Prostate MRI, with or without MRI‐targeted biopsy, and systematic biopsy for detecting prostate cancer

Frank‐Jan H Drost; Daniël F Osses; Daan Nieboer; Ewout W Steyerberg; Chris H Bangma; Monique J Roobol; Ivo G Schoots

doi:10.1002/14651858.CD012663.pub2

. 2019 Apr 25;2019(4):CD012663. doi: 10.1002/14651858.CD012663.pub2

Prostate MRI, with or without MRI‐targeted biopsy, and systematic biopsy for detecting prostate cancer

Frank‐Jan H Drost ^1,², Daniël F Osses ^1,², Daan Nieboer ², Ewout W Steyerberg ³, Chris H Bangma ², Monique J Roobol ², Ivo G Schoots ^1,^✉

Editor: Cochrane Urology Group

PMCID: PMC6483565 PMID: 31022301

Abstract

Background

Multiparametric magnetic resonance imaging (MRI), with or without MRI‐targeted biopsy, is an alternative test to systematic transrectal ultrasonography‐guided biopsy in men suspected of having prostate cancer. At present, evidence on which test to use is insufficient to inform detailed evidence‐based decision‐making.

Objectives

To determine the diagnostic accuracy of the index tests MRI only, MRI‐targeted biopsy, the MRI pathway (MRI with or without MRI‐targeted biopsy) and systematic biopsy as compared to template‐guided biopsy as the reference standard in detecting clinically significant prostate cancer as the target condition, defined as International Society of Urological Pathology (ISUP) grade 2 or higher. Secondary target conditions were the detection of grade 1 and grade 3 or higher‐grade prostate cancer, and a potential change in the number of biopsy procedures.

Search methods

We performed a comprehensive systematic literature search up to 31 July 2018. We searched CENTRAL, MEDLINE, Embase, eight other databases and one trials register.

Selection criteria

We considered for inclusion any cross‐sectional study if it investigated one or more index tests verified by the reference standard, or if it investigated the agreement between the MRI pathway and systematic biopsy, both performed in the same men. We included only studies on men who were biopsy naïve or who previously had a negative biopsy (or a mix of both). Studies involving MRI had to report on both MRI‐positive and MRI‐negative men. All studies had to report on the primary target condition.

Data collection and analysis

Two reviewers independently extracted data and assessed the risk of bias using the QUADAS‐2 tool. To estimate test accuracy, we calculated sensitivity and specificity using the bivariate model. To estimate agreement between the MRI pathway and systematic biopsy, we synthesised detection ratios by performing random‐effects meta‐analyses. To estimate the proportions of participants with prostate cancer detected by only one of the index tests, we used random‐effects multinomial or binary logistic regression models. For the main comparisions, we assessed the certainty of evidence using GRADE.

Main results

The test accuracy analyses included 18 studies overall.

MRI compared to template‐guided biopsy: Based on a pooled sensitivity of 0.91 (95% confidence interval (CI): 0.83 to 0.95; 12 studies; low certainty of evidence) and a pooled specificity of 0.37 (95% CI: 0.29 to 0.46; 12 studies; low certainty of evidence) using a baseline prevalence of 30%, MRI may result in 273 (95% CI: 249 to 285) true positives, 441 false positives (95% CI: 378 to 497), 259 true negatives (95% CI: 203 to 322) and 27 (95% CI: 15 to 51) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency.

MRI‐targeted biopsy compared to template‐guided biopsy: Based on a pooled sensitivity of 0.80 (95% CI: 0.69 to 0.87; 8 studies; low certainty of evidence) and a pooled specificity of 0.94 (95% CI: 0.90 to 0.97; 8 studies; low certainty of evidence) using a baseline prevalence of 30%, MRI‐targeted biopsy may result in 240 (95% CI: 207 to 261) true positives, 42 (95% CI: 21 to 70) false positives, 658 (95% CI: 630 to 679) true negatives and 60 (95% CI: 39 to 93) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency.

The MRI pathway compared to template‐guided biopsy: Based on a pooled sensitivity of 0.72 (95% CI: 0.60 to 0.82; 8 studies; low certainty of evidence) and a pooled specificity of 0.96 (95% CI: 0.94 to 0.98; 8 studies; low certainty of evidence) using a baseline prevalence of 30%, the MRI pathway may result in 216 (95% CI: 180 to 246) true positives, 28 (95% CI: 14 to 42) false positives, 672 (95% CI: 658 to 686) true negatives and 84 (95% CI: 54 to 120) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations, inconsistency and imprecision.

Systemic biopsy compared to template‐guided biopsy: Based on a pooled sensitivity of 0.63 (95% CI: 0.19 to 0.93; 4 studies; low certainty of evidence) and a pooled specificity of 1.00 (95% CI: 0.91 to 1.00; 4 studies; low certainty of evidence) using a baseline prevalence of 30%, systematic biopsy may result in 189 (95% CI: 57 to 279) true positives, 0 (95% CI: 0 to 63) false positives, 700 (95% CI: 637 to 700) true negatives and 111 (95% CI: 21 to 243) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency.

Agreement analyses: In a mixed population of both biopsy‐naïve and prior‐negative biopsy men comparing the MRI pathway to systematic biopsy, we found a pooled detection ratio of 1.12 (95% CI: 1.02 to 1.23; 25 studies). We found pooled detection ratios of 1.44 (95% CI 1.19 to 1.75; 10 studies) in prior‐negative biopsy men and 1.05 (95% CI: 0.95 to 1.16; 20 studies) in biopsy‐naïve men.

Authors' conclusions

Among the diagnostic strategies considered, the MRI pathway has the most favourable diagnostic accuracy in clinically significant prostate cancer detection. Compared to systematic biopsy, it increases the number of significant cancer detected while reducing the number of insignificant cancer diagnosed. The certainty in our findings was reduced by study limitations, specifically issues surrounding selection bias, as well as inconsistency. Based on these findings, further improvement of prostate cancer diagnostic pathways should be pursued.

Plain language summary

Is prostate MRI, with or without MRI‐targeted biopsy, better than systematic biopsy for detecting prostate cancer in men?

Background

Many prostate cancers are slow growing and may not have any harmful effects during a man's lifetime. Meanwhile, clinically significant cancers can cause problems such as blockage of the urinary tract, painful bone lesions and death. The prostate‐specific antigen (PSA) test followed by tissue samples of the prostate with ultrasound guidance is often used to detect these cancers early. More recently, magnetic resonance imaging (MRI) has also been used to help make the diagnosis.

What is the aim of this review?

The aim of this review was to compare MRI alone, MRI together with a biopsy, and a pathway that uses MRI to help decide whether to do a biopsy or not (hereinafter named ‘the MRI pathway’) with the standard ultrasound guided biopsy (hereinafter called ‘systematic biopsy’) in reference to template‐guided biopsy.

What are the main results?

We examined evidence up to July 2018. The review included 43 studies, mainly from Western countries, of men aged 61 to 73 years.

In a population of 1000 men at risk for prostate cancer, where 300 men actually have clinically significant prostate cancer, MRI will correctly identify 273 men as having clinically significant prostate cancer but miss the remaining 27 men; for the 700 men that do not have clinically significant prostate cancer, MRI will correctly identify 259 as not having prostate cancer but will misclassify 441 men as having clinically significant prostate cancer.

In the same population, MRI‐targeted biopsy will correctly identify 240 of 300 men as having clinically significant prostate cancer but miss the remaining 60 men; for the 700 men that do not have clinically significant prostate cancer, MRI will correctly identify 658 as not having prostate cancer but misclassify 42 men as having clinically significant prostate cancer.

The MRI pathway will correctly identify 216 of 300 men as having clinically significant prostate cancer but miss the remaining 84 men; for the 700 men that do not have clinically significant prostate cancer, MRI pathway will correctly identify 672 as not having prostate cancer but will misclassify 28 men as having clinically significant prostate cancer.

Systematic biopsies will correctly identify 189 of 300 men as having clinically significant prostate cancer but miss the remaining 111 men; for the 700 men that do not have clinically significant prostate cancer, systematic biopsies may correctly identify all 700 as not having prostate cancer and will not misclassify any men as having clinically significant prostate cancer.

When comparing the MRI pathway to systematic biopsy in a mixed group of men who may or may not have had a prior biopsy, we found that MRI pathway is 12% more likely to make the correct diagnosis. In men without a prior biopsy, the MRI pathway is 5% more likely to make the correct diagnosis, whereas in men who have had a negative biospy, it is 44% more likely to make the correct diagnosis.

How reliable is the evidence?

We rated the quality of evidence for the main findings of this review as low. Additional high‐quality research is likely to change these findings.

What are the implications of this review?

The findings of this Cochrane review suggest that the MRI pathway is better than systematic biopsies in making a correct diagnosis of clinically significant prostate cancer. However, the MRI pathway still misses some men with clinically significant prostate cancer. Therefore, further research in this area is important.

Summary of findings

Background

Target condition being diagnosed

Prostate cancer is the most frequently diagnosed solid cancer among men in high‐income countries (Torre 2015). Prostate cancer is the sixth leading cause of cancer death (7.4% of deaths) among men worldwide (Center 2012). A large proportion of prostate cancer, however, is indolent and will not lead to any complaints or death if left undetected (Bell 2015). When indolent prostate cancer is detected, it can be managed by active surveillance and does not necessarily need direct treatment. In contrast, clinically significant prostate cancer has direct therapeutic implications as it may progress, metastasise and lead to prostate cancer‐specific mortality.

Next to the psychological burden of becoming a cancer patient, the harm of overdiagnosing indolent prostate cancer mainly lies in overtreatment, as many men are still offered radical prostatectomy or radiotherapy. Given the sharp increase in prostate‐specific antigen (PSA)‐testing, prostate cancer diagnoses and the increasing concerns of overdiagnosis and overtreatment, the distinction between indolent and clinically significant prostate cancer has become more important (Ilic 2013). Defining clinically significant prostate cancer, however, remains difficult with varying definitions in the world literature (Moore 2013a). Established definitions are based on histologic parameters scored by the Gleason grading (Epstein 2010), or the International Society of Urological Pathology (ISUP) grade systems (Epstein 2016), with some using additional parameters like PSA, familial history, race or volume of cancer (Epstein 1994; Goto 1996; Harnden 2008; Wolters 2011). Moreover, other clinical parameters such as age and comorbidity may also influence the potential for progression and mortality of the individual with prostate cancer.

Clinical pathway

Opportunistic PSA‐based screening is practised worldwide and men considered to be at risk of clinically significant prostate cancer (elevated PSA level, abnormal digital rectal examination, African‐American origin and positive family history) are generally advised to have a systematic biopsy (Carter 2013; Carroll 2016; Mottet 2017). Prediction models and clinical risk calculators, using a variety of clinical parameters and biomarkers, are being investigated and implemented to help select patients for biopsy (Alberts 2019; Ankerst 2018; Ferro 2016; Foley 2016; Radtke 2017). The systematic biopsy may be repeated several times in the case of persistent suspicion of clinically significant prostate cancer after a prior‐negative biopsy or during active surveillance of indolent prostate cancer.

Any prostate biopsy is associated with a risk of infection (1% to 8%) and an increased risk of life‐threatening sepsis (1% to 4%), as a consequence of increasing antibiotic resistance (Borghesi 2017; Loeb 2013). Other associated morbidities include dysuria, hematospermia, haematuria, rectal bleeding, vasovagal episodes and urinary retention (Djavan 2001; Loeb 2013). These drawbacks of prostate biopsy limit the willingness of physicians and patients to perform and undergo potentially unnecessary biopsies.

In contrast with systematic biopsy, magnetic resonance imaging (MRI)‐targeted biopsy is only performed when suspected lesions for clinically significant prostate cancer are detected on MRI. Due to the selective performance of targeted biopsies, the MRI, with MRI‐targeted biopsy, is able to more accurately detect clinically significant prostate cancer while purposefully detecting less indolent prostate cancer (Schoots 2015; Siddiqui 2015). Therefore, MRI and MRI‐targeted biopsy are increasingly investigated in addition to or as a replacement for systematic biopsy, either in the setting of prior‐negative biopsy, initial biopsy or during active surveillance. Studies have shown that MRI and MRI‐targeted biopsy significantly improved the detection rate in the prior‐negative biopsy men, but not in biopsy‐naïve men (Schoots 2015; Valerio 2015). Moreover, randomised controlled trials performed in biopsy‐naïve men provide contradictory findings as to whether or not MRI with MRI‐targeted biopsy has a higher detection rate for clinically significant prostate cancer as compared to systematic biopsy (Baco 2016; Kasivisvanathan 2018; Panebianco 2015; Porpiglia 2017; Tonttilla 2016). Consequently, international guidelines recommend considering the use of MRI and MRI‐targeted biopsy, if available, in the setting of persistent clinical suspicion of prostate cancer after prior‐negative biopsy (AUA Guideline 2018; EAU Guideline 2018). However, international guidelines do not recommend a pre‐biopsy MRI or upfront MRI‐directed biopsy management in biopsy‐naïve men, let alone MRI‐directed biopsy management as an alternative to systematic biopsy. Figure 1 illustrates the clinical pathway and design of this review.

Clinical pathway flow diagram and study design

Index tests

MRI

MRI is used to identify and locate suspicious lesions for clinically significant prostate cancer. Different MRI techniques and MRI systems from different vendors are used worldwide. The multiparametric pulse sequences are T2‐weighted imaging (T2W), diffusion‐weighted imaging (DWI), dynamic contrast‐enhanced (DCE) imaging and spectroscopy. Furthermore, different MRI magnets on different platforms from different vendors exist.

