Electronic Supplementary Material for ‘TREC Based Newborn Screening for
Severe Combined Immunodeficiency Disease: A Systematic Review’
Journal of Clinical Immunology
Jet van der Spek, BSca
Rolf H. H. Groenwold, MD, PhDb
Mirjam van der Burg, PhDc
Joris M. van Montfrans, MD, PhDa
a
Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht,
Utrecht, The Netherlands
b
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The
Netherlands
c
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The
Netherlands
Corresponding author:
Joris M. van Montfrans, MD, PhD
University Medical Center Utrecht
Lundlaan 6, PO Box 85090, 3508 AB Utrecht, The Netherlands
Tel: +31 (0)88 755 4003
Fax: +31 (0)88 755 5030
j.vanmontfrans@umcutrecht.n
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1
ONLINE RESOURCE 1
2
3
Search strategy (conducted on June 20, 2014)
4
5
PubMed
6
7
#1 (17056 hits)
8
“Newborn
9
“Screening”[tiab]) OR (“Neonatal”[tiab] AND “Screening”[tiab]) OR “Guthrie card”[tiab] OR “Guthrie
10
test”[tiab] OR “Dried blood spot”[tiab] OR “Dried blood spots”[tiab] OR “T cell receptor excision
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circle”[tiab] OR “T cell receptor excision circles”[tiab] OR “T-cell receptor excision circle”[tiab] OR “T-
12
cell receptor excision circles”[tiab] OR “TREC”[tiab] OR “TRECs”[tiab] OR “Kappa deleting
13
recombination excision circle”[tiab] OR “Kappa deleting recombination excision circles”[tiab] OR
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“Kappa-deleting recombination excision circle”[tiab] OR “Kappa-deleting recombination excision
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circles”[tiab] OR “KREC”[tiab] OR “KRECs”[tiab] OR “Neonatal screening”[MeSH] OR “Dried Blood
16
Spot Testing”[MeSH]
screening”[tiab]
OR
“Neonatal
screening”[tiab]
OR
(“Newborn”[tiab]
AND
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18
#2 (30605 hits)
19
“PID”[tiab] OR “primary immune deficiency”[tiab] OR “primary immune deficiencies”[tiab] OR
20
“primary immunodeficiency”[tiab] OR “primary immunodeficiencies”[tiab] OR “SCID”[tiab] OR
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“Severe combined immunodeficiency”[tiab] OR “T cell lymphopenia”[tiab] OR “T cell
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lymphopenias”[tiab] OR “T-cell lymphopenia”[tiab] OR “T-cell lymphopenias”[tiab] OR “XLA”[tiab] OR
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“X linked agammaglobulinemia”[tiab] OR “X-linked agammaglobulinemia”[tiab] OR “22q11 deletion
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syndrome”[tiab] OR “DiGeorge syndrome”[tiab] OR “ataxia telangiectasia”[tiab] OR “ataxia-
25
telangiectasia”[tiab]
26
syndrome”[tiab] OR “B cell lymphopenia”[tiab] OR “B cell lymphopenias”[tiab] OR “B-cell
27
lymphopenia”[tiab] OR “B cell lymphopenias”[tiab] OR “B cell maturation defect”[tiab] OR “B cell
28
maturation defects”[tiab] OR “B-cell maturation defect”[tiab] OR “B-cell maturation defects”[tiab]
29
OR
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agammaglobulinemia”[Supplementary Concept] OR “22q11 Deletion Syndrome”[MeSH] OR
31
“DiGeorge Syndrome”[MeSH] OR “Ataxia Telangiectasia”[MeSH] OR “Nijmegen Breakage
32
Syndrome”[MeSH]
“Severe
OR
“Nijmegen
Combined
Breakage
Syndrome”[tiab]
Immunodeficiency”[MeSH]
OR
OR
“Nijmegen-breakage-
“Bruton
type
33
34
#3 (197 hits)
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#1 AND #2
2
36
EMBASE
37
38
#1 (16584 hits)
39
‘Newborn screening’:ti,ab OR ‘Neonatal screening’:ti,ab OR ‘Guthrie card’:ti,ab OR ‘Guthrie test’:ti,ab
40
OR ‘Dried blood spot’:ti,ab OR ‘Dried blood spots’:ti,ab OR ‘T cell receptor excision circle assay’:ti,ab
41
OR ‘T cell receptor excision circles’:ti,ab OR ‘T-cell receptor excision circle assay’:ti,ab OR ‘T-cell
42
receptor excision circles’:ti,ab OR TREC:ti,ab OR TRECs:ti,ab OR ‘Kappa deleting recombination
