evidence review workgroup advisory committee on heritable disorders in newborns and children report...
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Evidence Review WorkgroupEvidence Review WorkgroupAdvisory Committee on Heritable Disorders in Advisory Committee on Heritable Disorders in
Newborns and ChildrenNewborns and ChildrenReport November 2008Report November 2008
James M. Perrin, MDJames M. Perrin, MDProfessor of Pediatrics, Harvard Medical SchoolProfessor of Pediatrics, Harvard Medical SchoolDirector, MGH Center for Child and Adolescent Director, MGH Center for Child and Adolescent
Health PolicyHealth Policy
Current Progress and ActivitiesCurrent Progress and Activities
Pompe Disease – Final report submittedPompe Disease – Final report submitted
SCID – Discussion todaySCID – Discussion today
Krabbe Disease – Review in processKrabbe Disease – Review in process
SCID Report SCID Report
Key authors:Key authors:– Ellen Lipstein, MDEllen Lipstein, MD– Alix Knapp, MSAlix Knapp, MS
Program director:Program director:– James M. Perrin, MDJames M. Perrin, MD
Staff:Staff:– Marsha Browning, MD, Marsha Browning, MD,
MPHMPH– Alex R. Kemper, MD, Alex R. Kemper, MD,
MPH, MS MPH, MS – Nancy Green, MDNancy Green, MD– Lisa Prosser, PhDLisa Prosser, PhD– Denise Queally, JDDenise Queally, JD– Jennifer DeZarn, BAJennifer DeZarn, BA– Sienna Vorono, BASienna Vorono, BA
Severe Combined Severe Combined Immunodeficiency (SCID)Immunodeficiency (SCID)
Group of disorders characterized by absence of Group of disorders characterized by absence of both humoral and cellular immunityboth humoral and cellular immunity
Severe defect in T cell production and function, Severe defect in T cell production and function, with additional defects in B-lymphocytes and/or with additional defects in B-lymphocytes and/or NK cells depending on the mutated gene NK cells depending on the mutated gene
At least 15 genes cause SCID when mutated At least 15 genes cause SCID when mutated
As protection from maternal antibodies wanes, As protection from maternal antibodies wanes, infants with SCID develop infections due to both infants with SCID develop infections due to both common and opportunistic pathogens common and opportunistic pathogens
Rationale for ReviewRationale for Review
Without treatment SCID leads to death in early Without treatment SCID leads to death in early childhoodchildhood
Earlier treatment, particularly before the onset Earlier treatment, particularly before the onset of lung infection, may decrease mortality and of lung infection, may decrease mortality and morbidity associated with SCID and with morbidity associated with SCID and with treatmenttreatment
Methods to screen infants for SCID using Methods to screen infants for SCID using quantitative PCR for T-cell receptor excision quantitative PCR for T-cell receptor excision circles (TREC) have been developedcircles (TREC) have been developed
Methods of ReviewMethods of Review
Systematic literature review, summarizing Systematic literature review, summarizing the evidence available from published the evidence available from published studies studies
Assessment of critical unpublished data Assessment of critical unpublished data and data presented at meetings from key and data presented at meetings from key investigators investigators
Key Review QuestionsKey Review Questions
Incidence/prevalenceIncidence/prevalenceNatural historyNatural history– Timing of clinical onsetTiming of clinical onset– Severity of disease and variationsSeverity of disease and variations– Genotype/phenotype Genotype/phenotype
ScreeningScreening– Methods of screening Methods of screening – Accuracy of screening; sensitivity/specificityAccuracy of screening; sensitivity/specificity– Methods of diagnosisMethods of diagnosis– Risks and costsRisks and costs
Key Review Questions IIKey Review Questions II
TreatmentTreatment– MethodsMethods– Does treatment help?Does treatment help?– Does early treatment help?Does early treatment help?– AvailabilityAvailability– Risks and costsRisks and costs
Critical information still neededCritical information still needed
Materials Provided/AvailableMaterials Provided/Available
Draft review summaryDraft review summary
Evidence table/abstracted articlesEvidence table/abstracted articles
Bibliography of all identified articlesBibliography of all identified articles
List of intervieweesList of interviewees
