Validated imaging biomarkers as decision-making tools in clinical trials and routine practice: current status and recommendations from the EIBALL* subcommittee of the European Society of Radiology (ESR)

deSouza, Nandita M.; Achten, Eric; Alberich-Bayarri, Angel; Bamberg, Fabian; Boellaard, Ronald; Clément, Olivier; Fournier, Laure; Gallagher, Ferdia; Golay, Xavier; Heussel, Claus Peter; Jackson, Edward F.; Manniesing, Rashindra; Mayerhofer, Marius E.; Neri, Emanuele; O’Connor, James; Oguz, Kader Karli; Persson, Anders; Smits, Marion; van Beek, Edwin J. R.; Zech, Christoph J.

doi:10.1186/s13244-019-0764-0

Insights into Imaging

Table 1 Imaging biomarkers for disease detection (semi-quantitative and quantitative) with examples of current evidence for their use that would support decision-making

From: Validated imaging biomarkers as decision-making tools in clinical trials and routine practice: current status and recommendations from the EIBALL* subcommittee of the European Society of Radiology (ESR)

Disease detection
	Biomarker	SemiQ/Q	Disease	Question answered	Utility of biomarker	Data from	Potential decision for
Non-malignant disease	LVEF-US LVEF-MRI	Q	Cardiac function [28, 29] Cardiac function	Cardiac output Cardiac output	ICC US 0.72, single centre sensitivity 69% [29] ICC MRI 0.86,correlation of MRI and cineventriculography 0.72 [99]	Single centre US Multicentre MRI [99, 100]	Inotropes Inotropes
	Renal volume-US, CT, MRI	Q	Renal failure	Mass of parenchyma	ICC on US 0.64–0.86 [101] Correlation of US with CT 0.76–0.8 [102] Interobserver reproducibility on MRI 87–88% [103]	Single centre	Renal replacement, safety and toxicity of other pharmaceuticals
	Young’s modulus on elastography-US	Q	Thyroid [104], breast [50] and prostate cancer [51] Parkinson’s disease	Tumour presence Muscle stiffness	Thyroid sensitivity 80%, specificity 95% [104] Breast AUC 0.898 for conventional US, 0.932 for shear wave elastography, and 0.982 for combined data [105] Prostate sensitivity 0.84, spec 0.84 [51]	Thyroid, breast: single centre Prostate meta-analysis	Treatment with surgery/radiotherapy/chemotherapy
	Lung tissue density	Q	Emphysema [106, 107] and fibrosis [58]	Airways obstruction, interstitial lung disease present	Emphysema (density assessment) influences BODE (body mass index, airflow obstruction, dyspnea and exercise capacity) index. Odds ratio of interstitial lung abnormalities for reduced lung capacity 2.3	Multicentre Single centre	Surgery, valve and drug treatment
	Fibrosis and ground-glass index on CT lung	SQ	Idiopathic lung fibrosis	Development of inflammation and fibrosis	Mortality predicted by pulmonary vascular volume (HR 1.23 (1.08–1.40), p = 0.001) and honeycombing (HR 1.18 (1.06–1.32), p = 0.002) [108]	Single centre	Drug treatment
	ADC/pCT	SQ	Ischaemic stroke	Presence of salvageable tissue versus infarct core	Measure of infarct core/penumbra used for patient stratification for research [109]	Planned multicentre	Treatment
Malignant disease	Lung RADS, PanCan, NCCN criteria [110, 111]	SQ	Lung nodules	Risk of malignancy	AUC for malignancy 0.81–0.87 [110]	Multicentre	Time period of follow-up or surgery
	CT blood flow, perfusion, permeability metrics	Q	Malignant neck lymph nodes Hepatocellular cancer	Tumour presence	Sensitivity 0.73, specificity 0.70 [112] AUC 0.75, sensitivity 0.79, specificity 0.75 [113]	Single centre Single centre	Staging and management (surgery, radiotherapy or chemotherapy)
	BI-RADS [114] PI-RADS [115] LI-RADS [116]	SQ	Cancer	Risk of malignancy	PPV: BI-RADS0 14.1 %, BI-RADS4 39.1 % and BI-RADS5 92.9 % PI-RADS2 pooled sensitivity 0.85, pooled specificity 0.71 Pooled sensitivity for malignancy 0.93	Dutch breast cancer screening programme Meta-analysis Systematic review	Staging and management stratification (surgery, radiotherapy, chemotherapy, combination)
	ADC	Q	Cancer [117] Liver lesions [118] Prostate cancer [119]	Tumour presence	Liver AUC 0.82–0.95 Prostate AUC 0.84	Single centre Single centre	Staging and management stratification (surgery, radiotherapy, chemotherapy, combination)
	Dynamic contrast enhanced metrics (K^trans, K_ep, blood flow, V_e)	Q	Liver tumour Recurrent glioblastoma		Hepatocellular cancer AUC 0.85, sensitivity 0.85, specificity 0.81 [113] Brain- K^transAccuracy 86% [120]	Single centre Single centre	Further treatment
	¹⁸ FDG SUV	Q	Cancer Sarcoma [121] Lung cancer [105]	Tumour presence	Sarcoma—sensitivity 0.91, specificity 0.85, accuracy 0.88 Lung—sensitivity 0.68 to 0.95 depending on histology	Meta-analysis Meta-analysis	Staging and management stratification (surgery, radiotherapy, chemotherapy, combination)
	Targeted radionuclides [122]In-octreotide [123] [68]Ga DOTATOC and [68]Ga DOTATATE [124, 125] [68]Ga PSMA [4]	Non-Q	Cancer	Tumour presence	Sensitivity 97% and specificity 92% for octreotide [126] Sensitivity 100% and specificity 100% for PSMA [127]	Single centre Single centre	Validation remains difficult because of biopsying multiple positive sites.

Biomarkers used visually in the clinic are given in italics, and those that are used quantitatively are in bold
Abbreviations: ADC apparent diffusion coefficient, APT amide proton transfer, AUC area under curve, BI-RADS breast imaging reporting and data systems, CBV cerebral blood volume, CoV coefficient of variation, CR complete response, CT computerised tomography, DCE dynamic contrast enhanced, DFS disease-free survival, DOTATOC DOTA octreotitide, DOTATATE DOTA octreotate, DSC dynamic susceptibility contrast, ECG electro cardiogram, FDG fluorodeoxyglucose, FLT fluoro thymidine, HR hazard ratio, HU Hounsfield unit, ICC intraclass correlation, IQR interquartile range, LVEF left ventricular ejection fraction, MRF magnetic resonance fingerprinting, MRI magnetic resonance imaging, MTR magnetisation transfer ratio, NCCN National Comprehensive Cancer Network, OS overall survival, pCT perfusion computerised tomography, PERCIST positron emission tomography response criteria in solid tumours, PD progressive disease, PFS progression-free survival, PPV positive predictive value, PI-RADS prostate imaging reporting and data systems, PR partial response, PSMA prostate-specific membrane antigen, RECIL response evaluation in lymphoma, RECIST response evaluation criteria in solid tumours, ROC receiver operating characteristic, SD stable disease, SUV standardised uptake value, SWE shear wave elastography, US ultrasound

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