Biomarkers Paediatrics

The following list has been reviewed and approved by the European Society of Paediatric Radiology (ESPR)

PAEDIATRIC MUSCULOSKELETAL IMAGING

Paediatric MSK	Disease	Biomarker and evidence for use	Description of imaging technique	Pathophysiological process informed by MRI biomarker	Biomarker measured	Units of measurement
Suitable for use in clinical trials	Juvenile idiopathic arthritis (JIA) -synovial inflammation	CE MRI^1-3!	T1 fs weighted images, pre- and post Gadolinium	Key measure in grading synovitis	Inflammation score	0 - 3
	Developmental dysplasia of the hip (DDH)	US^4!	Coronal section through the mid-acetabulum (standard-view)	Acetabular dysplasia	Alpha angle	Degrees
	DDH	XR^5!	Pelvic XR	Acetabular dysplasia	Acetabular Index Sharp’s angle Wiberg’s CE angle FHEI, ATD, ADR	Degrees or mm
Biomarkers in development	DDH	XR^5!	Pelvic XR	Acetabular dysplasia	Ogata angle Acetabular roof angle
Biomarkers in development	Coxarthrosis	XR^5!	Pelvic XR	Coxarthrosis	Joint space width

References

Damasio MB, Malattia C, Tanturri de HL, et al. MRI of the wrist in juvenile idiopathic arthritis: proposal of a paediatric synovitis score by a consensus of an international working group. Results of a multicentre reliability study. PediatrRadiol 2012;42:1047-55.
Nusman CM, Ording Muller LS, Hemke R, et al. Current Status of Efforts on Standardizing Magnetic Resonance Imaging of Juvenile Idiopathic Arthritis: Report from the OMERACT MRI in JIA Working Group and Health-e-Child. J Rheumatol 2016;43:239-44.
Avenarius DFM, Ording Muller LS, Rosendahl K. Joint Fluid, Bone Marrow Edemalike Changes, and Ganglion Cysts in the Pediatric Wrist: Features That May Mimic Pathologic Abnormalities-Follow-Up of a
Rosendahl K, Aslaksen A, Lie RT, Markestad T. Reliability of ultrasound in the early diagnosis of developmental dysplasia of the hip. PediatrRadiol 1995;25:219-24.
Engesaeter IO, Laborie LB, Lehmann TG, et al. Radiological findings for hip dysplasia at skeletal maturity. Validation of digital and manual measurement techniques. Skeletal Radiol 2012;41:775-85.

PAEDIATRIC NEURO

Neuro	Disease	Biomarker and evidence for use	Description of imaging technique	Pathophysiological process informed by MRI biomarker	Biomarker measured	Units of measurement
Suitable for use in clinical trials	Hydrocephalus	US^1!	Coronal view through the 3^rd ventricle	Hydrocephalus	Ventricular / SAS dimensions	mm

References

Gravendeel J, Rosendahl K. Cerebral biometry at birth and at 4 and 8 months of age. A prospective study using US. Ped Radiol 2010 Oct;40(10):1651-6.

PHYSICAL ABUSE

	Disease	Biomarker and evidence for use	Description of imaging technique	Pathophysiological process informed by MRI biomarker	Biomarker measured	Units of measurement
Suitable for use in clinical trials	Physical abuse	XR skeletal survey^1!	High-resolution radiographs	Acute fracture of shafts of tubular bones, clavicles or ribs	Soft tissue swelling No periosteal reaction or callus^2,3!	Number
	Physical abuse	XR skeletal survey^1!	High-resolution radiographs	Healing fracture of shafts of tubular bones, clavicles or ribs	Periosteal reaction, callus, or remodelling^2,3!	Number
	Physical abuse	XR skeletal survey^1!	High-resolution radiographs	Metaphyseal fracture ≤ 2 weeks of age^4!	Thickness^4!	mm (≤1mm)⁴
	Physical abuse	XR skeletal survey^1!	High-resolution radiographs	Metaphyseal fracture > 2 weeks of age^4!	Thickness^4!	mm (>1mm)⁴
	Physical abuse	CT head^1!	Axial, coronal, sagittal and 3D recons (bone algorithm)^1,5!	Acute skull fracture (≤14 days)	Overlying scalp swelling	Presence/absence
	Abusive head injury	CT or MRI^1!	RCR protocol^1!	Intracranial/spinal haemorrhage, hypoxic ischaemic injury^6!	Presence/absence	Presence/absence