Systematic ReviewSystematic Review
January 1988- October 2008: Medline, OVID In-Process January 1988- October 2008: Medline, OVID In-Process and Other Non-Indexed Citations database and Other Non-Indexed Citations database – English language onlyEnglish language only– Human studies onlyHuman studies only– Eliminated: non-human data, reviews, editorials or other opinion Eliminated: non-human data, reviews, editorials or other opinion
pieces, case-series of <4 patients, only contained adult subjects pieces, case-series of <4 patients, only contained adult subjects or not addressing one or more of the key questions or not addressing one or more of the key questions
– References also from nomination form, reviewsReferences also from nomination form, reviews
725 abstracts selected for initial review725 abstracts selected for initial review60 articles selected for review and abstraction60 articles selected for review and abstraction
Quality assessment directed toward study designQuality assessment directed toward study design
Papers Meeting Review CriteriaPapers Meeting Review Criteria
Study Design Number of papers
Experimental intervention 0
Cohort study 11
Case-control study 8
Case series total 38
Sample size ≤ 10 11
Sample size 11 to 50 18
Sample size ≥ 51 9
Economic Evaluation 1
Other design 2*
Total 60*Epidemiologic studies using retrospective record review (Jones et al. 1991) and telephone survey (Boyle & Buckley, 2007)
Additional Expert CommunicationAdditional Expert Communication
Determined by literature review, Determined by literature review, discussion with genetic expertsdiscussion with genetic experts
Included experts representing all major Included experts representing all major issues related to SCIDissues related to SCID
Experts ContactedExperts ContactedMei Baker - Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin; Newborn Screening Program, Wisconsin State Laboratory of Hygiene
Tony (Francisco) Bonilla - Harvard Medical School and Children’s Hospital, Boston, Mass
Rebecca Buckley -Duke University Medical Center, Durham, North Carolina
Anne Comeau -Deputy Director New England Newborn Screening Program University of Massachusetts
Lisa Filipovich -Cincinnati Children's Hospital Medical Center
Alain Fischer -Pediatric Immunology Department and the INSERM Research Unit
Alan P. Knutsen -Pediatric Clinical Immunology Laboratory, St Louis University Health Sciences Center
Ronald Laessig -Population Health Sciences and Pathology, University of Wisconsin
Edward McCabe -Clinical Biochemical Genetics, Department of Pediatrics, Mattel Children’s Hospital at UCLA
Sean McGhee -Division of Pediatric Immunology, David Geffen School of Medicine at UCLA
Luigi Notarangelo -Division of Immunology, Children's Hospital Boston, Harvard Medical School
Hans Ochs -Pediatrics and Immunology, University of Washington
Sung-Yun Pai - Harvard Medical School and Children’s Hospital, Boston, Mass
Ken Pass -Molecular Medicine, New York State Department of Health, Albany, New York
Jennifer Puck -Department of Pediatrics, Institute for Human Genetics University of California, San Francisco
Robert Vogt -Centers for Disease Control and Prevention, Newborn Screening Quality Assurance Program, Atlanta, Georgia
IncidenceIncidence
Chan/Puck 2005 Chan/Puck 2005 – 1:105,000 live births 1:105,000 live births
Extrapolation from XSCID samples sent to single Extrapolation from XSCID samples sent to single lablab
Stephan et al., 1993Stephan et al., 1993– 1:100,000 live births1:100,000 live births
Based on 5 years of referrals to specialized units in Based on 5 years of referrals to specialized units in FranceFrance
Jones et al., 1991Jones et al., 1991– 52/100,000 births in Navajo families52/100,000 births in Navajo families
Quality Assessment of Abstracted Quality Assessment of Abstracted Natural History LiteratureNatural History Literature
Genotype/Phenotype Correlation 12
Data from retrospective screening studies in U.S. or similar population.
0
Data from systematic studies other than whole population screening.
5
Estimated from the known clinical features of the condition as described for individual cases or short series.
7
Incidence (cases per 100,000), average within the U.S. 4
Data obtained from whole-population screening or comprehensive national surveys of clinically detected cases.
1
Ia. As in I but more limited in geographical coverage or methodology.