43
excision circle’:ti,ab OR ‘Kappa deleting recombination excision circles’:ti,ab OR ‘Kappa-deleting
44
recombination excision circle’:ti,ab OR ‘Kappa-deleting recombination excision circles’:ti,ab OR
45
KREC:ti,ab OR KRECs:ti,ab OR ‘Newborn screening’/exp OR ‘Dried Blood Spot Testing’/exp
46
47
#2 (42391 hits)
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‘PID’:ti,ab OR ‘primary immune deficiency’:ti,ab OR ‘primary immune deficiencies’:ti,ab OR ‘primary
49
immunodeficiency’:ti,ab OR ‘primary immunodeficiencies’:ti,ab OR ‘SCID’:ti,ab OR ‘Severe combined
50
immunodeficiency’:ti,ab OR ‘T cell lymphopenia’:ti,ab OR ‘T cell lymphopenias’:ti,ab OR ‘T-cell
51
lymphopenia’:ti,ab
52
agammaglobulinemia’:ti,ab
53
syndrome’:ti,ab OR ‘DiGeorge syndrome’:ti,ab OR ‘ataxia telangiectasia’:ti,ab OR ‘ataxia-
54
telangiectasia’:ti,ab OR ‘Nijmegen Breakage Syndrome’:ti,ab OR ‘Nijmegen-breakage-syndrome’:ti,ab
55
OR ‘B cell lymphopenia’:ti,ab OR ‘B cell lymphopenias’:ti,ab OR ‘B-cell lymphopenia’:ti,ab OR ‘B cell
56
lymphopenias’:ti,ab OR ‘B cell maturation defect’:ti,ab OR ‘B cell maturation defects’:ti,ab OR ‘B-cell
57
maturation
58
Immunodeficiency’/exp OR ‘X linked agammaglobulinemia’/exp OR ‘chromosome deletion
59
22q11’/exp OR ‘DiGeorge syndrome’/exp OR ‘Ataxia Telangiectasia’/exp OR ‘Nijmegen Breakage
60
Syndrome’/exp
OR
defect’:ti,ab
‘T-cell
OR
OR
lymphopenias’:ti,ab
‘X-linked
‘B-cell
OR
‘XLA’:ti,ab
agammaglobulinemia’:ti,ab
maturation
defects’:ti,ab
OR
OR
OR
‘X
‘22q11
‘Severe
linked
deletion
Combined
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62
#3 (170 hits)
63
#1 AND #2 AND [embase]/lim NOT [medline]/lim
64
65
Cochrane
66
67
#1 (596 hits)
68
"Newborn screening" or "Neonatal screening" or ("Newborn" and "Screening") or ("Neonatal" and
69
"Screening") or "Guthrie card" or "Guthrie test" or "Dried blood spot" or "Dried blood spots" or "T
70
cell receptor excision circle" or "T cell receptor excision circles" or "T-cell receptor excision circle" or
3
71
"T-cell receptor excision circles" or "TREC" or "TRECs" or "Kappa deleting recombination excision
72
circle" or "Kappa deleting recombination excision circles" or "Kappa-deleting recombination excision
73
circle" or "Kappa-deleting recombination excision circles" or "KREC" or "KRECs":ti or "Newborn
74
screening" or "Neonatal screening" or ("Newborn" and "Screening") or ("Neonatal" and "Screening")
75
or "Guthrie card" or "Guthrie test" or "Dried blood spot" or "Dried blood spots" or "T cell receptor
76
excision circle" or "T cell receptor excision circles" or "T-cell receptor excision circle" or "T-cell
77
receptor excision circles" or "TREC" or "TRECs" or "Kappa deleting recombination excision circle" or
78
"Kappa deleting recombination excision circles" or "Kappa-deleting recombination excision circle" or
79
"Kappa-deleting recombination excision circles" or "KREC" or "KRECs":ab (Word variations have been
80
searched)
81
82
#2 (470 hits)
83
"PID" or "primary immune deficiency" or "primary immune deficiencies" or "primary
84
immunodeficiency"
85
immunodeficiency" or "T cell lymphopenia" or "T cell lymphopenias" or "T-cell lymphopenia" or "T-
86
cell lymphopenias" or "XLA" or "X linked agammaglobulinemia" or "X-linked agammaglobulinemia" or
87
"22q11 deletion syndrome" or "DiGeorge syndrome" or "ataxia telangiectasia" or "ataxia-
88
telangiectasia" or "Nijmegen Breakage Syndrome" or "Nijmegen-breakage-syndrome" or "B cell
89
lymphopenia" or "B cell lymphopenias" or "B-cell lymphopenia" or "B cell lymphopenias" or "B cell
90
maturation defect" or "B cell maturation defects" or "B-cell maturation defect" or "B-cell maturation
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defects" or "Bruton type agammaglobulinemia":ti or "PID" or "primary immune deficiency" or
