilary Vallance
Edmonton Ed t Alicia Chan Alicia Chan
Winnipeg Marni Brownell Ch l G Cheryl Greenberg b Aziz Mhanni Aziz Mhanni Toronto Annette Feigenbaum Astrid Guttman d Jonathan Kronick Jonathan Kronick Fiona Miller Fiona Miller Komudi Siriwardena
• emphasizes emphasizes research themes that capture the highest priority questions research themes that capture the highest priority questions across IEM regarding both clinical care and health policy. IEM di b th li i l d h lth li
• Integrative research themes that guide our work: Integrative research themes that guide our work: 1 Cli 1. Clinical heterogeneity and personalized care: Manifestations of many i lh t it d li d M if t ti f IEM range from mild forms that may require little intervention to severe IEM range from mild forms that may require little intervention to severe forms with high risk for morbidity and mortality. There is a need to g y y tailor approaches to health care to account for the needs of individual tailor approaches to health care to account for the needs of individual patients patients. 2 Paradigm 2. Paradigm shift from shift from “urgent urgent care care” to to “opportunity opportunity for improvement for improvement”:: Traditional treatment goals for many IEM focused on prevention of Traditional treatment goals for many IEM focused on prevention of catastrophic outcomes. Improvements in available treatments have t t hi t I t i il bl t t t h meant that more patients are surviving with future severe sequelae meant that more patients are surviving with future severe sequelae, leading to a shift in goals toward achievement of optimal outcomes. g g p 3. Comparative Comparative effectiveness: effectiveness: Treatments for IEM are developing rapidly. Treatments for IEM are developing rapidly. W We need to critically evaluate the comparative effectiveness of dt iti lly l t th p ti ff ti f emerging with established therapies focusing on outcomes across the emerging with established therapies, focusing on outcomes across the triple aim. triple aim.
Secondary prevention for Secondary prevention for early diagnosis & treatment l di i &t t t (e.g., newborn screening)
CIMDRN Practice Based Research Framework CIMDRN Practice‐Based Research Framework
AIM 1 AIM 1 I Improve experiences i
AIM 2 AIM 2 Improve Improve clinical outcomes clinical outcomes
AIM 3 AIM 3 Manage health Manage health system impacts system impacts
C. In In‐depth depth analysis: analysis: “Case Case Study Study” IEM
Research objectives h bj i
• focuses on a range of outcomes. f f t
B. Associations between interventions and outcomes for selected IEM, incorporating natural , p g history models history models
• Relevant outcomes include those described by Berwick et al.’s “triple aim” l l d h d b d by k l ’ “ pl ” framework as the goals for effective health care systems (Health Affairs framework as the goals for effective health care systems (Health Affairs, 2008):
• Randomized Randomized controlled trials (RCTs) are important for establishing efficacy controlled trials (RCTs) are important for establishing efficacy of clinical interventions but are not always feasible/appropriate: f li i l i t ti b t t l f ibl / i t
A Population‐based outcomes: broad range of IEM A. Population‐based outcomes: broad range of IEM
Priority y research research themes
THEME 1 Clinical heterogeneity Clinical heterogeneity
THEME 2 Opportunity for Opportunity for improvement
THEME 3 Comparative Comparative effectiveness
Research platform: p patient/family‐reported outcomes, clinical information, health p / y p , , care use data provincial policy information care use data, provincial policy information
• Rarity of IEM means number of patients available for study is small R i y f IEM b fp i il bl f dy i ll • Traditional Traditional RCTs do not account well for clinical heterogenetiy RCTs do not account well for clinical heterogenetiy nor nor complexity of co‐interventions embedded in systems of care l it f i t ti b dd d i t f • M Multiple approaches will be needed to generate the evidence required to l ipl pp h ill b d d g h id q i d inform effective and appropriate care for children with IEM inform effective and appropriate care for children with IEM
“Practice‐based Practice‐based evidence evidence” • Clinical Clinical evaluative research in a real‐world setting: rigorous observational evaluative research in a real world setting rigorous observational evidence (Westfall et al 2008 JAMA; Horn & Gassaway 2010 Med Care) evidence (Westfall et al., 2008, JAMA; Horn & Gassaway, 2010, Med Care) • “P “Practice‐based evidence… accommodates multiple concurrent ti b d id d t lti l t interventions and patient characteristics that reflect actual clinical interventions and patient characteristics that reflect actual clinical practice, using data from natural settings to describe the content p , g f g and timing of treatments that are associated with better outcomes and timing of treatments that are associated with better outcomes (including patient reported outcomes) for patients with specific (including patient reported outcomes) for patients with specific characteristics.” h i i ” ((Horn & Gassaway, 2010, p.S17). &G y, 20 0, p S ) • Identifying Identifying the best interventions at the appropriate times for the the best interventions at the appropriate times for the appropriate patients: personalized care (Feero pp p p p l d ( et al, 2008, l, , J Am Med Inform Assoc) J Am Med Inform Assoc)