2
Extrapolated from class I data for non-U.S. populations. 0
Estimated from number of cases clinically diagnosed in U.S. 1
Adapted from Pandor et al. 2004, Pollitt et al. 1997
Natural HistoryNatural History
Except for children diagnosed early in life, Except for children diagnosed early in life, because of affected sibling, most children are because of affected sibling, most children are diagnosed after recurrent (pulmonary) infections diagnosed after recurrent (pulmonary) infections All SCID subtypes exhibit infection with All SCID subtypes exhibit infection with opportunistic organisms, although timing of opportunistic organisms, although timing of onset may varyonset may varyWithout treatment of underlying Without treatment of underlying immunodeficiency, children with SCID die in immunodeficiency, children with SCID die in early childhood from infectionearly childhood from infectionKnown phenotype/genotype differences do not Known phenotype/genotype differences do not affect main findings related to infection and affect main findings related to infection and deathdeath
Quality Assessment of Abstracted Screening Quality Assessment of Abstracted Screening Test Characteristic LiteratureTest Characteristic Literature
Adapted from Pandor et al. 2004, Pollitt et al. 1997
Overall sensitivity and specificity of screening & false-positive rate 3
Data obtained from screening programs in U.S. population or similar. 0
Data from systematic studies other than from whole population screening. 3
Estimated from the known biochemistry of the condition. 0
Repeat specimen rate 0
Data obtained from screening programs in U.S. population or similar. 0
Data from systematic studies other than whole population screening. 0
Estimated from the known biochemistry of the condition. 0
Second-tier testing 1
Data obtained from screening programs in US population or similar. 0
Data from systematic studies other than whole population screening. 1
Estimated from the known biochemistry of the condition. 0
Main Screening MethodsMain Screening Methods
Whole blood lymphocyte countsWhole blood lymphocyte counts
Quantitative polymerase chain reactionQuantitative polymerase chain reaction
Enzyme-linked immunosorbent assay Enzyme-linked immunosorbent assay (ELISA) of dried blood spots(ELISA) of dried blood spots
Screening TestScreening Test
Chan, Puck 2005
23 children with SCID2 children with non-SCID immunodeficiencies242 anonymized newborn screening cards
DNA amplification of TREC from dried blood spot Among children known to have SCID, none had detectable levels of TREC and all had detectable β-actin. 2 children with non-SCID immunodeficiency had detectable TREC.
*False positive rate: 1.5% from routine nurseries;5% from special-care nurseries. ^Sensitivity: 84%-100% ^Specificity: 97-97.1%
Hague et al. 1994
135 total children: 45 with SCID; 90 without
First available lymphocyte count; cut-off of 2.8x109/l indicates SCID Children with SCID had significantly lower levels of lymphocytes. Unlike the 5 control children with low lymphocyte count, low lymphocyte count persisted in children with SCID
*False-positive rate: 8%^Sensitivity: 86.3%, and ^Specificity: 94.4%
Hennewig et al. 2007
36 children with rotavirus gastroenteritis; 18 with SCID 18 without SCID
Lymphocyte study SCID children more likely to have low WBC count:10/18 vs. 0/18, eosinophilia: 12/18 vs. 0/18 relative lymphopenia: 17/18 vs. 10/18absolute lymphopenia:16/18 vs. 4/18
^Sensitivity: 55.6% to 94.4% ^Specificity: 44.4% to 100%.
(Second-tier testing)
McGhee et al. 2005
13 children with SCID 183 anonymized dried blood spots, presumed to be from children without SCID
Dried blood spot study Evaluated 2-tiered screening approach first measuring IL-7 and then TREC only those with elevated IL-7
*Combined specificity of 100% (confidence interval, 97-100%) *Combined sensitivity of at least 85%
*Calculation stated in article ^Our calculation using data provided in article
Study Population Screening MethodsAccuracy of Screen; Sens/Spec.
Wisconsin Screening ExperienceWisconsin Screening ExperienceNumber Screened: 47,250 (01/01/2008-08/31/2008)
Abnormal Results: 20
o Premature (<37 weeks) 11 (0.023%)
o Full term 9 (0.019%)
Inconclusive Results 76
o Premature (<37 weeks) 57 (0.121%)
o Full term 19 (0.040%)
Courtesy of Dr. Mei Baker, presented at the Newborn Screening Symposium, November 2008
Abnormal Results: Inconclusive Results:
1 DiGeorge Syndrome1 Downs Syndrome with sepsis at birth1 Idiopathic T-cell lymphopenia1 Leukocyte migration defect4 normal Flow Cytometry results9 normal results on repeated newborn
screening2 pending cases1 expired case
1 DiGeorge Syndrome59 normal results on repeated newborn
screening2 pending cases14 expired cases
Treatment MethodsTreatment Methods
Over the last twenty years, three modes of Over the last twenty years, three modes of treatment for SCID have been treatment for SCID have been investigated: investigated: – Allogeneic hematopoietic stem cell transplant Allogeneic hematopoietic stem cell transplant
(HSCT) including bone marrow transplant (HSCT) including bone marrow transplant (BMT)(BMT)
– Enzyme replacement therapy (ERT) for some Enzyme replacement therapy (ERT) for some patients with ADA-deficient SCIDpatients with ADA-deficient SCID
– Small trials of gene therapySmall trials of gene therapy
Quality Assessment of Abstracted Quality Assessment of Abstracted Treatment LiteratureTreatment Literature
Adapted from Pandor et al. 2004, Pollitt et al. 1997
Effectiveness of treatment 47
I. Well-designed RCTs. 0
II-1. Well-designed controlled trials with pseudorandomization or no randomization.