In addition, several scoring systems for the suspicion of prostate cancer on MRI have been developed. Radiologists use multi‐level scoring systems according to the Likert scale principle; where the presence of clinically significant prostate cancer in a lesion can be subjectively categorised as highly unlikely to highly likely, with a varying number of subdivisions. The 1 to 5 scale according to the Prostate Imaging ‐ Reporting and Data System (PI‐RADS) version 2 (Weinreb 2016), provides guidance for radiologists with more objective criteria and is currently most often used.

MRI‐targeted biopsy

MRI‐targeted biopsy in men with a positive MRI can either be performed with MRI‐guidance within the MRI scanner (in‐bore), or by ultrasound guidance with the use of computer‐based software that overlays the target identified on MRI onto the ultrasound image, 'software registration', or without the use of software, 'visual registration'. No significant differences in clinically significant prostate cancer detection appear to exist between these navigational approaches (Moore 2013a; Schoots 2015; Wegelin 2017).

MRI pathway

The MRI pathway (MRI with or without MRI‐targeted biopsy) comprises the performance of an MRI and subsequent performance of MRI‐targeted biopsies if a suspicious lesion is seen. Therefore, men with a negative MRI do not receive MRI‐targeted biopsy.

Systematic biopsy

Systematic transrectal ultrasound (TRUS)‐guided biopsy is a biopsy technique in which the peripheral zone of the prostate is sampled by 8 to 12 cores (with a maximum of 19), depending on the size of the prostate. TRUS is performed primarily for anatomic guidance, as suspicious lesions for prostate cancer, in general, cannot be visualised by ultrasound. This approach may, therefore, result in random and systematic errors, which can lead to hitting insignificant lesions while missing significant lesions (El‐Shater Bosaily 2015). The estimated false‐negative rate of systematic biopsy for any cancer is 25% to 40% (Hu 2012). Also, misclassification occurs by not hitting the cancer lesion at its greatest diameter or highest grade, shown by reclassification in almost half of men when a more accurate biopsy test is applied (Barzell 2007; Barzell 2012; Taira 2010; Taira 2013).

Alternative test(s)

Different biopsy approaches, such as transrectal or transperineal, with different numbers of biopsy cores are used. Transrectal saturation biopsy (defined as more than 20 biopsies of the prostate) aims comprehensively to sample the prostate (Kuru 2013b). However, most transrectal biopsy approaches do not sample the anterior zones of the prostate and therefore lack accuracy. In addition, such an intensified biopsy approach is less frequently used in daily clinical practice as it is widely seen as being a high burden to patients, having an increased complication rate and contributing to overdiagnosing insignificant prostate cancer (Jiang 2013). Furthermore, different ultrasound imaging techniques for localizing suspicious lesions in the prostate are also being developed and evaluated, including contrast‐enhanced ultrasound, computer‐assisted TRUS, sonoelastography and histoscanning. However, these techniques need further development before considering a potential application in daily clinical care (Kuru 2015).

Rationale

To reduce overdiagnosis and overtreatment of indolent prostate cancer, while improving the detection of clinically significant prostate cancer and reducing the number of biopsy procedures, we need more accurate diagnostic methods and better risk‐stratification (Alberts 2015). In a recent international multicentre randomised controlled trial, MRI in combination with MRI‐targeted biopsy (the MRI pathway) detected 12% more clinically significant prostate cancer and 13% less indolent prostate cancer than systematic biopsy in biopsy‐naïve men, and achieved a 28% reduction of biopsies, because men with a negative MRI did not receive prostate biopsy (Kasivisvanathan 2018). These results indicate that a pre‐biopsy MRI and MRI‐targeted biopsy in the presence of an MRI‐suspicious lesion would be superior to a systematic biopsy. If that is confirmed by other studies and longer follow‐up of those men not biopsied, it may initiate a change to the guidelines.

Previous systematic reviews on diagnostic performances of the MRI pathway or the pre‐biopsy MRI approach written by De Rooij 2014a, Futterer 2015, Gayet 2016, Hamoen 2015, Moore 2013b, Schoots 2015, Valerio 2015 and Van Hove 2014 have been based on study designs that did not accurately capture target conditions and index or reference test definitions, leading to a number of biases and inaccurate findings. Studies in these reviews included mainly men with a positive MRI, and disregarded men with a negative MRI, inevitably leading to inaccurate true‐negative and false‐negative values of the MRI pathway. In addition, they used systematic biopsy or radical whole‐mount surgical specimens as reference standards, which inherently have a number of biases: systematic biopsy may miss clinically significant prostate cancer caused by both random and systematic errors, whereas radical whole‐mount surgical specimens are only available for men with a positive biopsy who opted for surgery. Furthermore, the established definitions of clinically significant prostate cancer, based on histology from systematic biopsy and possibly additional non‐histological parameters, cannot be applied to results from the MRI pathway (Robertson 2014). The intention of the MRI pathway is to oversample areas of high suspicion, with the result that MRI‐targeted biopsies tend to show longer cancer core length and higher Gleason grading than systematic biopsies (Haffner 2011). This results in a drift towards higher risk classification, which is an artefact of the MRI‐targeted sampling method and may prompt men and physicians to more radical treatment. Based on these observations, the International Working Group on Standards of Reporting for MRI‐targeted biopsy studies (START) agreed that definitions of clinical significance in MRI‐targeted biopsy studies should solely focus on histologic definitions, that is, Gleason grade and maximum cancer core length (Moore 2013a).

Considering the above information, we performed a systematic review and meta‐analysis of the literature. We only included studies with data on both MRI‐positive and ‐negative men, that reported histologically confirmed target conditions only. Furthermore, we only included studies that used an appropriate reference standard (described in Reference standards) for the test accuracy analyses. To provide additional evidence where test accuracy evidence was limited, we selected from the agreement evidence only those studies that investigated the MRI pathway and systematic biopsy in the same men according to the above‐stated criteria.

We aimed to assess the diagnostic accuracy of the four index tests (MRI, MRI‐targeted biopsy, the MRI pathway and systematic biopsy) and the agreement between the two main index tests (the MRI pathway versus systematic biopsy) for detecting prostate cancer.

Objectives

Primary objective

To determine the diagnostic accuracy of the index tests MRI only, MRI‐targeted biopsy, MRI pathway (MRI with or without MRI‐targeted biopsy) and systematic biopsy as compared to template‐guided biopsy as the reference standard in detecting ISUP grade 2 or higher, grade 3 or higher and grade 1 prostate cancer.

Secondary objectives

To compare the diagnostic accuracy between the index tests MRI only, MRI‐targeted biopsy, MRI pathway (MRI with or without MRI‐targeted biopsy) and systematic biopsy in detecting grade 2 or higher, grade 3 or higher and grade 1 prostate cancer.
To determine the agreement between the two index tests, the MRI pathway and systematic biopsy, for detecting grade 2 or higher, grade 3 or higher and grade 1 prostate cancer.
To determine the proportion of prostate cancer not detected by systematic biopsy but only by the MRI pathway (added value MRI pathway) and the proportion of prostate cancer not detected by the MRI pathway but only by systematic biopsy (added value systematic biopsy) for grade 2 or higher, grade 3 or higher and grade 1 prostate cancer.
To determine the potential change in the number of biopsy procedures between the MRI pathway and systematic biopsy in the test accuracy and the agreement analyses.
To investigate what clinical and methodological sources of heterogeneity affect the index tests, including type of population (prior‐negative biopsy or biopsy‐naïve), MRI pulse sequences (mpMRI or bpMRI or additional spectroscopy), MRI scoring system, MRI suspicion score threshold for MRI‐targeted biopsy, navigational approach of MRI‐targeted biopsy, MRI lesion location, number of biopsy cores (or biopsy density) and core distribution in the reference standard.

Methods

Criteria for considering studies for this review

Types of studies

We considered any cross‐sectional study, if it investigated:

the diagnostic accuracy of one or more of the index tests (MRI, MRI pathway (including MRI‐targeted biopsy) or systematic biopsy) verified by the reference standard (template‐guided biopsy), with each index test and reference standard performed in the same men or compared as in a randomised trial of test accuracy; or
agreement evidence between the MRI pathway and systematic biopsy, with each test performed in the same men.

Studies involving MRI had to report on both MRI‐positive and MRI‐negative men.

We excluded studies when we could not extract a complete two‐by‐two table on a per‐participant basis for the primary target condition, even after contacting the study authors.

We did not apply any language or other restrictions.

Participants

The study population consisted of men with a clinical suspicion of prostate cancer (based on PSA or digital rectal exam (DRE) outcome) in the biopsy‐naïve or prior‐negative biopsy setting (or a mix of both). We excluded men with a previous diagnosis of prostate cancer.

Index tests

MRI

MRI was comprised of at least T2‐weighted imaging and one functional imaging technique (DWI or DCE), reported according to any MRI‐scoring system. The assessment categories for prostate MRI are based on a 5‐point scale (Likert or PI‐RADS), defined as very low (1), low (2), intermediate (3), high (4) and very high (5) (Dickinson 2011; Weinreb 2016). We defined the default threshold for MRI‐positivity as 3/5 or more where possible. We categorised thresholds from related assessment scores such as 2/4 or more, 6/10 or more and 5/15 or more as low, intermediate and high, based on expert opinion, for the purpose of heterogeneity analyses. We performed sensitivity analyses with studies that used a threshold of 3/5 or more. We performed additional analyses by increasing or decreasing the MRI‐positivity threshold, categorizing the MRI scores into 4/5 or more and 2/5 or more. We based all the analyses on per‐participant analysis and not on per‐lesion analysis, therefore, we did not take into account spatial concordance between MRI findings and biopsy findings.

MRI‐targeted biopsy

MRI‐targeted biopsy included only MRI‐positive men. We included all methods for MRI‐targeted biopsy (direct in‐bore, visual‐registration or software‐registration). We extracted data for this index test from studies reporting on the MRI pathway verified by the reference standard. We defined a positive MRI‐targeted biopsy as a histopathological confirmation of one of the target conditions in the MRI‐targeted biopsy cores.

The MRI pathway

The MRI pathway included MRI‐positive men (in whom MRI‐targeted biopsy was performed) and MRI‐negative men (in whom no MRI‐targeted biopsy was performed), reflecting the complete spectrum of men in the clinical population. We defined a positive MRI pathway as a histopathological confirmation of one of the target conditions by MRI‐targeted biopsy in MRI‐positive men. Therefore, we defined a negative MRI pathway as a negative MRI or a negative MRI‐targeted biopsy Appendix 1.

Systematic biopsy

Systematic biopsy included either systematic transrectal or transperineal ultrasound‐guided biopsies, with generally 8 to 12 cores dedicated to the peripheral zone of the prostate; we excluded studies on additional ultrasound imaging techniques. We defined a positive systematic biopsy as a histopathological confirmation of one of the target conditions in the biopsy cores.

Target conditions

The primary target condition was clinically significant prostate cancer, defined as ISUP grade 2 or higher, based on histopathology findings and scored as Gleason score (GS) 3 + 4 or higher (Epstein 2016). Secondary target conditions were grade 1 (GS 3 + 3, indolent prostate cancer) and grade 3 or higher (GS 4 + 3 or higher). We based all target conditions on ISUP grade only, without cancer volume criteria, in order to overcome differences between definitions and biopsy methods, according to START guidelines (Moore 2013a).

Reference standards

Template‐guided biopsy served as the reference standard. In general, two different techniques are used: the transperineal template‐guided mapping biopsy (TTMB) and the template‐guided saturation biopsy (TSB). TTMB is defined as “transperineal TRUS‐guided biopsies of the prostate performed with the patient in lithotomy position using a 5‐mm brachytherapy grid, with at least one biopsy from each hole”. TSB is defined as “20 or more transperineal or transrectal TRUS‐guided biopsies of the prostate performed with the intention to comprehensively sample the whole prostate, according to a predefined core distribution pattern” (Kuru 2013b; Sivaraman 2015). Template‐guided biopsies using a uniform grid and taken at 5 mm intervals can technically only miss those tumours that are smaller than the distance between the adjacent cores (Ahmed 2011; Sivaraman 2015). The sensitivity and negative predictive value of this technique for detecting grade 2 or higher prostate cancer 0.5 cm³ or greater in volume have both been shown to be 95%, with a sensitivity of 76% for detecting all cancers (Ahmed 2011; Crawford 2013; Simmons 2014). Although the template‐guided biopsy is not perfect, owing to the fact that the test accuracy depends on the intensity of cores taken and core trajectory (Huo 2012; Pham 2015; Valerio 2015), it is the optimal reference standard, as it avoids the biases of other reference standards that have been used as described in the Rationale. An alternative approach could be to use template‐guided biopsy in combination with other biopsy methods (a ‘composite’ reference standard) to overcome the inadequacy of template‐guided biopsy only; however, this would introduce incorporation bias.

Therefore, in this analysis, we used only template‐guided biopsy as the reference standard. Template‐guided biopsy had to comprehensively sample all (including the anterior) zones of the prostate, with a minimum of 20 biopsy cores. We defined a positive template‐guided biopsy as histopathological confirmation of one of the target conditions within the biopsy cores. We used the alternative composite reference standard in the sensitivity analyses.

