Naranjo 2011a.

Clinical features and settings	Inclusion period: February 2001 to March 2006. Patient population: 350 patients with newly diagnosed histologically proven stage 4 neuroblastoma and with 926 ¹²³I‐MIBG scans of which 218 with a ¹²³I‐MIBG scan at first diagnosis. Patients were enrolled on COG protocol A3973 and had completed ¹²³I‐MIBG or ¹³¹I‐MIBG scans at one or more of the following time points: diagnosis, post‐induction, post‐transplant or post biotherapy. To be eligible for COG A3973, patients with stage 4 neuroblastoma had to be aged 30 years or younger at the time of initial diagnosis. If younger than 12 months, MYCN amplification (> 10 copies) was required; if between 12 and 18 months of age, any unfavourable (MYCN amplification, unfavourable histology, and diploid) or unknown biologic feature was required. Patients were excluded when pregnant or lactating. Patients of childbearing potential had to practice an effective method of birth control while participating on this study. Normal renal, cardiac, hepatic, and hematopoietic function was required, as well as no prior systemic therapy. Consecutive series: n.r. Diagnostic work‐up: ¹²³I‐MIBG or ¹³¹I‐MIBG scans, histopathology. Time spans symptoms‐index test, symptoms‐reference standard and index test‐reference standard: n.r. Treatment between index test‐reference standard: n.r.
Participants	Included patients: 218 children with stage 4 neuroblastoma and with a ¹²³I‐MIBG scan at first diagnosis. Median age at diagnosis:3.1 years (range 6.8 months to 15.2 years). Sex distribution: 124 boys (57%), 94 girls (43%). INSS stage: all stage 4 .
Study design	Case series with pathologically proven neuroblastoma (histopathology not known at the time of MIBG‐scintigraphy).
Target condition and reference standard(s)	Target condition: newly diagnosed stage 4 neuroblastoma. Reference standard: histopathology (biopsy of soft tissue or bone marrow).
Index and comparator tests	Assessed primary objective 1.1: to determine the diagnostic accuracy of ¹²³I‐MIBG (SPECT‐CT) scintigraphy for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. Index test: ¹²³I‐MIBG scintigraphy. Radiofarmacon: ¹²³I‐MIBG. Dose: 370 MBq/1.7 m² of body surface area. Collimator: low‐energy. Matrix: n.r. Acquisition protocol: overlapping anterior and posterior spot views for planar imaging or WB scans. The exact number of patients per dimension: n.r. SPECT: a low‐energy collimator, rotated 3608 with 120 projections at 20 seconds per stop; filtered back‐projection with a Butterworth filter and a cut‐off frequency of 0.2 to 0.5 to reconstruct the images Acquisition time: 24 hours after injection. Acquisition duration: 10 minutes per spot view and low‐speed for WB scans. Interfering medication: n.r. Thyroid prophylaxis: supersaturated potassium iodide generally 24 hours prior to the diagnostic ¹²³I‐MIBG injection and for three to seven days following the injection. Description of positive test result: Skeletal sites were individually scored: 0 = no MIBG involvement; 1 = one MIBG‐avid lesion present; 2 = greater than one MIBG‐avid lesion present; and 3 = MIBG‐avidity present in > 50% of an individual site. Soft tissue lesions were scored: 0 = no MIBG involvement; 1 = one MIBG‐avid soft tissue lesion present; 2 = greater than one MIBG‐avid soft tissue lesion present; and 3 = MIBG‐avidity in a soft tissue lesion occupying > 50% of the chest or abdomen. A patient's Curie score at each time point was calculated as the sum of his/her scores over all individual sites. Number and expertise of observers: ¹²³I‐MIBG scans were centrally reviewed by two nuclear medicine physicians without knowledge of the original scan reports or other clinical or imaging information. Interobserver concordance: n.r.
Follow‐up	n.r.; some patients were followed for approximately seven years.
Notes	We received additional data from the author to fill in the two‐by‐two‐table of objective 1.1.
Table of Methodological Quality
Item	Authors' judgement	Description
Representative spectrum? All tests	Yes	Children with stage 4 neuroblastoma at first diagnosis.
Acceptable reference standard? All tests	Yes	Histopathology.
Acceptable delay between tests? All tests	Unclear	n.r.
Partial verification avoided? All tests	Yes	Diagnosis confirmed by histopathology in all patients.
Differential verification avoided? All tests	Yes	Diagnosis confirmed by histopathology.
Incorporation avoided? All tests	Yes	Index test was not a part of the reference test.
Reference standard results blinded? All tests	Unclear	n.r.
Index test results blinded? All tests	Yes	¹²³I‐MIBG scans were centrally reviewed by two nuclear medicine physicians without knowledge of other clinical information (like histopathology).
Relevant clinical information? All tests	No	Clinical data, like demographic factors (sex and age), patient history and physical examination (e.g. abdominal extension, bone pains, respiratory distress); additional tests (urinary catecholamines, ferritin, LDH, other imaging modalities) were not available when the test results were interpreted.
Uninterpretable results reported? All tests	Unclear	n.r.
Withdrawals explained? All tests	Unclear	n.r.
Selection criteria clearly described? All tests	Yes	Newly diagnosed high‐risk patients with INSS stage 4 neuroblastoma enrolled on COG protocol A3973 who had completed ¹²³I‐MIBG or ¹³¹I‐MIBG scans at one or more of the following time points: diagnosis, post‐induction, post‐transplant, or post biotherapy. To be eligible for COG A3973, patients with stage 4 disease had to be aged 30 years or younger at the time of initial diagnosis. If younger than 12 months, MYCN amplification (> 10 copies) was required; if between 12 and 18 months of age, any unfavourable (MYCN amplification, unfavourable histology, and diploid) or unknown biologic feature was required. Normal renal, cardiac, hepatic, and hematopoietic function was required, as well as no prior systemic therapy.
Sufficient detail for replication index test? All tests	Yes	Radiofarmacon, dose, collimator, matrix, acquisition protocol, acquisition time and acquisition duration were reported.
Sufficient detail for replication reference test? All tests	No	n.r.
Clear definition of positive result index test? All tests	Yes	Skeletal sites: 0 = no MIBG involvement; 1 = one MIBG‐avid lesion present; 2 = greater than one MIBG‐avid lesion present; and 3 = MIBG‐avidity present in > 50% of an individual site. Soft tissue lesions: 0 = no MIBG involvement; 1 = one MIBG‐avid soft tissue lesion present; 2 = greater than one MIBG‐avid soft tissue lesion present; and 3 = MIBG‐avidity in a soft tissue lesion occupying > 50% of the chest or abdomen. A patient's Curie score at each time point was calculated as the sum of his/her scores over all individual sites.
Interobserver variation reported and acceptable? All tests	Unclear	n.r.