0
II-2. Well-designed cohort studies: 8
A. prospective with concurrent controls 0
B. prospective with historical control 1
C. retrospective with concurrent controls. 7
II-3. Well-designed case-control (retrospective) studies. 0
III. Large differences from comparisons between times and/or places with and without intervention
4
IV. Opinions of respected authorities based on clinical experience, descriptive studies and reports of expert committees.
35
Does Treatment for SCID Help?Does Treatment for SCID Help?
Efficacy of HSCT over time: Large case-seriesEfficacy of HSCT over time: Large case-series
Buckley et al. 1999Case series
89 children treated with HSCT between 1982 and 1998
72 (81%) survived to follow-up (median follow-up 5.6 years)HLA-identical transplant from a related donor: 12/12 (100%) survivedT-cell depleted haplo-identical: 60/77 (78%) survivedSurvival not statistically related to genotypeSurvival varied by race (white more likely to survive) and gender (all girls
survived)36 children developed GVHD; most cases of GVHD required no
treatment.
IV
Stephan et al. 1993*Case series
117 patients treated for SCID between 1970 and 1992; 85 with bone marrow transplant
HLA-identical transplant from a related donor 21/25 (84%) survived)Pheno-identical transplant (HLA genotypically haplo-identical) from
related donor 2/5 (40%) survivedHLA haplo-identical transplant without T-cell depletion 0/5 (0%) survivedT-cell depleted haplo-identical transplant 28/50 (56%) survived22 children did not receive any type of transplant and died 10 received fetal liver transplant, 9 died post transplant
IV
van Leeuwen et al. 1994 *Case series
31 patients between the ages of 1-94 months; BMT
HLA-identical related: 6/10 (60%) survivedHLA haplo-identical related: 9/19 (47%) survivedHLA-matched unrelated: 0/2 (0%) survived
IV
Study Population Significant Findings
Quality of Evidence
* Potential patient overlap with Stephan et al. 1993 and van Leeuwen et al. 1994
Does Treatment for SCID Help?Does Treatment for SCID Help?
Antoine et al. 2003; Fischer et al. 1990Cohort study
475 patients (566 transplants) from 37 European centers; 1968 to 1999
Three-year survival with sustained engraftment was 77% for HLA-identical and 54% for HLA-non-identical transplants
Survival has improved over time for both HLA-identical and HLA-non-identical transplant recipients
SCID phenotype was not associated with difference in survivalLung infection before HSCT and absence of a protective environment
significantly affected outcome
II-2 C, IV
Cavazzana-Calvo et al. 2007Case series
31 children 10-27 years post-transplant: focus on factors associated with long-term T-cell reconstitution
Myeloablation patients more likely to have evidence of donor-derived granulocytes and persistent naïve T-cells, as measured by TREC.
60% of TREC+ and 45% of TREC- had no clinical manifestations, at average follow-up in the TREC+ group was 13 years and in the TREC- was 16 years
IV
Friedrich, Honig & Muller 2007 Cohort study
7 children with SCID receiving HLA-identical transplant, 25 with HLA-haploidentical transplant, all at least 10 years out from transplant
3 patients’ T-cell numbers were decreased4 patients’ PHA responses were decreased (all in HLA-haploidentical
group and no chemotherapy)HLA-haploidentical with no conditioning had lower levels of naïve CD4+
cells and impaired B cell functioning
IV
Study Population Significant Findings
Quality of Evidence
Survival after HSCT: Long-term follow-up Survival after HSCT: Long-term follow-up
Does Treatment for SCID Help?Does Treatment for SCID Help?