Search methods for identification of studies

Electronic searches

We performed a comprehensive search, with no restriction on language of publication or publication status, in the following electronic databases:

Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 7) in the Cochrane Library (searched 31 July 2018), including ClinicalTrials;
MEDLINE Ovid, including electronic publications ahead of print (from inception to 31 July 2018);
Embase.com (from inception to 31 July 2018);
CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from inception to 31 July 2018);
Web of Science (Core Collection) (from inception to 31 July 2018);
Scopus (from inception to 31 July 2018);
Google.com (31 July 2018);
Google Scholar (31 July 2018);
WorldCat (31 July 2018);
ProQuest (ProQuest Dissertations & Theses; 31 July 2018);
OpenGrey (31 July 2018).

The search strategies are provided in Appendix 2.

Searching other resources

We searched for additional references in the Science Citation Index of Web of Science and by manually searching the references of relevant articles.

We also searched the following trials registers for planned or ongoing studies:

ClinicalTrials.gov (31 July 2018);
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 31 July 2018);
Open trials (https://opentrials.net/, searched 31 July 2018).

We searched Embase and Web of Science for conference proceedings.

Data collection and analysis

Selection of studies

We checked the primary search results for overlapping content and Cochrane Urology's Information Specialist deduplicated the search results (Bramer 2016). Two reviewers (FD, DO) independently screened all abstracts and full‐text articles for eligibility according to the Criteria for considering studies for this review. We contacted study authors to obtain additional information when reported data were insufficient. When more than one publication on the same cohort was found, we selected the most complete publication. We resolved disagreements by consensus (FD, DO and IS).

Data extraction and management

Two review authors (FD, DO) extracted data using a predefined data‐extraction form. FD and DO extracted variables on study methodology, patient characteristics, test characteristics, the definition of target conditions and results. We constructed two‐by‐two tables for cross‐classification of the index tests versus reference standard for test accuracy data, and the MRI pathway versus systematic biopsy for agreement data, based on per‐participant data (Appendix 1). We contacted study authors to obtain additional information when necessary. We resolved any data extraction disagreements by consensus (FD, DO, IS).

Assessment of methodological quality

Two review authors (FD, DO) independently assessed all included studies for methodological quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool (Whiting 2011), tailored to this review (Table 7). We resolved any discrepancies by discussion (FD, DO, IS).

1. QUADAS‐2 tool for assessing methodological quality of included studies.

Domain 1: Participant selection
SQ 1: Was a consecutive or random sample of participants enrolled?	Yes: if stated that participants were consecutively or randomly selected No: if one of these criteria was not met Unclear: if insufficient information to make a judgement
SQ 2: Did the study avoid inappropriate exclusions?	Yes: if stated that the study did not exclude men 1) aged between 50 and 70 years, 2) with PSA values between 4 and 10 ng/mL, or 3) with an abnormal DRE No: if one of these criteria was not met Unclear: insufficient information to make a judgement
Risk of bias Could the selection of participants have introduced bias?	Low risk: if ‘Yes’ for all SQ's High risk: if ‘No’ for at least 1 SQ Unclear risk: if 'Unclear' for at least 1 SQ
Concerns for applicability Are there concerns that the included participants and setting do not match the review question?	Low concern: the participants were referred because of a suspicion of prostate cancer. High concern: the participants were not referred because of a suspicion of prostate cancer, e.g. PSA‐screening trials are less applicable to the current clinical practice. Unclear concern: insufficient information to make a judgement
Domain 2: Index texts
SQ 1: If applicable, was the MRI assessed without knowledge of the results of the reference (or other index) biopsies?	Yes: if stated that the radiologist was unaware of all biopsy results; or, if the order of testing was MRI before all biopsies for every participant No: if stated that the radiologist was aware of any biopsy results during MRI assessment Unclear: insufficient information to make a judgement
SQ 2: If applicable, were the MRI‐targeted biopsies performed independently of the performance and the results of the reference (or other index) biopsies?	Yes: if stated that the performance of MRI‐targeted biopsies was not influenced by the performance or trajectory of reference (or other index) biopsies No: if stated that MRI‐targeted biopsies were not, or differently, taken from locations already hit by the reference (or other index) biopsies; or, if the performance of MRI‐targeted biopsies was dependent on the judgement of the same operator that also performed the reference (or other index) biopsies without blinding Unclear: insufficient information to make a judgement
SQ 3: If applicable, were the systematic biopsies taken independently of the performance and the results of the reference (of other index) biopsies?	Yes: if stated that the systematic biopsies were taken blinded for the results of the MRI the reference or other index biopsy trajectories No: if stated that the systematic biopsy operator was not blinded for MRI results, or was the same operator that also performed the reference (or other index) biopsies without blinding Unclear: insufficient information to make a judgement
Risk of bias Could the conduct or interpretation of the index test have introduced bias?	Low risk: ‘Yes’ for all applicable SQs High risk: ‘No’ for at least one applicable SQ Unclear risk: ‘Unclear’ for at least one applicable SQ
Concerns for applicability Are there concerns that the index tests, their conduct or their interpretation differ from the review question?	Low concern: if stated that, when applicable, a 1.5 or 3 Tesla magnet was used for MRI acquisition, with at least T2 and DWI or DCE sequencing; the MRI‐scoring system and positivity‐threshold for MRI‐targeted biopsy consisted of a 1‐5 score with threshold ≥ 3; software‐assisted, cognitive or in‐bore MRI‐targeted biopsies were taken, an extended sextant systematic biopsy was performed with 8‐19 cores distributed appropriately to sample the peripheral zone. High concern: the index test did not meet the criteria above Unclear concern: insufficient information to make a judgement
Domain 3: Reference standard
SQ1: Is the reference standard likely to correctly classify the target condition? (i.e. Is histological diagnosis made from appropriately sampled tissue?)	Yes: if stated that the whole prostate was comprehensively sampled by a full 5‐mm transperineal TTMB, or by a equivalently well described transperineal template‐guided biopsy method with a prostate volume based median of ≤ 20 biopsy cores. No: one of these criteria was not met (i.e. in‐house transperineal saturation biopsy or transrectal saturation biopsy are less likely to appropriately sample the whole prostate). Unclear: insufficient information to make a judgement
SQ2: Was the reference standard performed independent of the index test?	Yes: if stated that the reference biopsies were taken without knowledge of the MRI‐score and location of target lesions; and, if incorporation was avoided (i.e. the index test was not part of the reference standard). No: one of these criteria was not met Unclear: insufficient information to make a judgement
Risk of bias Could the reference standard, its conduct, or its interpretation have introduced bias?	Low risk: 'Yes’ for all SQs High risk: ’No’ for at least 1 of the 3 SQs Unclear risk: ’Unclear’ for at least 1 SQ
Concerns for applicability Are there concerns that the target condition as defined by the reference standard does not match the question?	Low concern: data were presented for GS ≥ 3+4 without any volume criteria (ISUP grade ≥ 2), if necessary after requesting additional data from study authors High concern: data were presented for an alternative target condition definition and study authors did not provide additional data. Unclear: insufficient information to make a judgement
Domain 4: Flow and timing
SQ1: Did all participants receive the same biopsy methods (i.e. was differential verification avoided)?	Yes: if stated that all participants received the same type of index test(s) and reference standard, prostate volume dependency was allowed. No: if one of these criteria was not met Unclear: if insufficient information to make a judgement
SQ2: Were all enrolled participants included in the analysis, or were exclusions explained and not leading to a relevant bias?	Yes: if stated that all eligible participants were enrolled and included in the final analyses; or, if reasons to excluded participants did not cause a relevant bias (e.g. participants with claustrophobia who refused MRI). No: one of these criteria was not met. Unclear: if insufficient information to make a judgement
Risk of bias Could the participant flow have introduced bias?	Low risk: ’Yes’ for all SQs High risk: ’No’ for at least 1 SQ Unclear risk: ’Unclear’, for at least 1 SQ
DCE: dynamic contrast‐enhanced; DRE: digital rectal examination; DWI: diffusion‐weighted imaging; MRI: magnetic resonance imaging; PSA: prostate‐specific antigen; QUADAS: Quality Assessment of Diagnostic Accuracy Studies; SQ: signalling question; TTMB: template‐guided mapping biopsy; ISUP: International Society of Urological Pathology

Question: Should MRI be used to diagnose ISUP grade 2 or higher prostate cancer in men suspected of having clinically significant prostate cancer?
Population: men suspected of having clinically significant prostate cancer undergoing their first biopsy (biopsy‐naïve men) or a repeat biopsy (prior‐negative biopsy men)
Setting: university hospitals and specialized care centers
New test: MRI only \| Cut‐off value: MRI score ≥ 3 out of 5
Reference test: template‐guided biopsy, which comprehensively samples all zones of the prostate \| Threshold: ISUP grade 2 or higher prostate cancer
Pooled sensitivity: 0.91 (95% CI: 0.83 to 0.95) \| Pooled specificity: 0.37 (95% CI: 0.29 to 0.46)
Test result	Number of results per 1,000 men tested (95% CI)			Number of participants (studies)	Certainty of the evidence (GRADE)
	Prevalence 10%	Prevalence 30%	Prevalence 40%
True positives	9 (83 to 95)	273 (249 to 285)	364 (332 to 380)	3091 (12)	⊕⊕○○ LOW^{a, b}
False negatives	9 (5 to 17)	27 (15 to 51)	36 (20 to 68)
True negatives	333 (261 to 414)	259 (203 to 322)	222 (174 to 276)	3091 (12)	⊕⊕○○ LOW^{a, b}
False positives	567 (486 to 639)	441 (378 to 497)	378 (324 to 426)
MRI: magnetic resonance imaging; ISUP: International Society of Urological Pathology; CI: confidence interval ^aA considerable number of studies had a high or unclear risk of bias, mainly in the participant selection and reference standard domains.  ^bA considerable, clinically relevant heterogeneity was observed across pooled study results.

Question: Should MRI‐targeted biopsy be used to diagnose ISUP grade 2 or higher prostate cancer in men suspected of having clinically significant prostate cancer?
Population: men with a positive MRI suspected of having clinically significant prostate cancer undergoing their first biopsy (biopsy‐naïve men) or a repeat biopsy (prior‐negative biopsy men)
Setting: university hospitals and specialized care centers
New test: MRI‐targeted biopsy \| Threshold: ISUP grade 2 or higher prostate cancer
Reference test: template‐guided biopsy, which comprehensively samples all zones of the prostate \| Threshold: ISUP grade 2 or higher prostate cancer
Pooled sensitivity: 0.80 (95% CI: 0.69 to 0.87) \| Pooled specificity: 0.94 (95% CI: 0.90 to 0.97)
Test result	Number of results per 1,000 men tested (95% CI)			Number of participants (studies)	Certainty of the evidence (GRADE)
	Prevalence 10%	Prevalence 30%	Prevalence 40%
True positives	80 (69 to 87)	240 (207 to 261)	320 (276 to 348)	1553 (8)	⊕⊕○○ LOW^{a, b}
False negatives	20 (13 to 31)	60 (39 to 93)	80 (52 to 124)
True negatives	846 (810 to 873)	658 (630 to 679)	564 (540 to 582)	1553 (8)	⊕⊕○○ LOW^{a, b}
False positives	54 (27 to 90)	42 (21 to 70)	36 (18 to 60)
MRI: magnetic resonance imaging; ISUP: International Society of Urological Pathology; CI: confidence interval ^aA considerable number of studies had a high or unclear risk of bias, mainly in the participant selection and reference standard domains.  ^bA considerable, clinically relevant heterogeneity was observed across pooled study results.

Question: Should an MRI pathway be used to diagnose ISUP grade 2 or higher prostate cancer in men suspected of having clinically significant prostate cancer?
Population: men suspected of having clinically significant prostate cancer undergoing their first biopsy (biopsy‐naïve men) or a repeat biopsy (prior‐negative biopsy men)
Setting: university hospitals and specialized care centers
New test: MRI pathway \| Threshold: ISUP grade 2 or higher prostate cancer
Reference test: template‐guided biopsy, which comprehensively samples all zones of the prostate \| Threshold: ISUP grade 2 or higher prostate cancer
Pooled sensitivity: 0.72 (95% CI: 0.60 to 0.82) \| Pooled specificity: 0.96 (95% CI: 0.94 to 0.98)
Test result	Number of results per 1,000 men tested (95% CI)			Number of participants (studies)	Certainty of the evidence (GRADE)
	Prevalence 10%	Prevalence 30%	Prevalence 40%
True positives	72 (60 to 82)	216 (180 to 246)	288 (240 to 328)	2257 (8)	⊕⊕○○ LOW^{a, b}
False negatives	28 (18 to 40)	84 (54 to 120)	112 (72 to 160)
True negatives	864 (846 to 882)	672 (658 to 686)	576 (564 to 588)	2257 (8)	⊕⊕○○ LOW^{a, b}
False positives	36 (18 to 54)	28 (14 to 42)	24 (12 to 36)
MRI pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; ISUP: International Society of Urological Pathology; CI: confidence interval ^aA considerable number of studies had a high or unclear risk of bias, mainly in the participant selection and reference standard domains.  ^bA considerable, clinically relevant heterogeneity was observed across pooled study results.