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"primary immune deficiencies" or "primary immunodeficiency" or "primary immunodeficiencies" or
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"SCID" or "Severe combined immunodeficiency" or "T cell lymphopenia" or "T cell lymphopenias" or
94
"T-cell lymphopenia" or "T-cell lymphopenias" or "XLA" or "X linked agammaglobulinemia" or "X-
95
linked agammaglobulinemia" or "22q11 deletion syndrome" or "DiGeorge syndrome" or "ataxia
96
telangiectasia" or "ataxia-telangiectasia" or "Nijmegen Breakage Syndrome" or "Nijmegen-breakage-
97
syndrome" or "B cell lymphopenia" or "B cell lymphopenias" or "B-cell lymphopenia" or "B cell
98
lymphopenias" or "B cell maturation defect" or "B cell maturation defects" or "B-cell maturation
99
defect" or "B-cell maturation defects" or "Bruton type agammaglobulinemia":ab (Word variations
100
or
"primary
immunodeficiencies"
or
"SCID"
or
"Severe
combined
have been searched)
101
102
#3 (3 hits)
103
#1 AND #2
104
4
105
ONLINE RESOURCE 2
106
107
Completeness of reporting assessment protocol for included studies
108
109
Assessment items per domain:
110
111
1) Methods
112
a. Describes TREC assay (incl. control gene)
113
b. Reports TREC unit clearly
114
c. Reports TREC cut-off value
115
d. Reports rationale for cut-off
116
2) Results
117
a. Reports number of re-tests precisely
118
b. Reports number of repeat DBSs precisely
119
c. Reports number of referrals precisely
120
d. Reports mean normal TREC content
121
e. Reports exact TREC content for newborns with TCL
122
f.
123
g. Reports genetic diagnoses of individual typical SCID patients with TREC content
124
h. Reports diagnosis of individual other TCL patients with TREC content
125
i.
Reports how many newborns referred did were lost to diagnostic follow-up
126
j.
Describes why newborns were lost to follow-up
127
Reports CD3 values for identified cases
3) Discussion
128
a. Discusses whether cases could have been missed
129
130
Assessment protocol
131
132
I.
Case series were assessed on items 1a-d, 2d-g. Pilot cohort studies were assessed on items
133
1a-d, 2a-d. Other items were considered non applicable (NA). If only typical SCID patients
134
were tested item 2g was NA. If only other TCL patients were tested item 2f was NA.
135
Population-based cohort studies were assessed on all items.
136
137
II.
All questions were answered with yes (X) or no (O).
138
5
139
140
III.
If more than half of applicable items within methods, results or discussion was scored as ‘no’,
the study was considered to have low completeness of reporting.
6
ONLINE RESOURCE 3
Table 5. Assessment of completeness of reporting in studies included in systematic review based on adjusted STARD criteria
Methods
Results
TREC
TREC
TREC
Rationale
Nr.
Nr. repeat
Nr.
Mean
Exact
CD3 values
Genetic
assay
unit
cut-off
cut-off
retests
DBS
referrals
normal
TREC
diagnosis
TREC
content
SCID
content
Case series
Morinishi
X
X
O
O
NA
NA
NA
X
X
X
X
Borte
X
X
X
X
NA
NA
NA
O
O
O
X
La Marca
X
X
X
O
NA
NA
NA
O
X
O
X
Mallott
X
X
X
O
NA
NA
NA
O
X
X
NA
Somech
X
X
X
X
NA
NA
NA
X
X
X
X
Adams
X
X
X
X
NA
NA
NA
X
X
O
O
Audrain
X
X
X
X
NA
NA
NA
O
X
O
X
Lingman
X
X
X
X
NA
NA
NA
O
X
X
NA
Cohort studies
Borte
X
X
X
X
X
X
X
O
NA
NA
NA
Adams
X
X
X
X
X
X
X
X
NA
NA
NA
Audrain
X
X
X
X
X
X
X
O
NA
NA
NA
Chien
X
X
X
X
O
O
O
X
X
X
X
Verbsky
X
X
X
X
X
X
X
O
X
X
X
Kwan (2013)
X
X
X
O
O
X
X
O
X
X
X
Kwan (2014)
X
X
X
O
O
O
X
O
O
O
X
Vogel
X
O
X
X
X
X
X
X
X
X
X
X, item reported; O, item not reported (for specification of individual items see Online Resource 2); NA, not applicable
Diagnoses
other TCL
Nr. loss to
follow-up
Reason loss
to followup
Discussion
Missed
cases
Overall
comple
tness
NA
X
NA
X
NA
NA
NA
X
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
high
high
high
high
high
high
high
high
NA
NA
NA
X
X
X
X
X
NA
NA
NA
O
O
X
O
X
NA
NA
NA
O
O
X
O
X
NA
NA
NA
X
X
X
X
X
high
high
high
low
high
high
low
high
7