Staff/Trainees Monica Hernandez Maria Karaceper Sara Khangura Ashley Orton Ashley Orton Yannis Trakadis Yannis Trakadis
Research Platform Research Platform • Our Our platform has some commonalities with traditional disease registries: platform has some commonalities with traditional disease registries: observational data, multi‐centre, observational data, multi centre, flexible, population flexible, population‐based, based, longitudinal; longitudinal; • But But it is explicitly research driven, to create generalizable knowledge; all it is explicitly research driven to create generalizable knowledge; all d data collected will be guided by our research framework. ll d ill b g id d by hf k • Approximately 1,000 children will be eligible, across 16 practice centres. pp o ate y ,000 c d e be e g b e, ac oss 6 p act ce ce t es • Participants Participants will include a population will include a population‐based based cohort of nearly all Canadian cohort of nearly all Canadian children born between 2006‐2015 and diagnosed with one of 27‐30 IEM: hild b b t 2006 2015 d di g d ith f 27 30 IEM Proposed IEM (others may yet be added) Proposed IEM (others may yet be added) Argininosuccinic g acidemia ((argininosuccinate g lyase y deficiency, ASA), Citrullinemia y, ), ((argininosuccinic g acid synthetase y deficiency), Carbamyl y), y p phosphate synthetase p y ((CPS1) deficiency, N‐acetylglutamate ) y, yg synthetase y ((NAGS) ) deficiency, Ornithine transcarbamylase y, y ((OTC) deficiency, Arginase ) y, g ((AG) deficiency, Homocystinuria: CBS ) y, y deficiency, Maple syrup urine disease (MSUD), Phenylalanine hydroxylase (PAH) deficiency: phenylketonuria deficiency, Maple syrup urine disease (MSUD), Phenylalanine hydroxylase (PAH) deficiency: phenylketonuria (PKU) and non‐PKU (PKU) and non PKU hyperphenylalaninemia hyperphenylalaninemia (non (non‐PKU PKU HPA), Tyrosinemia HPA), Tyrosinemia (Type I) (Type I)
Organic acid disorders Organic acid disorders ß‐Ketothiolase ß Ketothiolase (BKT) deficiency, Glutaric (BKT) deficiency Glutaric acidemia type I (GAI), HMG‐CoA lyase type I (GAI) HMG CoA lyase Deficiency, Isovaleric Deficiency Isovaleric acidemia (IVA) 3 Methylcrotonyl CoA carboxylase (3MCC) deficiency Methylmalonic acidemias (methylmalonyl‐CoA (IVA), 3‐Methylcrotonyl‐CoA carboxylase (3MCC) deficiency, Methylmalonic (methylmalonyl CoA mutase deficiency; cobalamin deficiency; cobalamin defects), Multiple carboxylase deficiency (MCD), Propionic acidemia defects) Multiple carboxylase deficiency (MCD) Propionic acidemia (PA)
Carnitine C i i uptake defect (CUD), Long‐chain 3‐hydroxyacyl‐CoA dehydrogenase (LCHAD) deficiency, Medium chain k d f (CUD) L h i 3h d l C Ad h d (LCHAD) d fi i M di h i acyl‐CoA dehydrogenase (MCAD) deficiency, Trifunctional l d h d ( ) d fi i if i l protein (TFP) deficiency, Very long‐chain acyl‐CoA i ( ) d fi i l h i l dehydrogenase (VLCAD) deficiency
Galactosemia (GALT), excluding epimerase and kinase deficiency, Biotinidase deficiency, Hurler disease (MPS 1), Glycogen storage disease type 1 (GSD1, types A and B), pyridoxine‐dependent epilepsy
• Interventions for IEM would ideally be evaluated in a way that: I t ti f IEM ld id ll b l t di th t
• Managing health system impacts M i h lth t i t
Halifax Linda Dodds Linda Dodds Sarah Dyack y
Oth di d Other disorders
Evaluative evidence to support improved care & outcomes for IEM Evaluative evidence to support improved care & outcomes for IEM
• Improving clinical health outcomes Improving clinical health outcomes
Quebec City & Sh b k Sherbrooke Bruno Maranda Bruno Maranda
Fatty acid oxidation disorders Fatty acid oxidation disorders The “TRIPLE AIM” AIM
• Improving patient experiences with care Improving patient experiences with care
St. John’s Lesley Turner
External Advisory Board External Advisory Board Darren Bidulka Tim Caulfield Joseph Clarke Cheryl Doiron Cheryl Doiron Khaled El Emam Khaled El Emam Jane Evans Alex Kemper Wilma McCormack A Anne Stephenson S h
Amino acid / urea cycle disorders i id / l di d
N d f E id Need for Evidence
• accommodates the interaction between clinical care and the health d h b l l d h h lh system and; system and;
Montreal John Mitchell G t Mit h ll Grant Mitchell Meranda Nakhla
Ottawa Pranesh Chakrabortyy Doug Coyle Deshayne Fell London Michael Geraghty i h lG h Chitra Prasad Kingston Julian Little Julian Little K h S Kathy Speechley hl Jennifer MacKenzie Beth Potter Beth Potter Hamilton Brenda Wilson Murray Potter M P tt Kumanan Wilson