Question: Should systematic biopsy be used to diagnose ISUP grade 2 or higher prostate cancer in men suspected of having clinically significant prostate cancer?
Population: men suspected of having clinically significant prostate cancer undergoing their first biopsy (biopsy‐naïve men) or a repeat biopsy (prior‐negative biopsy men)
Setting: university hospitals and specialized care centers
New test: systematic biopsy \| Threshold: ISUP grade 2 or higher prostate cancer
Reference test: template‐guided biopsy, which comprehensively samples all zones of the prostate \| Threshold: ISUP grade 2 or higher prostate cancer
Pooled sensitivity: 0.63 (95% CI: 0.19 to 0.93) \| Pooled specificity: 1.00 (95% CI: 0.91 to 1.00)
Test result	Number of results per 1,000 men tested (95% CI)			Number of participants (studies)	Certainty of the evidence (GRADE)
	Prevalence 10%	Prevalence 30%	Prevalence 40%
True positives	63 (19 to 93)	189 (57 to 279)	252 (76 to 372)	3421 (4)	⊕⊕⊕○ MODERATE^{a, b, c}
False negatives	37 (7 to 81)	111 (21 to 243)	148 (28 to 324)
True negatives	900 (819 to 900)	700 (637 to 700)	600 (546 to 600)	3421 (4)	⊕⊕○○ LOW^{a, b, c}
False positives	0 (0 to 81)	0 (0 to 63)	0 (0 to 54)
ISUP: International Society of Urological Pathology; CI: confidence interval ^aA considerable number of studies had a high or unclear risk of bias, mainly in the participant selection and reference standard domains.  ^bA considerable, clinically relevant heterogeneity was observed across pooled study results.  ^cImportant imprecision was noted, which contributed to decision to downgrade for inconsistency.

Study				MRI	Index biopsy	Reference standard			Target  conditions
Study	Consecutive  enrolment  (study design^a)	N of  participants	Index  test(s)	MRI‐scale;  threshold	MRI‐TBx  Technique/route	Technique	Median N  cores (range)	Independence	ISUP  grade  (G)
Abd‐Alazeez 2014	No  (retrospective)	54	MRI	1‐5; ≥ 3	Cognitive/transperineal	TTMB	45 (21‐137)	No	G = 1  G ≥ 2  G ≥ 3
Ahmed 2017	Yes  (prospective)	576	MRI, SBx	1‐5; ≥ 3	NA/transrectal	TTMB	> 40^b	Yes	G = 1  G ≥ 2  G ≥ 3
Dal Moro 2019	Yes  (prospective)	123	MRI,  MRI‐TBx,  MRI‐pathway	1‐5; ≥ 3	Cognitive/transrectal	TSB^c	24^d	Yes	G = 1  G ≥ 2  G ≥ 3
Distler 2017	Yes  (prospective)	Bx‐naïve: 597  Prior‐negative Bx: 443	MRI,  MRI‐TBx,  MRI‐pathway	1‐5; ≥ 3	Software/transperineal	TSB^e	24 (22‐25)	No	G ≥ 2
Grey 2015	Yes  (prospective)	Bx‐naïve: 83  Prior‐negative Bx: 103	MRI	1‐5; ≥ 3	Cognitive/transperineal	TSB^e	(24‐40)	No	G = 1  G ≥ 2  G ≥ 3
Hansen 2016a	Yes  (prospective)	295	MRI,  MRI‐TBx,  MRI‐pathway	1‐5; ≥ 3	Software/transperineal	TSB^e	(18‐24)	Unclear	G = 1  G ≥ 2  G ≥ 3
Hansen 2018	Yes  (prospective)	Centre 1: 163  Centre 3: 242	MRI	1‐5; ≥ 3	Software,  cognitive/transperineal	TSB^e	24 (22‐26^f),  20 (20‐21^f)	No	G = 1  G ≥ 2  G ≥ 3
Hansen 2017	Unclear  (prospective)	287	MRI,  MRI‐TBx,  MRI‐pathway	1‐5; ≥ 3	Software/transperineal	TSB^e	24 (24‐25)	Unclear	G ≥ 2
Kesch 2017	Unclear  (prospective)	Bx‐naïve: 95  Prior‐negative Bx: 51	MRI,  MRI‐TBx,  MRI‐pathway	1‐5; ≥ 3	Software/transperineal	TSB^g	24 (23‐27^f)	Yes	G = 1  G ≥ 2  G ≥ 3
Lawrence 2014	No  (retrospective)	39	MRI,  MRI‐TBx,  MRI‐pathway	1‐4; ≥2	Software/transperineal	TSB^e	24 (14‐34)	No	G = 1  G ≥ 2
Mortezavi 2018	Yes  (retrospective)	163  86	MRI,  MRI‐TBx,  MRI‐pathway	1‐5; ≥ 3	Software/Transrectal	TSB	40 (30‐55)	No	G = 1  G ≥ 2  G ≥ 3
Muthuveloe 2016	Unclear  (retrospective)	9  162	MRI	1‐5; ≥ 3	NA	TSB^h	24 (24–28)	Unclear	G = 1  G ≥ 2  G ≥ 3
Pepe 2013	Unclear  (prospective)	78	MRI,  MRI‐TBx,  MRI‐pathway	0‐1: ≥1	Cognitive/transrectal	TSB^h	28 (26‐32)	No	G = 1  G ≥ 2
Thompson 2016	Yes  (prospective)	344	MRI	1‐5; ≥ 3	Software,  cognitive/transperineal	TTMB	30	No	G = 1  G ≥ 2  G ≥ 3
Tsivian 2017	Unclear  (retrospective)	33	MRI	1‐5; ≥ 3	NA	TTMB	55 (42‐63^f)	Yes	G = 1  G ≥ 2  G ≥ 3
Nafie 2014	Unclear  (prospective)	50	SBx	NA	NA/transrectal	TSB^h	36	Yes	G = 1  G ≥ 2  G ≥ 3
Nafie 2017	Unclear  (prospective)	42	SBx	NA	NA/transrectal	TSB^h	36	Yes	G = 1  G ≥ 2
Ploussard 2014	Yes  (prospective)	2753	SBx	NA	NA/transrectal	TSB^c	21	No	G = 1  G ≥ 2
Bx: biopsy; ISUP G : International Society of Urological Pathology grade; MRI: magnetic resonance imaging; MRI‐pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy; N: number; NA: not applicable; PI‐RADS v1, v2: Prostate Imaging Reporting Data System version 1 or 2; SBx: systematic biopsy; TSB: transperineal saturation biopsy; TTMB: transperineal template mapping biopsy

Patient characteristics of the included diagnostic test accuracy studies
Study	Population	Median age  (range/SD)	Median PSA  in ng/mL (range)	Median prostate  volume in cm³  (range)
Abd‐Alazeez 2014	Prior‐negative Bx	64 (39‐75)	10 (2‐23)	53 (19‐136)
Ahmed 2017	Bx‐naïve	63 (7.6)^a	7.1 (2.9)^a	NR
Dal Moro 2019	Prior‐negative Bx	62 (57‐68^b)	6.3 (4,8‐8,9^b)	55 (20‐149)^a
Distler 2017	Mixed^c	65 (60‐71^b)	7.2 (5.3‐10.4^b)	45 (34‐64^b)
Grey 2015	Mixed^c	64 (6.8)^a  65 (7.6)^a	13.3 (12,1)^a  12.6 (13.7)^a	68 (35)^a  54 (31)^a
Hansen 2016a	Prior‐negative Bx	65 (59‐69^b)	7.8 (6.0‐12^b)	65 (44‐83^b)
Hansen 2018	Bx‐naïve	64 (57‐69^b)  65 (60‐70^b)	6.6 (4.6‐9.0^b)  5.9 (4.6‐8.0^b)	44 (33‐55^b)  25 (24‐47^b)
Hansen 2017	Prior‐negative Bx	66 (61‐72^b)	9.7 (7.1‐13.9^b)	52 (36‐75^b)
Kesch 2017	Mixed^c	65 (58‐71^b)	7.2 (5.4‐10.2^b)	46 (36‐60^b)
Lawrence 2014	Prior‐negative Bx	64 (47‐77)^a	10 (1.2‐36)	NR
Mortezavi 2018	Bx‐naïve  Prior‐negative Bx	63 (57‐68^b)  64 (60‐69^b)	5.8 (4.4‐8.9^b)  8.6 (5.7‐13^b)	44 (34‐60^b)  54 (41‐70^b)
Muthuveloe 2016	Bx‐naïve  Prior‐negative Bx	68 (46‐81)  65 (47‐78)^d	11.5 (1.2‐92.5) 10 (2.7‐61)^d	NR
Pepe 2013	Prior‐negative Bx	63 (49‐72)	11 (3.7‐45)	NR
Thompson 2016	Bx‐naïve	63 (56‐67^b)	5.2 (3.7‐7.1^b)	40 (30‐54^b)
Tsivian 2017	Prior‐negative Bx	65 (61‐69^b)	7.1 (5.1‐13.6^b)	44 (32‐65^b)
Nafie 2014	Bx‐naïve	67 (54‐84)^a	8 (4‐18)^a	58 (19‐165)^a
Nafie 2017	Prior‐negative Bx	65 (50‐75)^a	8.3 (4.4‐19)^a	59 (21‐152)^a
Ploussard 2014	Bx‐naïve	64 (8)^a	12.5 (7.2)^a	46 (25)^a
Bx: biopsy; NR: not reported; PSA: prostate specific antigen

Study	Population	Median age  (range)	Median PSA  in ng/mL (range)	Median prostate  volume in cm³  (range)
Alberts 2017^a	Bx‐naïve  Prior‐negative Bx	73 (72‐74^b)	4.2 (3.4–5.8^b)	53 (37‐71^b)
Boesen 2017a	Prior‐negative Bx	65 (58‐68^b)	12.8 (8.9‐19.6^b)	NR
Boesen 2018	Bx‐naïve	67 (61‐71^b)	8 (5.7‐13^b)	53 (40‐72^b)
Castellucci 2017	Bx‐naïve	61 (8)^c	8.3 (6.1)^c	49 (7)^c
Chang 2017	Prior‐negative Bx	64 (60‐68^b)	10.9 (7.2‐14.7^b)	48 (34‐63^b)
Chen 2015	Bx‐naïve	67 (45‐91)	9.7 (2.4‐35.7)	45 (21‐83)
Cool 2016	Bx‐naïve  Prior‐negative Bx	59 (8)^c  62 (7)^c	6.0 (3.5)^c  7.9 (3.9)^c	38 (18)^c  56 (27)^c
Costa 2013	Prior‐negative Bx	64 (48‐77)^c	14.4 (1.8‐33.1)^c	NR
Delongchamps 2013	Bx‐naïve	64 (7)^c	8.5 (3.9)^c	56 (30)^c
Filson 2016	Bx‐naïve  Prior‐negative Bx	64 (59‐69^b)  66 (59‐70^b)	5.8 (4.4‐8.1^b)  7.6 (5‐11.5^b)	45(33‐62^b)  58 (40‐84^b)
Garcia Bennett 2017	Bx‐naïve	64 (6.7)^c	7.2 (6‐9.4^b)	48 (35‐63^b)
Grönberg 2018^a	Bx‐naïve  Prior‐negative Bx	64 (45–74)^c	6.3 (4.4^b)	(32‐70)^d
Jambor 2015	Bx‐naïve	66 (47‐76)	7.4 (4‐14)	42 (17‐107)
Jambor 2017^a	Mixed	65 (6)^c	7.5 (5.7‐9.6^b)	37 (28‐49^b)
Kim 2017	Bx‐naïve  Prior‐negative Bx	64 (7)^c	10.2 (15.1)^c	NR
Lee 2016	Bx‐naïve	66 (43‐83)	6.4 (3.3‐9.8)	39 (17‐127)
Lee 2017	Bx‐naïve	62 (10)^c	6.4 (1.8)^c	40 (18)^c
Okcelik 2016	Bx‐naïve	62 (43‐79)	5 (3‐8.9)	45 (17‐93)
Panebianco 2015^a	Bx‐naïve  Prior‐negative Bx	64 (51‐82)	NR	NR
Peltier 2015	Bx‐naïve	65 (7)^c	8.4 (6.3)^c	49 (22)^c
Pokorny 2014	Bx‐naïve	63 (57‐68^b)	5.3 (4.1‐6.6^b)	41 (30‐59^b)
Rouvière 2019a	Bx‐naïve	64 (59‐68^b)	6.5 (5.6‐9.6^b)	50 (38‐63^b)
Say 2016	Prior‐negative Bx	64 (47‐82)^c	11.59 (0.4‐96.9)^c	69 (17‐309)^c
Tonttilla 2016	Bx‐naïve	63 (60‐66^b)	6.1 (4.2‐9.9^b)	28 (24‐37^b)
Van der Leest 2018	Bx‐naïve	65 (59‐68^b)	6.4 (4.6‐8.2^b)	55 (41‐77^b)
Bx: biopsy; NR: not reported; PSA: prostate specific antigen