Gennery et al. 2001Case series
19 children treated from 1987-1998 using CAMPATH-1MT depleted BMT for SCID
19/30 children survived longer than 1 year post-BMTMost deaths attributed to pre-existing infection17 had normal immune function following transplantation
IV
Haddad et al. 1998Case series
193 patients from 18 European centers between 1982 and 1993: focus on immune reconstitution
116 alive with evidence of engraftment 5 months after BMT. 24 later died (20%)
T-cell function improved during the 2 years after BMT and continued to be better than B-cell function
Poor outcomes associated with: absence of T-cell reconstitution, presence chronic GVHD 6 months after transplant, B- SCID (multivariate analysis)
At last follow up (median, 6 years after transplant), 93% had normal T-cell function and 68% had normal B-cell function
IV
Slatter et al. 2008Cohort study
36 children treated with BMT with depletion of T-cells from non-identical donor
No significant survival difference between children receiving transplants depleted using anti-CD52 or anti-CD34 antibodies
5 patients in the anti-CD52 group and 2 in anti-CD34 group had GvHD
II-2 C
Study Population Significant Findings
Quality of Evidence
Additional Long-term follow-up studiesAdditional Long-term follow-up studies
Does Early Treatment Help?Does Early Treatment Help?
Buckley et al. 1999*
Case series
22 infants transplanted prior to 3.5 months of life67 infants transplanted later than 3.5 months of life
21/22 (95%) infants alive at follow-up 51/67 (76%) who received transplants at 3.5 months or older survived to follow-up
Median follow-up 5.6 years (range 3 months -16.5 years)
IV
Kane et al. 2001
Case series
13 children transplanted between 7 and 68 days-old
All patients alive and well 0.5-11.5 years post-transplant (median 3 years).
children required more than one transplantAll children achieved neutrophil engraftment and normal levels of
IgA, 7 have normal IgG, 12 have normal IgM10/12 maintained normal development, of the other two: 1/12 has
developmental problems and 1/12 has motor delay
IV
Myers et al. 2002*
Cohort study
21 children transplanted prior to 28 days of life (early treatment)96 children transplanted at a median age of 190 days (range 45-516) (late treatment)
20/21 (95%) early treatment children survivedOne ADA-deficient patient died of CMV despite successful
engraftment71/96 (74%) late treatment children survivedMean time to significant T-cell function in all early treatment was 33
days and to normal T-cell function was 103 daysMean TREC value peaked earlier post-transplant for early treatment
recipients but the 2 groups were indistinguishable by 5 years
II-2 C
* Potential patient overlap of Myers et al. 2002, Buckley et al. 1999
Study Population Significant FindingsQuality of Evidence
Efficacy of HSCT in neonates/infantsEfficacy of HSCT in neonates/infants
Early Treatment for SCIDEarly Treatment for SCID
Graph 1A. Transplanted in First 3.5 Months of Life Graph 1B. Transplanted after First 3.5 Months of Life
Years Post-TransplantationYears Post-Transplantation
Per
cent
Sur
vivi
ng
The Kaplan-Meier graphs from Dr. Buckley (with permission)
161 SCID infants transplanted over the past 26 161 SCID infants transplanted over the past 26 years, overall survival rate of 125/161 (78%) years, overall survival rate of 125/161 (78%)
survival rate 71%survival rate 71%survival rate 96%survival rate 96%
Treatment for SCID: AvailabilityTreatment for SCID: Availability
From SCID expert interviews:From SCID expert interviews:– Dr. Buckley reports there are fifteen major and 34 Dr. Buckley reports there are fifteen major and 34
minor centers in the U.S. and Canada currently minor centers in the U.S. and Canada currently performing stem cell transplantation for SCID. performing stem cell transplantation for SCID.