References

The radiological investigation of suspected physical abuse in children RCR 2017
Walters MM, Forbes PW, Buonomo C, Kleinman PK Healing patterns of clavicular birth injuries as a guide to fracture dating in cases of possible infant abuse Pediatr Radiol 2014;44:1224-1229
Fadell M, Miller A, Trefan L et al Radiological features of healing in newborn clavicular fractures Eur Radiol 2017;27:2180-2187
Karmazyn B, Marine MB, Wanner MR et al Establishing signs for acute and healing phases of distal tibial classic metaphyseal lesions Pediatr Radiol 2020;50:715-725
Choudhary A, Servaes S, Slovis TL et al Consensus statement on abusive head trauma in infants and young children Pediatr Radiol 2018 48:1048-1065
Martin A, Paddock M, Johns CS et al Avoiding skull radiographs in infants with suspected inflicted injury who also undergo head CT: “A no-brainer” Eur Radiol 2020;30:1480-1487

PAEDIATRIC ONCOLOGY

Paediatric Oncology	Disease	Biomarker and evidence for use	Description of imaging technique	Pathophysiological process informed by MRI biomarker	Biomarker measured	Units of measurement
Suitable for use in clinical trials	Neuroblastoma	ADC^1-4!	Diffusion weighted imaging	Restriction of the free diffusibility correlates with histologic subtypes	Diffusion restriction	mm²/s
	Nephroblastoma	ADC^5-8!	Diffusion weighted imaging	Restriction of the free diffusibility correlates with histologic subtypes	Diffusion restriction	mm²/s
	Hodgkin Lymphoma	Deauville Score^9-11!	18F-FDG-PET/CT	18F-FDG Uptake after chemoth. correlates with outcome	Points	n.a.
	Neuroblastoma	SIOPEN Score^12,13!	123I-metaiodobenzylguanidine scintigraphy	Prognostic value of the SIOPEN skeletal score	Points	n.a.
	Neuroblastoma	18F-FDG^14-20! Uptake	18F-FDG-PET/CT	18F-FDG Uptake correlate with tumor grading	SUV	n.a.
	Brain tumor	18F-FET Uptake^21!	18F-FET-PET/CT	Brain tumor detection and recurrence	SUV	n.a.
	Solid tumor	Tumor size^22-25! RECIST 1.1	Cross sectional imaging	Tumor dimension before and after chemotherapy correlates with outcome	1 dimensional	cm

References

PAEDIATRIC CARDIAC IMAGING

Paediatric Cardiac imaging	Disease	Biomarker and evidence for use	Description of imaging technique	Pathophysiological process informed by MRI biomarker	Biomarker measured	Units of measurement
Suitable for use in clinical trials	Myocarditis	Values of T1 native, T2 mapping and ECV in CMR in pediatric patients with myocarditis.	CMR	Myocardial inflamation	CMR relaxation parameter T1 and T2	ms
	Normal values in pediatric healthy population	- Normal values of diameter of Coronary Artery Diameters in pediatric population ( most of them with Congenital Heart Disease) , determined by Prospectively EKG- triggered coronary CT angiography (CCTA). - Normal values of T1 native, T2 mapping and ECV in CMR in pediatric healthy population.	CCTA CMR	Diameter coronary arteries Values in healthy pediatric population	Measure in orthogonal plane in coronary arteries CMR relaxation parameter T1 and T2	Mm ms
	Thalassaemia Major	Value of T2* on CMR for the early identification and treatment of patients at high risk of heart failure and arrhythmia^1!	CMR (direct assessment of myocardial iron concentration with CMR because iron deposits shorten T2*)	Myocardial siderosis	CMR relaxation parameter T2*	ms Cardiac T2* values > 20 ms are considered normal