Diagnostic accuracy of the index tests verified by template‐guided biopsy as the reference standard
Index test	MRI  population^a	Target  condition	N participants  (studies)	Proportion  negative MRI  (95% CI)	Sensitivity  (95% CI)	Specificity  (95% CI)	P value
MRI	Positive + negative	G = 1	1764 (10)	0.28 (0.20 to 0.38)	0.70 (0.59 to 0.80)	0.27 (0.19 to 0.37)	P < 0.01^b
		G ≥ 1	1764 (10)	0.39 (0.30 to 0.50)	0.84 (0.74 to 0.90)	0.39 (0.30 to 0.50)	NA
		G ≥ 2	3091 (12)	0.29 (0.22 to 0.37)	0.91 (0.83 to 0.95)	0.37 (0.29 to 0.46)	P < 0.01^b
		G ≥ 3	1438 (7)	0.31 (0.21 to 0.42)	0.95 (0.87 to 0.99)	0.35 (0.26 to 0.46)	ID
MRI‐TBx	Positive	G = 1	497 (5)	NA	0.51 (0.21 to 0.81)	1.00 (0.77 to 1.00)	NA
		G ≥ 1	611 (6)	NA	0.71 (0.61 to 0.80)	0.93 (0.87 to 0.96)	NA
		G ≥ 2	1553 (8)	NA	0.80 (0.69 to 0.87)	0.94 (0.90 to 0.97)	NA
		G ≥ 3	428 (3)	NA	ID	ID	ID
MRI‐pathway	Positive + negative	G = 1	681 (5)	0.24 (0.16 to 0.36)	0.34 (0.19 to 0.53)	1.00 (0.90 to 1.00)	P = 0.52^c
		G ≥ 1	844 (6)	0.28 (0.21 to 0.35)	0.58 (0.52 to 0.65)	0.96 (0.92 to 0.98)	NA
		G ≥ 2	2257 (8)	0.29 (0.24 to 0.35)	0.72 (0.60 to 0.82)	0.96 (0.94 to 0.98)	P = 0.06^c
		G ≥ 3	604 (3)	0.29 (0.26 to 0.33)	ID	ID	ID
SBx	NA	G = 1	3421 (4)	NA	0.55 (0.25 to 0.83)	0.99 (0.81 to 1.00)	NA
		G ≥ 1	3421 (4)	NA	0.65 (0.31 to 0.88)	1.00 (0.88 to 1.00)	NA
		G ≥ 2	3421 (4)	NA	0.63 (0.19 to 0.93)	1.00 (0.91 to 1.00)	NA
		G ≥ 3	626 (2)	NA	ID	ID	ID
CI: confidence interval; G: International Society of Urological Pathology grade; ID: inadequate data; MRI: magnetic resonance imaging; MRI‐pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy; N: number; NA: not applicable; SBx: systematic biopsy

Predictive values of the index tests and prostate cancer prevalences
Test	MRI  population^a	Target  condition	N participants  (studies)	Prevalence^b  (95% CI)	NPV^c  (95% CI)	PPV^c  (95% CI)
MRI	Positive + negative	G = 1	1764 (10)	0.20 (0.17 to 0.23)	0.79 (0.74 to 0.82)	0.20 (0.18 to 0.21)
		G ≥ 2	3091 (12)	0.29 (0.22 to 0.38)	0.91 (0.86 to 0.94)	0.37 (0.35 to 0.39)
		G ≥ 3	1438 (7)	0.14 (0.08 to 0.23)	0.98 (0.95 to 0.99)	0.19 (0.17 to 0.21)
MRI‐TBx	Positive	G = 1	497 (5)	0.22 (0.19 to 0.26)	0.88 (0.78 to 0.94)	0.98 (0.23 to 1.00)
		G ≥ 2	1553 (8)	0.34 (0.24 to 0.46)	0.90 (0.85 to 0.93)	0.88 (0.80 to 0.92)
		G ≥ 3	428 (3)	0.21 (0.12 to 0.35)	ID	ID
MRI‐pathway	Positive + negative	G = 1	681 (5)	0.21 (0.18 to 0.24)	0.85 (0.81 to 0.88)	0.95 (0.38 to 1.00)
		G ≥ 2	2257 (8)	0.26 (0.18 to 0.36)	0.91 (0.87 to 0.94)	0.88 (0.80 to 0.92)
		G ≥ 3	604 (3)	0.16 (0.09 to 0.27)	ID	ID
SBx	NA	G = 1	3421 (4)	0.20 (0.16 to 0.25)	0.90 (0.81 to 0.95)	0.94 (0.37 to 1.00)
		G ≥ 2	3421 (4)	0.34 (0.21 to 0.51)	0.84 (0.60 to 0.95)	1.00 (0.76 to 1.00)
		G ≥ 3	626 (2)	0.10 (0.08 to 0.12)	ID	ID
CI: confidence interval; G: International Society of Urological Pathology grade; ID: inadequate data; MRI: magnetic resonance imaging; MRI‐pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy; NA: not applicable; NPV: negative predictive value; PPV: positive predictive value; SBx: systematic biopsy

MRI‐positivity threshold effect, verified by template‐guided biopsy as the reference standard, with threshold ≥ 3and ≥ 4 out of 5 for identifying prostate cancer
MRI threshold	Target  condition	N participants  (studies)^a	Proportion  negative MRI  (95% CI)	Sensitivity  (95% CI)	Specificity  (95% CI)
≥ 3/5	G = 1	1647 (8)	0.29 (0.21 to 0.40)	0.68 (0.57 to 0.77)	0.28 (0.19 to 0.39)
	G ≥ 2	2974 (10)	0.30 (0.23 to 0.38)	0.89 (0.82 to 0.94)	0.39 (0.32 to 0.47)
	G ≥ 3	1438 (7)	0.31 (0.21 to 0.42)	0.96 (0.87 to 0.99)	0.35 (0.26 to 0.46)
≥ 4/5	G = 1	834 (4)	0.60 (0.38 to 0.78)	0.26 (0.16 to 0.40)	0.57 (0.36 to 0.76)
	G ≥ 2	1083 (5)	0.59 (0.43 to 0.74)	0.72 (0.52 to 0.86)	0.78 (0.68 to 0.86)
	G ≥ 3	834 (4)	0.60 (0.38 to 0.78)	0.86 (0.51 to 0.97)	0.68 (0.51 to 0.81)
CI: confidence interval; G: International Society of Urological Pathology grade; MRI: magnetic resonance imaging; N: number

Population		Target condition	N participants (studies)	Proportion prostate cancer detected in % (95% CI)			Detection ratio^b  (95% CI)		Difference  between  populations,  P value^c
Biopsy status	MRI, proportion in % (95% CI)^a	Target condition	N participants (studies)	MRI‐pathway and SBx combined (total cancer detected)	MRI‐pathway	SBx	MRI‐pathway versus SBx	P value	Difference  between  populations,  P value^c
Mixed^d	Positive + negative  100 (100 to 100)	G = 1	5442 (21)	25.6 (22.8 to 28.8)	12.3 (10.1 to 15.1)	20.8 (18.0 to 24.1)	0.61 (0.52 to 0.71)	P < 0.01	NA
		G ≥ 1	6524 (24)	50.2 (46.4 to 54.3)	37.9 (33.4 to 42.6)	43.3 (39.1 to 47.8)	0.88 (0.81 to 0.95)	P < 0.01	NA
		G ≥ 2	6944 (25)	26.7 (23.3 to 30.7)	22.9 (19.5 to 26.8)	19.4 (15.9 to 23.5)	1.12 (1.02 to 1.23)	P = 0.01	NA
		G ≥ 3	5981 (21)	15.0 (12.7 to 18.0)	12.7 (10.5 to 15.6)	9.7 (7.5 to 12.7)	1.20 (1.06 to 1.36)	P < 0.01	NA
	Positive  67.6 (60.2 to 74.3)	G = 1	3460 (19)	29.5 (26.0 to 33.8)	18.8 (15.2 to 23.4)	22.4 (18.9 to 26.9)	0.85 (0.75 to 0.97)	P = 0.01	NA
		G ≥ 1	3998 (20)	68.0 (62.3 to 73.5)	61.1 (54.1 to 67.7)	58.9 (51.5 to 65.9)	1.03 (0.95 to 1.10)	P = 0.52	NA
		G ≥ 2	3998 (20)	42.6 (37.6 to 48.1)	37.9 (32.7 to 43.7)	31.6 (26.2 to 37.9)	1.17 (1.07 to 1.28)	P < 0.01	NA
		G ≥ 3	3902 (18)	24.2 (20.9 to 28.1)	21.0 (17.8 to 24.8)	16.3 (13.1 to 20.3)	1.24 (1.11 to 1.38)	P < 0.01	NA
Biopsy‐naïve	Positive + negative  100 (100 to 100)	G = 1	4079 (17)	27.2 (23.9 to 31.1)	13.5 (10.7 to 17.2)	22.4 (19.1 to 26.3)	0.63 (0.54 to 0.74)	P < 0.01	P = 0.91
		G ≥ 1	4799 (19)	53.2 (48.7 to 57.9)	41.0 (35.8 to 46.4)	47.8 (42.8 to 52.9)	0.85 (0.77 to 0.93)	P < 0.01	P = 0.12
		G ≥ 2	5219 (20)	27.7 (23.7 to 32.6)	23.4 (19.3 to 28.1)	21.4 (17.2 to 26.5)	1.05 (0.95 to 1.16)	P = 0.35	P < 0.01
		G ≥ 3	4306 (16)	15.5 (12.6 to 19.5)	12.7 (9.9 to 16.5)	10.8 (8.0 to 14.8)	1.09 (0.94 to 1.26)	P = 0.27	P < 0.01
	Positive  67.0 (58.7 to 74.4)	G = 1	2682 (16)	31.8 (27.7 to 36.9)	21.3 (17.0 to 26.9)	23.7 (19.6 to 29.1)	0.85 (0.74 to 0.98)	P = 0.03	P = 0.35
		G ≥ 1	2955 (17)	70.9 (65.0 to 76.6)	63.7 (56.3 to 70.6)	63.8 (56.2 to 70.7)	0.99 (0.92 to 1.08)	P = 0.88	P = 0.05
		G ≥ 2	2955 (17)	44.2 (38.6 to 50.4)	39.2 (33.3 to 45.7)	34.4 (28.3 to 41.3)	1.12 (1.01 to 1.23)	P = 0.03	P < 0.01
		G ≥ 3	2899 (15)	24.8 (21.0 to 29.6)	21.2 (17.4 to 25.7)	17.5 (13.8 to 22.3)	1.16 (1.02 to 1.31)	P = 0.02	P < 0.01
Prior‐negative biopsy	Positive + negative  100 (100 to 100)	G = 1	1202 (8)	23.0 (18.0 to 30.2)	10.9 (7.9 to 15.3)	17.8 (12.7 to 25.2)	0.62 (0.44 to 0.88)	P < 0.01	P = 0.91
		G ≥ 1	1564 (10)	40.7 (35.1 to 47.2)	30.0 (24.1 to 37.0)	30.3 (24.3 to 37.5)	0.97 (0.85 to 1.11)	P = 0.70	P = 0.12
		G ≥ 2	1564 (10)	22.8 (20.0 to 26.2)	20.5 (17.7 to 23.5)	13.2 (10.8 to 16.4)	1.44 (1.19 to 1.75)	P < 0.01	P < 0.01
		G ≥ 3	1514 (9)	12.6 (10.5 to 15.6)	11.5 (9.4 to 14.2)	6.3 (4.4 to 9.1)	1.64 (1.27 to 2.11)	P < 0.01	P < 0.01
	Positive  69.6 (54.7 to 81.3)	G = 1	655 (7)	27.9 (22.1 to 36.2)	18.2 (12.8 to 26.7)	18.9 (13.3 to 27.5)	1.03 (0.89 to 1.18)	P = 0.71	P = 0.35
		G ≥ 1	920 (8)	54.8 (44.6 to 66.4)	48.5 (37.0 to 61.5)	39.4 (27.1 to 53.9)	1.16 (1.02 to 1.32)	P = 0.02	P = 0.05
		G ≥ 2	920 (8)	31.3 (27.4 to 36.1)	28.6 (24.7 to 33.1)	18.3 (15.1 to 22.5)	1.49 (1.22 to 1.82)	P < 0.01	P < 0.01
		G ≥ 3	880 (7)	17.9 (14.3 to 22.9)	16.7 (13.1 to 21.5)	9.4 (6.4 to 14.2)	1.65 (1.30 to 2.09)	P < 0.01	P < 0.01
CI: confidence interval; G: International Society of Urological Pathology grade; MRI: magnetic resonance imaging; MRI‐pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy; N: number; SBx: systematic biopsy