– Dr. Notarangelo, Bonilla, and Pai stated that an Dr. Notarangelo, Bonilla, and Pai stated that an informal survey performed under the auspices of the informal survey performed under the auspices of the NIAID/Rare Diseases workshop identified 34 centers NIAID/Rare Diseases workshop identified 34 centers in the United States and Canada that currently in the United States and Canada that currently perform HCT for SCIDperform HCT for SCID
Harms and Cost-effectivenessHarms and Cost-effectiveness
Screening and DiagnosisScreening and Diagnosis– No studies identifiedNo studies identified
DiagnosisDiagnosis– None identifiedNone identified
Treatment (2 studies)Treatment (2 studies)– 8/41 children undergoing HSCT developed auto-immune 8/41 children undergoing HSCT developed auto-immune
hemolytic anemia; 3 died from complications hemolytic anemia; 3 died from complications – 4 children (of the 9/10 who had successful gene therapy) 4 children (of the 9/10 who had successful gene therapy)
developed leukemia between 30 and 68 months after gene developed leukemia between 30 and 68 months after gene therapy. 3/4 were successfully treated with chemotherapy and therapy. 3/4 were successfully treated with chemotherapy and regained poly-clonal T-cell populationsregained poly-clonal T-cell populations
Cost-effectiveness (1 study)Cost-effectiveness (1 study)– Using a deterministic decision-tree model, comparing universal Using a deterministic decision-tree model, comparing universal
and targeted screening approaches, the authors assessed the and targeted screening approaches, the authors assessed the thresholds at which screening would be cost-effective from a thresholds at which screening would be cost-effective from a health care system perspective. Study reported, at a threshold health care system perspective. Study reported, at a threshold of $100,000 per quality adjusted life year, an 86% likelihood of of $100,000 per quality adjusted life year, an 86% likelihood of screening being cost-effective screening being cost-effective
SummarySummary
Key findings:Key findings:– SCID affects at least 1/100,000 newborns in the USSCID affects at least 1/100,000 newborns in the US– Several population-based screening trials are underway Several population-based screening trials are underway
(Wisconsin) or planned; to date no population-based (Wisconsin) or planned; to date no population-based screening trial has been completed screening trial has been completed
– Without curative treatment, newborns develop severe, Without curative treatment, newborns develop severe, often opportunistic, infections which lead to early deathoften opportunistic, infections which lead to early death
– Treatment, most commonly with hematopoietic stem cell Treatment, most commonly with hematopoietic stem cell transplant, decreases morbidity and mortality associated transplant, decreases morbidity and mortality associated with SCIDwith SCID
– Some evidence supports the notion that earlier treatment Some evidence supports the notion that earlier treatment may lead to better outcomesmay lead to better outcomes
Critical Needed InformationCritical Needed InformationPrevalence of SCIDPrevalence of SCID– A systematic method of case finding is needed in order to A systematic method of case finding is needed in order to
determine prevalence accurately. The new consortium of determine prevalence accurately. The new consortium of treatment centers (USIDNET) may serve as a method of more treatment centers (USIDNET) may serve as a method of more systematic case-finding.systematic case-finding.
Accuracy of ScreeningAccuracy of Screening– Initial pilot screening data from Wisconsin suggest that a Initial pilot screening data from Wisconsin suggest that a
relatively low false-positive rate. However, current data are relatively low false-positive rate. However, current data are limited. limited.
– Data regarding the accuracy of other screening methods in Data regarding the accuracy of other screening methods in population-based protocols, are not availablepopulation-based protocols, are not available
Feasibility of ScreeningFeasibility of Screening– Wisconsin’s experience provides at least pilot data re feasibility. Wisconsin’s experience provides at least pilot data re feasibility.
Data are needed regarding the ability of other newborn Data are needed regarding the ability of other newborn screening laboratories to offer SCID screeningscreening laboratories to offer SCID screening
Critical Needed InformationCritical Needed Information
Acceptability of ScreeningAcceptability of Screening– No data describe consumer or physician acceptance of newborn No data describe consumer or physician acceptance of newborn
screening for SCIDscreening for SCID
Is the evidence for early treatment enough?Is the evidence for early treatment enough?Cost-effectiveness (of screening and treatment)Cost-effectiveness (of screening and treatment)– Cost-effectiveness analyses utilizing measured costs and Cost-effectiveness analyses utilizing measured costs and
utilities, as well as applicable sensitivity analyses, are neededutilities, as well as applicable sensitivity analyses, are needed
Adequacy of available treatment centersAdequacy of available treatment centers– No current data address variation in treatment success among No current data address variation in treatment success among
centers or the number of centers in the United States and their centers or the number of centers in the United States and their capacity to provide treatment for SCID. Data from USIDNET capacity to provide treatment for SCID. Data from USIDNET and CIBMTR may, in the future, provide evidence on this topicand CIBMTR may, in the future, provide evidence on this topic
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