United States Scott Grosse
• Integrating Integrating our research themes with the need to consider complex, multi‐ our research themes with the need to consider complex multi‐ level interventions in a multidisciplinary practice‐based context, this p yp , framework guides our program of research: framework guides our program of research:
Funded by: (TR3 119195)) ((TR3-119195)
CIMDRN Investigators
Priority research themes Priority research themes
Interventions to improve care for IEM Interventions to improve care for IEM
System‐level interventions System‐level interventions
Our Network: Participating Centres &Team Members Our Network: Participating Centres &Team Members
Research Program Research Program • Guided Guided by our practice‐based research framework, our initial program will by our practice based research framework our initial program will focus on three key objectives: focus on three key objectives: A To A. To describe the distribution of clinical, patient describe the distribution of clinical patient‐centred centred, and health and health system outcomes for Canadian children with a broad range of IEM; y f d h ld h b d g f ;
Data Collection and Analysis Data Collection and Analysis • For participating children and families, with consent, we will assemble, link For participating children and families with consent we will assemble link and analyze existing observational data from multiple sources: d ly g b ld f l pl Data source Data source
Type of information Type of information
Health care H lth administrative data administrative data
Method of collection Method of collection
Health services (physician, H lth i ( h i i emergency, hospital care) emergency, hospital care)
EExisting datasets linked at i ti d t t li k d t individual level individual level
Patient charts: Patient charts: Clinical interventions and Clinical interventions and participating treatment outcomes participating treatment centres
Abstracted by a study Abstracted by a study research coordinator with research coordinator with families’ p permission
Clinic level data from Clinic‐level data from participating centres participating centres
Organization of care Organization of care
Reported by clinical Reported by clinical investigators
Patient and Patient and family‐reported y p information
Quality of life, Q alit of life experiences with care, p , psychosocial outcomes psychosocial outcomes
Patient/family surveys, Patient/famil s r e s qualitative data q
Provincial policy Provincial policy information
Newborn screening, Newborn screening access to therapies p
Interviews with Interviews with decision‐makers
CIMDRN’ss Value and Contributions CIMDRN Value and Contributions • CIMDRN’s research will: CIMDRN’ h ill
B. To To investigate the association between patterns of clinical and health investigate the association between patterns of clinical and health system interventions and these outcomes for a smaller set of IEM. We t i t ti d th t f ll t f IEM W will account for differences in patient characteristics and disease will account for differences in patient characteristics and disease severity and use natural history models to generate robust estimates; severity and use natural history models to generate robust estimates;
• llead to specific recommendations for delivering health services to d p ifi d i f d li i g h l h i children with IEM; children with IEM;
C To C. To investigate each priority research theme through investigate each priority research theme through “Case Case Studies Studies”. Th These in‐depth analyses will focus on sets of research questions that i d ph ly ill f f hq i h serve to answer key questions about particular IEM and provide insight serve to answer key questions about particular IEM and provide insight into the theme as a whole. into the theme as a whole.
• yield yield insights generalizable across IEM, to other rare diseases, and to insights generalizable across IEM to other rare diseases and to personalized and patient‐centred personalized and patient centred care; care;
• Our Our research platform, framework, and network are sustainable tools that research platform framework and network are sustainable tools that can accommodate new research questions, themes, and IEM in the future. d hq , h , d h f
• provide an empirical foundation to support personalized health care id i i lf d ti t t li d h lth decisions and improve understanding of system impacts; decisions and improve understanding of system impacts;
• establish establish a sustainable research network in paediatric IEM that will a sustainable research network in paediatric IEM that will continue to produce high‐quality policy‐ p g q y p y and clinically‐relevant y research research. • For additional information, visit www.cimdrn.ca F dditi li f ti i it i d
Administered and supported pp t d b by: y