Population		Target  condition	N participants  (studies)	Proportion prostate cancer detected in % (95% CI)
Biopsy status	MRI,  proportion in % (95% CI)^a	Target  condition	N participants  (studies)	MRI‐pathway and SBx combined (total cancer detected)	MRI‐pathway	SBx	Both MRI‐pathway and SBx	Only MRI‐pathway (added value^b)	Only SBx (added value^b)
Mixed^c	Positive + negative  100 (100 to 100)	G = 1^d	5442 (21)	19.5 (16.9 to 22.7)	10.3 (8.1 to 13.1)	16.8 (14.2 to 19.9)	7.6 (5.5 to 10.2)	2.7 (1.8 to 4.0)	9.2 (7.4 to 11.4)
		G ≥ 1	6524 (24)	50.2 (46.4 to 54.3)	37.9 (33.4 to 42.6)	43.3 (39.1 to 47.8)	30.9 (26.3 to 36.0)	6.9 (5.2 to 9.2)	12.4 (10.2 to 14.9)
		G ≥ 2	6944 (25)	26.7 (23.3 to 30.7)	22.9 (19.5 to 26.9)	19.4 (15.9 to 23.6)	15.6 (12.2 to 19.6)	7.3 (5.9 to 9.0)	3.8 (2.5 to 5.7)
		G ≥ 3	5981 (21)	15.0 (12.7 to 18.0)	12.7 (10.5 to 15.6)	9.7 (7.5 to 12.7)	7.4 (5.3 to 10.2)	5.3 (4.3 to 6.5)	2.3 (1.4 to 3.7)
	Positive  67.6 (60.2 to 74.3)	G = 1^d	3460 (19)	19.7 (15.9 to 24.7)	15.8 (12.2 to 20.7)	15.8 (12 to 20.8)	12.0 (8.4 to 16.8)	3.9 (2.6 to 5.7)	3.8 (2.3 to 6.2)
		G ≥ 1	3998 (20)	68.0 (62.3 to 73.5)	61.1 (54.1 to 67.7)	58.9 (51.5 to 65.9)	52.0 (43.6 to 59.9)	9.1 (5.9 to 13.5)	6.9 (4.6 to 10.1)
		G ≥ 2	3998 (20)	42.6 (37.6 to 48.1)	37.9 (32.7 to 43.7)	31.6 (26.2 to 37.9)	27.0 (21.4 to 33.4)	10.9 (8.5 to 13.9)	4.6 (2.9 to 7.2)
		G ≥ 3	3902 (18)	24.2 (20.9 to 28.1)	21 (17.8 to 24.8)	16.3 (13.1 to 20.3)	13.2 (10.1 to 16.9)	7.9 (6.3 to 9.7)	3.1 (1.9 to 5.2)
	Negative  32.4 (25.7 to 39.8)	G = 1^d	1666 (19)	16.8 (12.9 to 21.6)	NA	16.8 (12.9 to 21.6)	NA	NA	16.8 (12.9 to 21.6)
		G ≥ 1	1781 (20)	23.1 (19.7 to 26.9)	NA	23.1 (19.7 to 26.9)	NA	NA	23.1 (19.7 to 26.9)
		G ≥ 2	1781 (20)	7.2 (5.3 to 9.8)	NA	7.2 (5.3 to 9.8)	NA	NA	7.2 (5.3 to 9.8)
		G ≥ 3	1725 (18)	2.7 (1.6 to 4.6)	NA	2.7 (1.6 to 4.6)	NA	NA	2.7 (1.6 to 4.6)
Biopsy‐naïve	Positive + negative  100 (100 to 100)	G = 1^d	4079 (17)	20.9 (18.0 to 24.7)	11.2 (8.4 to 14.9)	18.5 (15.6 to 22.2)	8.8 (6.2 to 12.3)	2.4 (1.4 to 4.0)	9.8 (8.0 to 11.8)
		G ≥ 1	4799 (19)	53.2 (48.7 to 57.9)	41.0 (35.8 to 46.4)	47.8 (42.8 to 52.9)	35.6 (30.2 to 41.2)	5.4 (3.6 to 8.0)	12.2 (8.7 to 16.7)
		G ≥ 2	5219 (20)	27.7 (23.7 to 32.6)	23.4 (19.4 to 28.2)	21.4 (17.2 to 26.5)	17.1 (13.0 to 22)	6.3 (4.8 to 8.2)	4.3 (2.6 to 6.9)
		G ≥ 3	4306 (16)	15.5 (12.6 to 19.5)	12.7 (9.9 to 16.5)	10.8 (8.0 to 14.8)	8.0 (5.4 to 11.6)	4.7 (3.5 to 6.3)	2.8 (1.7 to 4.8)
	Positive  67.0 (58.7 to 74.4)	G = 1^d	2682 (16)	21.1 (16.7 to 27.1)	17.0 (12.6 to 22.9)	17.7 (13.3 to 23.8)	13.6 (9.3 to 19.5)	3.4 (2.1 to 5.3)	4.1 (2.5 to 6.7)
		G ≥ 1	2955 (17)	70.9 (65.0 to 76.6)	63.7 (56.3 to 70.6)	63.8 (56.2 to 70.7)	56.6 (47.7 to 64.6)	7.1 (4.2 to 11.9)	7.2 (4.7 to 10.8)
		G ≥ 2	2955 (17)	44.2 (38.6 to 50.4)	39.2 (33.3 to 45.7)	34.4 (28.3 to 41.3)	29.5 (23.2 to 36.5)	9.8 (7.1 to 13.2)	4.9 (2.8 to 8.3)
		G ≥ 3	2899 (15)	24.8 (21.0 to 29.6)	21.2 (17.4 to 25.7)	17.5 (13.8 to 22.3)	13.9 (10.3 to 18.3)	7.3 (5.4 to 9.7)	3.7 (2.2 to 6.1)
	Negative  33.0 (25.6 to 41.3)	G = 1	1287 (16)	18.4 (14.2 to 23.7)	NA	18.4 (14.2 to 23.7)	NA	NA	18.4 (14.2 to 23.7)
		G ≥ 1	1343 (17)	25.5 (20.7 to 30.9)	NA	25.5 (20.7 to 30.9)	NA	NA	25.5 (20.7 to 30.9)
		G ≥ 2	1343 (17)	8.1 (5.6 to 11.6)	NA	8.1 (5.6 to 11.6)	NA	NA	8.1 (5.6 to 11.6)
		G ≥ 3	1297 (15)	3.0 (1.6 to 5.5)	NA	3.0 (1.6 to 5.5)	NA	NA	3.0 (1.6 to 5.5)
Prior‐negative biopsy	Positive + negative  100 (100 to 100)	G = 1^d	1202 (8)	17.6 (13.0 to 25.0)	9.8 (6.9 to 14.3)	13.5 (8.9 to 21.0)	5.8 (3.2 to 10.0)	4.1 (2.6 to 6.2)	7.7 (3.9 to 14.8)
		G ≥ 1	1564 (10)	40.7 (35.1 to 47.2)	30.0 (24.1 to 37.0)	30.3 (24.3 to 37.5)	19.6 (13.7 to 27.1)	10.3 (7.5 to 13.9)	10.7 (7.4 to 15)
		G ≥ 2	1564 (10)	22.8 (20.0 to 26.2)	20.5 (17.7 to 23.5)	13.2 (10.8 to 16.4)	10.9 (8.7 to 13.5)	9.6 (7.7 to 11.8)	2.3 (1.2 to 4.5)
		G ≥ 3	1514 (9)	12.6 (10.5 to 15.6)	11.5 (9.4 to 14.2)	6.3 (4.4 to 9.1)	5.1 (3.4 to 7.7)	6.3 (5.2 to 7.7)	1.1 (0.5 to 2.6)
	Positive  69.6 (54.7 to 81.3)	G = 1^d	655 (7)	19.5 (13.9 to 28.8)	16.5 (11.0 to 25.2)	12.4 (7.2 to 21.6)	9.4 (4.6 to 17.9)	7.1 (4.1 to 11.8)	3.0 (1.0 to 8.0)
		G ≥ 1	920 (8)	54.8 (44.6 to 66.4)	48.5 (37.0 to 61.5)	39.4 (27.1 to 53.9)	33.1 (20.1 to 48.7)	15.4 (8.2 to 26.4)	6.3 (3.8 to 9.8)
		G ≥ 2	920 (8)	31.3 (27.4 to 36.1)	28.6 (24.7 to 33.1)	18.3 (15.1 to 22.5)	15.7 (12.7 to 19.1)	13.0 (9.7 to 17.0)	2.7 (1.2 to 5.7)
		G ≥ 3	880 (7)	17.9 (14.3 to 22.9)	16.7 (13.1 to 21.5)	9.4 (6.4 to 14.2)	8.2 (5.2 to 12.6)	8.5 (6.1 to 11.5)	1.2 (0.4 to 3.2)
	Negative  30.4 (18.7 to 45.3)	G = 1	341 (7)	14.2 (5.9 to 30.2)	NA	14.2 (5.9 to 30.2)	NA	NA	14.2 (5.9 to 30.2)
		G ≥ 1	400 (8)	19.5 (12.9 to 28.3)	NA	19.5 (12.9 to 28.3)	NA	NA	19.5 (12.9 to 28.3)
		G ≥ 2	400 (8)	5.3 (3.1 to 8.9)	NA	5.3 (3.1 to 8.9)	NA	NA	5.3 (3.1 to 8.9)
		G ≥ 3	390 (7)	3.3 (1.7 to 6.3)	NA	3.3 (1.7 to 6.3)	NA	NA	3.3 (1.7 to 6.3)
CI: confidence interval; G: International Society of Urological Pathology grade; MRI: magnetic resonance imaging; MRI‐pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy: N: number; NA: not applicable; SBx: systematic biopsy

		Histopathology by
	MRI threshold	MRI‐TBx outcome	Template‐guided biopsies		Total
	MRI threshold	MRI‐TBx outcome	+	‐	Total
MRI±MRI‐TBx (MRI pathway)	+	+	TP	FP
	+	‐	FN/TP	TN/FP
	‐	x	FN	TN
		Total

		Histopathology by
	MRI threshold	MRI‐TBx outcome	SBx		Total
	MRI threshold	MRI‐TBx outcome	+	‐	Total
MRI pathway	+	+	Concordant  positive	Discordant  (Dposneg)
	+	‐	Discordant  (Dnegpos)	Concordant  negative
	‐	x	Discordant  (Dnegpos)	Concordant  negative
		Total

Agreement analysis: number needed to biopsy by systematic biopsy to detect one extra prostate cancer not detected by the MRI‐pathway
Population		Target  condition	NNB^a  (95% CI)
Biopsy status	MRI	Target  condition	NNB^a  (95% CI)
Biopsy‐naïve	Positive	G = 1	24 (15 to 40)
		G ≥ 2	20 (12 to 36)
		G ≥ 3	27 (16 to 45)
	Negative	G = 1	5 (4 to 7)
		G ≥ 2	13 (9 to 18)
		G ≥ 3	33 (18 to 63)
Prior‐negative biopsy	Positive	G = 1	33 (13 to 100)
		G ≥ 2	37 (18 to 83)
		G ≥ 3	83 (31 to 250)
	Negative	G = 1	7 (3 to 17)
		G ≥ 2	19 (11 to 32)
		G ≥ 3	31 (16 to 63)
CI: confidence interval; G: International Society of Urological Pathology grade; MRI: magnetic resonance imaging; MRI‐pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; N: number; NA: not applicable; NNB: number needed to biopsy; SBx: systematic biopsy

Heterogeneity exploration in the agreement analysis: detection ratio MRI‐pathway vs systematic biopsy for G ≥ 2 prostate cancer
Covariate	Category	N participants  (studies)	Detection ratio  for G ≥ 2 PCa  (95% CI)^a	P value
Population	Biopsy‐naïve	5219 (20)	1.05 (0.95 to 1.16)	0.002
Population	Prior to negative biopsy	1564 (10)	1.44 (1.19 to 1.75)	0.002
Field strength	3T	5407 (19)	ID	ID
Field strength	1.5T	1143 (4)	ID	ID
Endorectal coil	Yes	1815 (6)	1.42 (1.07 to 1.88)	0.008
Endorectal coil	No	4082 (14)	1.03 (0.94 to 1.12)	0.008
MRI pulse sequence	mpMRI	4941 (16)	1.18 (1.05 to 1.33)	0.233
	bpMRI	1775 (6)	1.03 (0.91 to 1.17)	0.233
	mpMRI + spectroscopy	105 (2)	ID	ID
MRI risk threshold	Low	605 (6)	1.18 (1.03 to 1.35)	0.556
	Intermediate	5859 (15)	1.14 (1.03 to 1.26)	0.556
	High	428 (3)	ID	ID
MRI‐TBx technique	Software	3313 (9)	1.15 (0.99 to 1.33)	0.483
	Cognitive	2194 (12)	1.17 (1.00 to 1.36)	0.483
	In‐bore	849 (2)	ID	ID
Route index test	Transrectal	6464 (23)	ID	ID
Route index test	Transperineal	480 (2)	ID	ID
bpMRI: biparametric magnetic resonance imaging; CI: confidence interval; G: International Society of Urological Pathology grade; ID: inadequate data; mpMRI: multiparametric magnetic resonance imaging; MRI: magnetic resonance imaging; MRI‐pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy; N: number; SBx: systematic biopsy

