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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Ahmed HU, El-Shater Bosaily A, Brown LC, et al, and the PROMIS study group. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017; published online Jan 19.

2 Appendix 1 - The PROMIS Study Group Trial Sponsor: Trial Coordination: Funders: University College London (UCL) Medical Research Council Clinical Trial Unit (MRC CTU) at UCL National Institute for Health Research (NIHR) Health Technology Assessment (HTA) & Prostate Cancer UK (blood and urine sample collection for biobanking) Trial Management Group: Professor Mark Emberton (Chief Investigator) Mr Hashim Ahmed (Co-chief Investigator) Dr Ahmed El-Shater Bosaily Dr Alex Kirkham Dr Alex Freeman Dr Charles Jameson Mr Richard Hindley Dr Christopher Parker Professor Colin Cooper Robert Oldroyd Professor Richard Kaplan Dr Louise Brown Dr Rhian Gabe Dr Yolanda Collaco-Moraes Cybil Adusei, Katie Ward Sophie Stewart, Katie Thompson Claire Mulrenan, Hannah Gardner, Alex Maytum Carlos Diaz-Montana Dr Chris Coyle UCLH (Urologist) UCLH (Urologist) UCLH (Clinical Research Fellow) UCLH (Radiologist) UCLH (Pathologist) UCLH (Pathologist) Basingstoke (Urologist) Royal Marsden (Translational Research) Royal Marsden (Translational Research) Patient representative MRC CTU (Programme Lead/Oncologist) MRC CTU (Project Lead/statistician) University of York (Statistician) MRC CTU (Clinical Operations Manager) MRC CTU (Trial Manager) MRC CTU (Data Managers) MRC CTU (Data programmer) MRC CTU (Clinical Fellow)

3 Professor Mark Sculpher Dr Rita Faria Dr Eldon Spackman University of York (Health Economics) University of York (Health Economics) University of York (Health Economics) Trial Steering Committee (also act as Data Monitoring Committee): Dr David Guthrie (Chair) Professor John Chester Professor Richard Cowan Professor Michael Jewitt Derbyshire Royal Infirmary (Oncologist) University of Cardiff (Oncologist) Christie Hospital Manchester (Oncologist) University of Toronto (Urologist) Participating Centres (Number of men registered): University College London Hospital (304): H. Ahmed (PI), A. El-Shater Bosaily, M. Emberton, A. Kirkham, S. Punwani, A. Freeman, C. Jameson, M. Hung, J. Coe, V. Abu, R. Scott, M. Ahmed. Basingstoke and North Hampshire Hospital (130): R. Hindley (PI), P. Aslet, A. Emara, A. Chetwood, D. Peppercorn, A. Thrower, H. El-Mahallawi, A. Mustajab, H. Alkhazaraji, A. Edwards, J. Smith. Southampton General Hospital (55): T. Dudderidge (PI), J. Dyer, J. Smart, K. Tung, H. Markham, B. Birch, R. Lockyer, A. Lodge, L. Dando, J. Gwilt. Southmead Hospital, Bristol (44): R. Persad (PI), M. Elmahdy, S. Pandian, D. Gillatt, J. Ash-Miles, M. Sohail, C. Shiridzinomwa, A. Treasure. Charing Cross Hospital, Imperial College London (41): M. Winkler (PI), T. Barwick, V. Stewart, L. Honeyfield, N. Qazi, B. Statton, N. Ngo, K. Ansu, S. Edwards, E. Temple. Wrexham Maelor Hospital (39): I. Shergill (PI), S. Agarwal, K. Pradeep, M. Atkinson, S. Ackerley.

4 Royal Hallamshire Hospital, Sheffield (36): D. Rosario (PI), J. Catto, F. Salim, S. Morgan, J. Howson. Musgrove Park Hospital, Taunton (36): N. Burns-Cox (PI), K. Gordon, A. Birring, A. Maccormick, P. Burn, D. Paterson, H. Routley. Frimley Park Hospital (25): S. Bott (PI), H. Evans, G. Kousparos, A.M. Silvanto, A. Mann, J. Amero, A. Pilcher, N. Pereira. The Whittington Hospital (18): M. Ghei (PI), T.T. Shah, J. Kumaradevan, A. Trinidade, R. Katz, D. Arul, L. Harbin, V. Conteh, A. Verjee. Maidstone Hospital (12): A. Henderson (PI), S. Ghosh, P. McMillan, J. James, G. Russell, E. Bernsten, R. Casey, T. Nolan, D. Da

