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

Thank youThank you