Sensitivity analyses of the diagnostic test accuracy of MRI and the MRI‐pathway for detecting G ≥ 2 prostate cancer, verified by template‐guided biopsy as the reference standard
Covariate		Category	MRI			MRI‐pathway^a
Covariate		Category	N  studies	Sensitivity  (95% CI)	Specificity  (95% CI)	N  studies	Sensitivity  (95% CI)	Specificity  (95% CI)
Main analyses (as reference)		No selection	12	0.91 (0.83 to 0.95)	0.37 (0.29 to 0.46)	8	0.72 (0.60 to 0.82)	0.96 (0.94 to 0.98)
QUADAS domains	Participant selection	Only low risk of bias	5	0.86 (0.83 to 0.88)	0.39 (0.31 to 0.47)	4	0.61 (0.54 to 0.69)	0.97 (0.92 to 0.99)
	Participant selection	Only low applicability concern	11	0.91 (0.83 to 0.96)	0.36 (0.28 to 0.46)	7	0.69 (0.60 to 0.77)	0.97 (0.94 to 0.98)
	Index test	Only low risk of bias	12	0.91 (0.83 to 0.95)	0.37 (0.29 to 0.46)	8	0.72 (0.60 to 0.82)	0.96 (0.94 to 0.98)
	Index test	Only low applicability concern	9	0.90 (0.85 to 0.94)	0.37 (0.31 to 0.43)	6	0.68 (0.59 to 0.77)	0.97 (0.94 to 0.99)
	Reference standard	Only low risk of bias	4	0.93 (0.82 to 0.98)	0.34 (0.24 to 0.45)	2	ID	ID
	Reference standard	Only low applicability concern	12	0.91 (0.83 to 0.95)	0.37 (0.29 to 0.46)	8	0.72 (0.60 to 0.82)	0.96 (0.94 to 0.98)
	Flow and timing	Only low risk of bias	11	0.91 (0.83 to 0.96)	0.36 (0.28 to 0.46)	8	0.72 (0.60 to 0.82)	0.96 (0.94 to 0.98)
Additional analyses	MRI positivity threshold	Only threshold 3/5	10	0.89 (0.82 to 0.94)	0.39 (0.32 to 0.47)	6	0.68 (0.59 to 0.77)	0.97 (0.94 to 0.98)
	MRI positivity threshold effect	MRI positivity threshold 3/5 (only studies with also 4/5)	5	0.87 (0.73 to 0.94)	0.45 (0.33 to 0.57)	0	ID	ID
	MRI positivity threshold effect	MRI positivity threshold 4/5 (only studies with also 3/5)	5	0.72 (0.52 to 0.86)	0.78 (0.68 to 0.86)	0	ID	ID
	MRI vs MRI‐pathway	Only MRI and MRI‐pathway in the same men (paired data)	8	0.92 (0.83 to 0.96)	0.35 (0.27 to 0.44)	8	0.72 (0.60 to 0.82)	0.96 (0.94 to 0.98)
	Reference standard	Only TTMB, TSB or TOP	9	0.90 (0.84 to 0.93)	0.36 (0.29 to 0.44)	6	0.69 (0.58 to 0.78)	0.96 (0.93 to 0.97)
	Reference standard	Template‐guided biopsy + MRI‐TBx (composite reference standard)	11	0.94 (0.91 to 0.96)	1.00 (1.00 to 1.00)	8	0.72 (0.63 to 0.80)	1.00 (1.00 to 1.00)
	Experience of radiologist	Only high experience	10	0.91 (0.85 to 0.95)	0.34 (0.27 to 0.42)	7	0.69 (0.60 to 0.77)	0.97 (0.94 to 0.98)
CI: confidence interval; G: International Society of Urological Pathology grade; ID: inadequate data; MRI: magnetic resonance imaging; MRI‐pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy; N: number; NA: not applicable; QUADAS: Quality Assessment of Diagnostic Accuracy Studies; SBx: systematic biopsy; TOP: transperineal optimised prostate biopsy;TSB: Ginsburg transperineal saturation biopsy; TTMB: transperineal template mapping biopsy

Sensitivity analyses of the agreement between the MRI‐pathway vs systematic biopsy for detecting G ≥ 2 prostate cancer
Covariate		Category	N  studies	Detection ratio  (95% CI)^a
Main analyses (as reference)		Mixed population	25	1.12 (1.02 to 1.23)
QUADAS domains	Patient selection	Only low risk of bias	12	1.08 (1.00 to 1.17)
	Patient selection	Only low applicability concern	23	1.09 (1.01 to 1.17)
	Index test (MRI‐pathway)	Only low risk of bias	24	1.11 (1.02 to 1.22)
	Index test (MRI‐pathway)	Only low applicability concern	14	1.13 (1.01 to 1.26)
	Index test (SBx)	Only low risk of bias	10	1.04 (0.94 to 1.15)
	Index test (SBx)	Only low applicability concern	20	1.07 (0.99 to 1.15)
	Flow and timing	Only low risk of bias	17	1.10 (1.00 to 1.22)
Additional analyses	MRI positivity threshold	Only threshold 3/5	15	1.14 (1.03 to 1.26)
	Population	Biopsy‐naïve (only studies with also prior‐negative biopsy men)	6	0.98 (0.76 to 1.28)^b
	Population	Prior‐negative biopsy (only studies with also biopsy‐naïve men)	6	1.42 (1.03 to 1.95)^b
	Experience of radiologist	Only high experience	21	1.13 (1.03 to 1.24)
CI: confidence interval; G: International Society of Urological Pathology grade; MRI‐pathway: magnetic resonance imaging (MRI) with or without MRI‐targeted biopsy; N: number; QUADAS: Quality Assessment of Diagnostic Accuracy Studies; SBx: systematic biopsy

Detecting ISUP grade 2 or higher prostate cancer by MRI, MRI‐targeted biopsy, MRI pathway and systematic biopsy
Population	13,770 men with a suspicion of prostate cancer (PSA‐ or DRE‐based) undergoing their first biopsy (biopsy‐naïve men) or a repeat biopsy (prior‐negative biopsy men)
Setting	University hospitals and specialized care centers
Index tests	MRI; MRI‐targeted biopsy (MRI‐TBx) in men with a positive MRI; the MRI pathway (MRI with or without MRI‐TBx); and systematic biopsy (SBx)
Reference standard	Template‐guided biopsy, which comprehensively samples all zones of the prostate
Tests	Population type (biopsy‐naïve, prior‐negative biopsy, or mixed)	Summary  sensitivity  (95% CI)	Summary  specificity  (95% CI)	Detection  ratio  (95% CI)	Missed grade 2 or higher prostate cancer per 1000 men (95% CI)^a	Number of  participants  (studies)	Number of studies with a  high or unclear risk of bias
Tests		Summary  sensitivity  (95% CI)	Summary  specificity  (95% CI)	Detection  ratio  (95% CI)		Number of  participants  (studies)	Participant  selection	Index  test(s)	Reference  standard	Flow and timing
MRI	Mixed	0.91  (0.83 to 0.95)	0.37  (0.29 to 0.46)	NA	27  (15 to 51)	3091 (12)	7	0	11	2
MRI‐TBx	Mixed	0.80  (0.69 to 0.87)	0.94  (0.90 to 0.97)	NA	60  (39 to 93)	1553 (8)	4	0	6	0
MRI pathway	Mixed	0.72  (0.60 to 0.82)	0.96  (0.94 to 0.98)	NA	84  (54 to 120)	2257 (8)	4	0	6	0
SBx	Mixed	0.63  (0.19 to 0.93)	1.00  (0.91 to 1.00)	NA	111  (21 to 243)	3421 (4)	2	1	1	1
MRI pathwayvs SBx	Mixed	NA	NA	1.12  (1.02 to 1.23)	MRI pathway missed 12% (2 to 23) less than SBx	6944 (25)	13	15	NA	8
	Biopsy‐naïve	NA	NA	1.05  (0.95 to 1.16)	MRI pathway missed 5% (−5 to 16) less than SBx	5219 (20)	9	12	NA	7
	Prior‐negative biopsy	NA	NA	1.44  (1.19 to 1.75)	MRI pathway missed 44% (19 to 75) less than SBx	1564 (10)	5	6	NA	1
DRE: digital rectal exam; ISUP: International Society of Urological Pathology; MRI: magnetic resonance imaging; MRI‐TBx: MRI‐targeted biopsy; MRI pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; N: number; NA: not applicable; PSA: prostate‐specific antigen; SBx: systematic biopsy.  ^aAt the representative pre‐test probability of 30% of having grade 2 or higher prostate cancer, based on prevalence findings in the test accuracy analysis (proportion missed = [prevalence1000][1‐sensitivity]).

Detecting ISUP grade 1 prostate cancer by MRI, MRI‐targeted biopsy, MRI pathway and systematic biopsy
Population	10,051 men with a suspicion of prostate cancer (PSA‐ or DRE‐based) undergoing their first biopsy (biopsy‐naïve men) or a repeat biopsy (prior‐negative biopsy men)
Setting	University hospitals and specialized care centers
Index tests	MRI; MRI‐targeted biopsy (MRI‐TBx) in men with a positive MRI; the MRI pathway (MRI with or without MRI‐TBx); and systematic biopsy (SBx)
Reference standard	Template‐guided biopsy, which comprehensively samples all zones of the prostate
Tests	Population type (biopsy‐naïve, prior‐negative biopsy, or mixed)	Summary  sensitivity  (95% CI)	Summary  specificity  (95% CI)	Detection  ratio  (95% CI)	Avoided  overdiagnosis  per 1000  men (95% CI)^a	Number of  participants  (studies)	Number of studies with a  high or unclear risk of bias
Tests		Summary  sensitivity  (95% CI)	Summary  specificity  (95% CI)	Detection  ratio  (95% CI)	Avoided  overdiagnosis  per 1000  men (95% CI)^a	Number of  participants  (studies)	Participant  selection	Index  test(s)	Reference  standard	Flow and timing
MRI	Mixed	0.70  (0.59‐0.80)	0.27  (0.19‐0.37)	NA	63  (42‐86)	1764 (10)	5	0	5	1
MRI‐TBx	Mixed	0.51  (0.21‐0.81)	1.00  (0.77‐1.00)	NA	103  (40‐166)	497 (5)	3	0	3	0
MRI pathway	Mixed	0.34  (0.19‐0.53)	1.00  (0.90‐1.00)	NA	139  (99‐170)	681 (5)	3	0	3	0
SBx	Mixed	0.55  (0.25‐0.83)	0.99  (0.81‐1.00)	NA	95  (36‐158)	3421 (4)	2	1	1	1
MRI pathwayvs SBx	Mixed	NA	NA	0.61  (0.52‐0.71)	MRI pathway  avoided more  overdiagnosis  (and biopsy  procedures^b)  than SBx	5442 (21)	11	11	NA	8
	Biopsy‐naïve	NA	NA	0.63  (0.54‐0.74)		4079 (17)	9	9	NA	7
	Prior‐negative biopsy	NA	NA	0.62  (0.44‐0.88)		1202 (8)	5	5	NA	2
DRE: digital rectal exam; ISUP: International Society of Urological Pathology; MRI: magnetic resonance imaging; MRI‐TBx: MRI‐targeted biopsy; MRI pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; N: number; NA: not applicable; PSA: prostate‐specific antigen; SBx: systematic biopsy. ^aAt the representative pre‐test probability of 21% of having grade 1 prostate cancer, based on prevalence findings in the test accuracy analysis (proportion avoided = [prevalence1000][1‐sensitivity]).  ^bMRI‐TBx is not performed in 29% (24‐35) of men with a negative MRI, whereas SBx is performed in 100% of men.

	Histopathology by
	SBx outcome	Template‐guided biopsies		Totals
	SBx outcome	+	‐	Totals
SBx	+	TP	FP
SBx	‐	FN	TN
	Totals

			Systematic biopsy (SBx)
			No PCa	G = 1	G ≥ 2
MRI	MRI‐negative	No MRI‐TBx	Concordant negative	Concordant negative	Discordant (Dnegpos)
	MRI‐positive + TBx	No PCa	Concordant negative	Concordant negative	Discordant (Dnegpos)
		G = 1	Concordant negative	Concordant negative	Discordant (Dnegpos)
		G ≥ 2	Discordant (Dposneg)	Discordant (Dposneg)	Concordant positive