5 Trial Schema Eligible Patient identified with clinical suspicion of prostate cancer Start: 0 Visit 1 Registration Visit 2 Index test: MP-MRI (Report initially kept blind from patient and clinicians) Visit 3 [As soon as possible after MRI, up to a maximum of 3 months after MRI] Combined Prostate Biopsy (CPB) Procedure First: Template Prostate Mapping (TPM) biopsy Second: Transrectal Ultrasound (TRUS) guided biopsy (Pathologists kept blind to MP-MRI results) (Pathologists kept blind to MP-MRI results) Visit 4 End of study Follow up End: usually <4 months Results of all tests given to patients Patients to follow standard care according to outcomes of tests

6 List of Figures and Tables for supplementary material Figure S1 Flow chart presenting completion of tests for all registered men Figure S2 - Proportion of men with no cancer, insignificant cancer and significant cancer (primary definition) based upon TPM biopsy within each MRI score Table S1 MP-MRI scan specification Table S2 Timing and reasons for withdrawal after registration Table S3 Baseline characteristics for men included and excluded from the final analysis Table S4 Gleason scores for 230 men classified as having primary definition of clinically significant cancer on TPM-biopsy Table S5 Histological characteristics on TPM-biopsy of cases missed by MP-MRI and TRUS-biopsy Table S6 Clinical scenarios for the introduction of MP-MRI as a triage test to the standard pathway Table S7 - Histological characteristics on TPM-biopsy of cases missed by MP-MRI and TRUS-biopsy using the 3 definitions of clinically significant prostate cancer Table S8 Assessment of inter-observer variability in 132 random cases double reported by a second expert urologic radiologist Table S9 Occurrence of side effects after each test for the 576 patients who underwent all tests

Figure S1 Flow chart presenting completion of tests for all registered men Registrations N=740 17 withdrew before MRI was performed Ineligible=1 Large prostate=1 Clinical reasons=5 No longer wished

7 Figure S1 Flow chart presenting completion of tests for all registered men Registrations N= withdrew before MRI was performed Ineligible=1 Large prostate=1 Clinical reasons=5 No longer wished to participate=10 MRI scans completed N= withdrew before CPB Ineligible=2 Unblinded=2 Large prostate>100cc=46 T4 or nodal disease=5 Clinical reasons=15 CPB procedure attempted N=601 No longer wished to participate=42 Other=10 21 withdrew during CPB procedure Large prostate=21 CPB completed N=580 Men with all 3 tests completed according to protocol N=576 (572 attended final study visit) 4 withdrew after CPB procedure Large prostate=1 Ineligible=1 Original MRI scan found to be incomplete=1 Theatre complications, TRUS not completed=1

8 Figure S2 Proportion of men with no cancer, insignificant cancer and significant cancer (primary definition) based upon TPM biopsy within each MRI score % by status of disease Significant cancer Insignificant cancer No cancer N=23 N=135 N=163 N=120 N=135 MRI score

9 Table S1 MP-MRI scan specification TR TE Flip angle/d egrees Plane T2 TSE Axial, coronal, sagittal VIBE at multiple flip angles for T1calculat ion(optio nal) VIBE fat sat Slice thicknes s(gap) 3mm (10% gap) Matrix Size Field of View/m m Time from scan 256x x180 3m 54s (ax) Will be included in the Phoenix file Axial 3mm 192x x260 Continue for at least 5m30s after contrast Diffusion (b values: 0, 150, 500, 1000) Diffusion (b=1400) 2200 Min (<98) 2200 Min (<98) Axial 5mm 172x x260 5m 44s (16 average) Axial 5mm 172x x320 3m 39s (32 averages)

10 Table S2 Timing and reasons for withdrawal of men after registration Reason Before MP- MRI Timing of withdrawal Before CPB During CPB After CPB Total Ineligible Unblinded Large prostate T4 or nodal disease Clinical reasons* Did not want biopsy Did not want to wait went private No longer wished to participate Other Total * Various reasons including cardiovascular events, renal/urological problems, other cancers