References

Kirk P, Roughton M, Porter JB et al. Cardiac T2* Magnetic Resonance for Prediction of Cardiac Complications in Thalassemia Major. Circulation 2009;120:1961-1968

PAEDIATRIC LUNG IMAGING

Paediatric lung imaging	Disease	Biomarker and evidence for use	Description of radiology technique	Pathophysiological process informed by biomarker	Biomarker measured	Units of measurement
	Cystic Fibrosis Bronchiectasis and airway wall thickening	CT	End-inspiratory or free-breathing non-contrast enhanced CTR	Key measure in disease progression^1-4!, risk of pulmonary exacerbation^3,5!, lower QoL	Severity and extent of bronchiectasis Airway Tapering	Score depends on disease and scoring system^6-7!: Semiquantitative (Bhalla, Brody, CF-CT), score range from 0-3 (mild-moderate-severe, tubular, varicose and cystic) Intra and inter branches tapering index
	Small Airways Diseases	CT	End-expiratory CT	Key measure in disease progression^1,8,9!, reflecting small airways disease	Low Attenuation Region (LAR) (LAR/Lungvolume)*100%	Volume quantified with HU-based software or PRAGMA-CF scoring system^7!
	Airways – artery ratio	CT	End-inspiratory of free-breathing CT non contrast enhanced	Key measure of bronchiectasis, air wall thickening and lack of tapering	Inflammation	Automatic segmentation with software^{11,12, 13!} Fraction of abnormal airways per generation
	PRAGMA-CF	CT	End-inspiratory and expiratory CT of free-breathing CT non contrast enhanced	Measure of key CF features, such as bronchiectasis, bronchial wall thickening, mucus plugging, consolidation, air trapping	Disease progression	Each feature is express as % of total lung volume or ml
	Quantification of lung water	MR	Half-Fourier singleshot turbo spin-echo	Measure the severity of lung disease or pulmonary oedema.	Monitoring lung disease	Lung water density (LWD, %) is the ratio of lung to liver signal intensity multiplied by 70%, the estimated hepatic water density^16!
	Diaphragmatic motion disorders/Diaphragm hernia	US/MRI	M-mode sonography of hemidiaphragms during respiratory movements, subxiphoid and subcostal approach T2- be used for clinical trials Half-fourier-acqusition single-shot turbo spin-echo (HASTE) , T2- (true fast imaging with steady-state free precession) (TRUFI) at least two planes (coronal, axial or sagittal)	Key measure in evaluation of hemidiaphragmatic respiratory movements Key measure is to identify the diaphragm defect, hernia content, mediastinal shift, associated lung abnormalities	Hemidiaphragmatic excursions, difference of excursions between the hemidiaphragms Severity and extent of the diaphragm defect	mm, % ^14,15! mm, %

References

Mott Thorax 2012 Jun;67(6):509-16.
De Jong Thorax 2006, Thorax, 61(1):80-85
Tepper ERJ 2013, 42: 371-379;
Owens Thorax 2012 Jun;67(6):471-2
Loeve Thorax 2009 Oct;64(10):876-82
Tiddens Eur Respir Rev. 2018 Feb 28;27(147):170097
Szczesniak J Cyst Fibros. 2017 Mar;16(2):175-185
Loeve Radiology 2012 2012 Mar;262(3):969-76
Loeve AJRCCM 2012 185(10):1096-103
Kuo 2020, European radiol 2020 May;30(5):2703-2711
Perez-Rovira Med Phys. 2016 Oct;43(10):5736
Kuo Eur Radiol. 2017 Nov;27(11):4680-4689.
Kuo J Cyst Fibros. 2017 Jan;16(1):116-123
Urvoas E Pediatr Radiol 1994;24:564-568
Epelman M, Pediatr Radiol. 2005;35(7):661-667
Thompson RB Journal of Cardiovascular Magnetic Resonance 2019; 21:58