11 Table S3 Baseline characteristics for 576 men included and 164 men excluded from the final analysis Characteristic [missing data] 576 men included 164 withdrawals Mean (SD) age, years [0] 63.4 (7.6) 64.5 (7.5) Ethnicity, n (%) [1] White Mixed Asian or Asian British Black or Black British Other Family history of prostate cancer, n (%) [7] Yes No 502 (87) 6 (1) 16 (3) 39 (7) 12 (2) 127 (22) 442 (78) 136 (83) 2 (1) 5 (3) 16 (10) 4 (3) 27 (17) 130 (83) Mean (SD) BMI, Kg/m 2 [62] 27.8 (4.4) 28.6 (5.2) Mean (SD) PSA, ng/ml [0] 7.1 (2.9) Range 0.5 to (2.7) Range 1.0 to 14.7

12 Table S4 Gleason scores for 230 men classified as having primary definition of clinically significant cancer on TPM-biopsy Gleason grades Clinically significant cancer* N=230 Mean (SD) cancer core length, mm 9.1 (2.7) # # *Defined as maximum cancer core length of 6mm or greater in any one location and/or the presence of dominant/primary Gleason pattern 4 or greater (i.e., Gleason >/=4+3). # Men classified as clinically significant on the basis of core length despite having low Gleason grades

13 Table S5 Histological characteristics on TPM-biopsy of clinically significant cases missed by MP- MRI and TRUS-biopsy Number (range of maximum cancer core length, mm) MP-MRI Total = 17 TRUS-biopsy Total = 119 Gleason (8mm) (6-11mm) Gleason (6-12mm) (6-14mm) Gleason (3-16mm)

14 Table S6 Potential clinical implications for the introduction of MP-MRI as a triage test to the standard pathway TRUS-biopsy alone pathway Primary biopsy % [99-100] Over-diagnosis 90 (clinically insignificant 16% [13-19] cancer detected) Significant cancer 111 correctly detected 19% [16-23] MP-MRI triage followed by standard, non-directed TRUS biopsy (worst case scenario)# % [69-76] 62 11% [8-14] MP-MRI triage followed by MRI-directed TRUS-biopsy (best case scenario)* % [69-76] % [18-25] % [15-22] 37% [33-41] For all percentages, the denominator used is the total number of cases, n=576 with 95% confidence intervals provided in square brackets. # Worst case scenario where MP-MRI is not used to direct subsequent TRUS biopsies and the TRUS results for each patient have been used to calculate over-diagnosis. * Best case scenario where MP-MRI is used to direct subsequent biopsies with the same accuracy as TPM-biopsy

15 Table S7 - Histological characteristics on TPM-biopsy of cases missed by MP-MRI and TRUS-biopsy using the 3 definitions of clinically significant prostate cancer Definition of significant Primary n=230 Secondary n=331 Gleason >/=7 n=308 MP-MRI missed cases Total = 17 1 x 3+3 with core length 8mm 16 x 3+4 with core lengths 6-12mm Total = 44 6 x 3+3 with core lengths 4-8mm 38 x 3+4 with core lengths 1-12mm Total = x 3+4 with core lengths 1-12mm TRUS-Biopsy missed cases Total = x 3+3 with core lengths 6-11mm 99 x 3+4 with core lengths 6-14mm 13 x 4+3 with core lengths 3-16mm Total = x 3+3 with core lengths 4-11mm 104 x 3+4 with core lengths 1-14mm 10 x 4+3 with core lengths 3-16mm Total = x 3+4 with core lengths 1-14mm 13 x 4+3 with core lengths 3-16mm

16 Table S8 Assessment of inter-observer variability in 132 random cases double reported by a second expert urologic radiologist Radiologist 2 Radiologist Total Total Key Agreement No agreement

17 Table S9 Occurrence of side effects after each test for the 576 patients who underwent all tests Side effect [missing data] Number (%) MP-MRI Pain/discomfort [15] 11 (2) Allergic reaction to contrast medium [16] 1 (<1) Other 3 (<1) Combined Prostate Biopsy Procedure Pain/discomfort [13] 362 (64) Dysuria [17] 256 (46) Haematuria [11] 380 (67) Haematospermia [51] 291 (55) Erectile dysfunction (requiring medication, injection therapy or devices) [48] 76 (14) Urinary tract infection (only if confirmed by a lab test) [11] 32 (6) Systemic urosepsis [9] 8 (1) Acute urinary retention [12] 58 (10) Symptoms associated with general/spinal anaesthetic [43] 19 (4) Other 65 (11) Total patients with any side effect [8] 501 (88)

Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the PROMIS study

Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the PROMIS study Louise Clare Brown, 1 Hashim U Ahmed, 2,3 * Rita Faria, 4