Study		MRI technique				MRI reading		MRI‐TBx
Study	Inclusion  period	Machine	Magnetic field strength	Pulse sequences	Endorectal coil	MRI score  system	Experience / consensus reading	Technique	N cores
Diagnostic test accuracy analyses studies
Abd‐Alazeez 2014	< Apr 2013	Achieva, Philips/Avanto, Siemens	1.5 & 3	T2, DWI, DCE	No	PI‐RADS  v1	Experienced / NR	Cognitive	NR
Ahmed 2017	May 2012  Nov 2015	NR	1.5	T2, DWI, DCE	No	PI‐RADS  v1^a	Experienced / NR	NA	NA
Dal Moro 2019	Jan 2013  Dec 2016	NR	1.5	T2, DWI	NR	PI‐RADS  v1	Experienced / NR	Cognitive	1/lesion
Distler 2017	Oct 2012  Dec 2015	Magnetom Prisma, Siemens/Biograph mMR, Siemens	3	T2, DWI, DCE	No	PI‐RADS  v1	Experienced / No	BiopSee, Pi Medical/MedCom (rigid)	3/lesion
Grey 2015	Jul 2012  Nov 2013	Signa Excite, GE/Magnetom Symphony, Siemens	1.5	T2, DWI	No	PI‐RADS  v1	Experienced / No	Cognitive	NR
Hansen 2016a	Mar 2013  Oct 2015	NR	1.5 & 3	T2, DWI	No	PI‐RADS  v1	Experienced / No	BiopSee, Pi Medical/MedCom (rigid)	2/lesion
Hansen 2018	Oct 2012  May 2016	Discovery MR450/MR750 HDx, GE/Magnetom, Siemens	1.5 & 3	T2, DWI, DCE	NR	PI‐RADS  v1, v2	Experienced / Yes	BiopSee, Pi Medical/MedCom (rigid)	2‐4/pt  (IQR 2‐5)
Hansen 2017	Oct 2013  Nov 2015	Magnetom, Siemens	3	T2, DWI, DCE	No	PI‐RADS  v1	Experienced / NR	BiopSee, Pi Medical/MedCom (rigid)	2/pt  (IQR 2‐4)
Kesch 2017	Oct 2013  Mar 2014	Magnetom, Siemens	3	T2, DWI, DCE	NR	PI‐RADS  v1	Experienced / NR	BiopSee, Pi Medical/MedCom (rigid)	2/lesion (range 2‐3)
Lawrence 2014	Feb 2012  Jun 2012	MR450, GE	1.5 & 3	T2, DWI	No	PI‐RADS  v1	Experienced / Yes	BiopSee, Pi Medical/MedCom (rigid)	7/pt  (range 0‐14)
Mortezavi 2018	Nov 2014  Sep 2016	Magnetom Skyra, Siemens	3	T2, DWI, DCE	Yes/No	PI‐RADS  v1	Experienced / Yes and No	BiopSee, Pi (Medical)/MedCom (non‐rigid)	2‐4/lesion
Muthuveloe 2016	Mar 2013  Dec 2014	NR	NR	T2, DWI, DCE	NR	PI‐RADS  v1	Unclear / NR	NA	NA
Pepe 2013	Jun 2011  Dec 2012	Achieva, Philips	3	T2, DWI, DCE, spectroscopy	No	In‐house	Unclear / No	Cognitive	3,5/pt  (range 3‐4)
Thompson 2016	Apr 2012  Mar 2014	NR	1.5 & 3	T2, DWI, DCE	No	PI‐RADS  v1	Experienced / Yes	BioJet, Geoscan (rigid)	NR
Tsivian 2017	2011  2014	Signa HDx, GE/Skyra, Siemens	3	T2, DWI, DCE	Yes/No	PI‐RADS  v1^a	Experienced / No	NA	NA
Agreement analyses studies
Alberts 2017	Oct 2013  Apr 2016	Discovery MR750, GE	3	T2, DWI, DCE	No	PI‐RADS  v2	Experienced / Yes	Urostation, Koelis (elastic)	2‐3/pt
Boesen 2017a	Sep 2012  Sep 2013	Ingenia, Philips	3	T2, DWI, DCE	No	PI‐RADS  v1	Experienced / No	Real‐Time Virtual Sonography,  Hitachi (rigid)	1‐2/lesion
Boesen 2018	Nov 2015  Jun 2017	Philips Healthcare	3	T2, DWI	No	PI‐RADS  v2^a	Experienced / No	HI‐RVS (Hitachi; n=877),  Uro‐Nav system (Invivo; n=143)	1‐2/lesion
Castellucci 2017	Jul 2011  Jul 2014	Achieva, Philips	1.5	T2, DWI	NR	PI‐RADS  v1	Experienced / Yes	Cognitive	2/lesion
Chang 2017	Mar 2012  Dec2014	Signa HDx, GE	3	T2, DWI, DCE	NR	PI‐RADS  v1, v2	Experienced / NR	Cognitive	≥ 2/lesion
Chen 2015	Jun 2008  Dec 2013	Achieva, Philips	3	T2, DWI	No	In‐house	Experienced / NR	Cognitive	1‐2/lesion
Cool 2016	Sep 2011  Mar 2014	NR, GE	3	T2, DWI, DCE	Yes/No	In‐house	Experienced / No	Artemis, Eigen (elastic)	1.9/lesion
Costa 2013	Aug 2003  Aug 2008	Genesis Signa LX Excite, GE	3	T2, DCE	Yes	In‐house	Experienced / NR	Cognitive	NR
Delongchamps 2013	Jan 2011  Mar 2012	NR	1.5	T2, DWI, DCE	Yes/No	In‐house	Experienced / Yes	Urostation, Koelis (elastic)/Virtual Navigator, Esaote  (rigid)/Cognitive	4/pt  (range 2‐10)
Filson 2016	Sep 2009  Feb 2015	TrioTim Somatom, Siemens	3	T2, DWI, DCE	No	In‐house	Experienced / No	Artemis, Eigen (elastic)	1 per 3 mm. lesion diameter
Garcia Bennett 2017	Oct 2014  Apr 2016	Signa, GE	3	T2, DWI	No	PI‐RADS  v1	Experienced / Yes	Cognitive	NR
Grönberg 2018	May 2016  May 2017	Magnetom Avanto, Siemens/Magnetom Aera, Siemens	1.5	T2, DWI	No	PI‐RADS  v2	Experienced / Yes	Urostation, Koelis/Artemis, Eigen/BioJet, D&K Technologies	NR
Jambor 2015	Apr 2011  Mar 2013	Magnetom Verio, Siemens	3	T2, DWI, DCE, spectroscopy	No	In‐house	Unclear / NR	Cognitive	NR
Jambor 2017	Mar 2013  Feb 2015	Magnetom Verio, Siemens	3	T2, DWI	NR	In‐house	Experienced/ No	Cognitive	2/index lesion
Kim 2017	Jan 2012  Dec 2015	Magnetom Trio/Skyra, Siemens	3	T2, DWI, DCE	No	In‐house,  PI‐RADS  v1, v2	Experienced / No	UroNav, Invivo (rigid)	6.7/pt
Lee 2016	Jan 2014  Dec 2014	Intera Achieva, Philips	3	T2, DWI	No	In‐house	Experienced / NR	Cognitive	2.4/pt
Lee 2017	2016	Intera Achieva, Philips	3	T2, DWI, (DCE 55 pts)  T2, DWI (68 pts)	No	PI‐RADS  v2^a	Experienced / NR	Cognitive	NR
Okcelik 2016	Feb 2013  Mar 2014	Avanto, Siemens	1.5	T2, DWI, DCE, spectroscopy	NR	In‐house	Unclear / NR	Cognitive	NR
Panebianco 2015	Oct 2011  Mar 2014	Discovery MR750, GE/Magnetom Verio, Siemens	3	T2, DWI, DCE	Yes/No	PI‐RADS  v1	Experienced / Yes	Cognitive	2/pt
Peltier 2015	Mar 2012  Sep 2013	Magnetom Verio, Siemens	3	T2, DWI, DCE	Yes/No	PI‐RADS  v1^a	Experienced / No	Urostation, Koelis (elastic)	2,4/lesion  (range 1‐4)
Pokorny 2014	Jul 2012  Jan 2013	Magnetom Skyra, Siemens	3	T2, DWI, DCE	No	PI‐RADS  v1	Experienced / Yes	In‐bore	2/pt  (range 2‐3)
Rouvière 2019a	Jul 2015  Aug2016	MR 750, GE/MR 450, GE/Ingenia, Philips/Avanto, Siemens/Intera, Philips/Aera, Siemens/Achieva, Philips/Skyra, Siemens/Priesma, Siemens	1.5 & 3	T2, DWI, DCE	Yes/No	PI‐RADS  v1/v2^a	Experienced / No	Urostation, Koelis/Smart Fusion, Toshiba/Percunav, Philips	3/lesion
Say 2016	Dec 2012  Jun 2015	NR	NR	T2, DWI, DCE	NR	In‐house,  PI‐RADS  v1	Unclear / NR	Artemis, Eigen (elastic)	NR
Tonttilla 2016	Apr 2011  Dec 2014	Magnetom Skyra, Siemens	3	T2, DWI, DCE	No	In‐house	No experience / Unclear	Cognitive	2/pt  (range 2‐3)
Van der Leest 2018	Feb 2015  Feb 2017	Magnetom Skyra, Siemens	3	T2, DWI, DCE	NR	PI‐RADS  v2	Experienced / Yes	In‐bore, Invivo	2‐4/lesion
^abased on the PI‐RADS v1/v2 guidelines but either before official publication or practically identical. DCE: dynamic contrast‐enhanced imaging; DWI: diffusion‐weighted imaging; MRI: magnetic resonance imaging; NA: not applicable; NR: not reported; PI‐RADS v1, v2: Prostate Imaging Reporting Data System version 1 or 2; pt(s): participant(s); SBx: systematic biopsy; T2: T2‐weighted imaging

Index test	MRI population^a	Target condition	Prevalence	NPV (95% CI)^b	PPV (95% CI)^b
MRI	Positive + Negative	G = 1	0.10	0.89 (0.87 to 0.91)	0.10 (0.09 to 0.11)
			0.20	0.79 (0.74 to 0.82)	0.20 (0.18 to 0.21)
			0.30	0.68 (0.63 to 0.73)	0.29 (0.27 to 0.31)
			0.40	0.58 (0.52 to 0.64)	0.39 (0.37 to 0.42)
			0.50	0.48 (0.42 to 0.54)	0.49 (0.47 to 0.52)
		G ≥ 2	0.10	0.97 (0.96 to 0.98)	0.14 (0.13 to 0.15)
			0.20	0.94 (0.91 to 0.96)	0.27 (0.25 to 0.28)
			0.30	0.91 (0.86 to 0.94)	0.38 (0.36 to 0.40)
			0.40	0.86 (0.79 to 0.91)	0.49 (0.47 to 0.51)
			0.50	0.81 (0.72 to 0.87)	0.59 (0.57 to 0.61)
		G ≥ 3	0.05	0.99 (0.98 to 1.00)	0.07 (0.06 to 0.08)
			0.10	0.99 (0.97 to 0.99)	0.14 (0.13 to 0.16)
			0.15	0.98 (0.95 to 0.99)	0.21 (0.19 to 0.23)
			0.20	0.97 (0.93 to 0.99)	0.27 (0.25 to 0.29)
			0.25	0.96 (0.90 to 0.98)	0.33 (0.30 to 0.36)
MRI‐TBx	Positive	G = 1	0.10	0.95 (0.90 to 0.97)	0.94 (0.11 to 1.00)
			0.20	0.89 (0.80 to 0.94)	0.97 (0.21 to 1.00)
			0.30	0.83 (0.70 to 0.91)	0.98 (0.32 to 1.00)
			0.40	0.75 (0.60 to 0.86)	0.99 (0.42 to 1.00)
			0.50	0.67 (0.50 to 0.81)	0.99 (0.52 to 1.00)
		G ≥ 2	0.10	0.98 (0.96 to 0.98)	0.60 (0.47 to 0.72)
			0.20	0.95 (0.92 to 0.97)	0.77 (0.67 to 0.86)
			0.30	0.92 (0.88 to 0.94)	0.85 (0.77 to 0.91)
			0.40	0.88 (0.82 to 0.91)	0.90 (0.84 to 0.94)
			0.50	0.83 (0.75 to 0.88)	0.93 (0.89 to 0.96)
		G ≥ 3	0.05	ID	ID
			0.10	ID	ID
			0.15	ID	ID
			0.20	ID	ID
			0.25	ID	ID
MRI pathway	Positive + Negative	G = 1	0.10	0.93 (0.91 to 0.95)	0.89 (0.21 to 1.00)
			0.20	0.86 (0.82 to 0.89)	0.95 (0.37 to 1.00)
			0.30	0.78 (0.73 to 0.82)	0.97 (0.50 to 1.00)
			0.40	0.69 (0.63 to 0.75)	0.98 (0.61 to 1.00)
			0.50	0.60 (0.53 to 0.66)	0.99 (0.70 to 1.00)
		G ≥ 2	0.10	0.97 (0.96 to 0.98)	0.69 (0.56 to 0.79)
			0.20	0.93 (0.90 to 0.95)	0.83 (0.74 to 0.90)
			0.30	0.89 (0.85 to 0.92)	0.90 (0.83 to 0.94)
			0.40	0.84 (0.78 to 0.89)	0.93 (0.88 to 0.96)
			0.50	0.78 (0.70 to 0.84)	0.95 (0.92 to 0.97)
		G ≥ 3	0.05	ID	ID
			0.10	ID	ID
			0.15	ID	ID
			0.20	ID	ID
			0.25	ID	ID
SBx	NA	G = 1	0.10	0.95 (0.91 to 0.98)	0.87 (0.20 to 0.99)
			0.20	0.90 (0.81 to 0.95)	0.94 (0.37 to 1.00)
			0.30	0.84 (0.71 to 0.92)	0.96 (0.50 to 1.00)
			0.40	0.77 (0.61 to 0.88)	0.98 (0.61 to 1.00)
			0.50	0.69 (0.52 to 0.83)	0.98 (0.70 to 1.00)
		G ≥ 2	0.10	0.96 (0.88 to 0.99)	1.00 (0.41 to 1.00)
			0.20	0.92 (0.76 to 0.97)	1.00 (0.61 to 1.00)
			0.30	0.86 (0.65 to 0.95)	1.00 (0.73 to 1.00)
			0.40	0.80 (0.54 to 0.93)	1.00 (0.81 to 1.00)
			0.50	0.73 (0.44 to 0.90)	1.00 (0.86 to 1.00)
		G ≥ 3	0.05	ID	ID
			0.10	ID	ID
			0.15	ID	ID
			0.20	ID	ID
			0.25	ID	ID
^aData did not allow differentiation between the mix of included participants (biopsy‐naïve and prior‐negative biopsy men).  ^bNPV and PPV are based on the Bayes’ theorem, using the point estimates and 95% confidence intervals of the pooled positive and negative likelihood ratio and prespecified prevalences.  CI: confidence interval; G: International Society of Urological Pathology grade; ID: inadequate data; MRI: magnetic resonance imaging; MRI pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy; NA: not applicable; NPV: negative predictive value; PPV: positive predictive value; SBx: systematic biopsy

PERMALINK

Prostate MRI, with or without MRI‐targeted biopsy, and systematic biopsy for detecting prostate cancer

Frank‐Jan H Drost

Daniël F Osses

Daan Nieboer

Ewout W Steyerberg

Chris H Bangma

Monique J Roobol

Ivo G Schoots

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Target condition being diagnosed

Clinical pathway

1.

Index tests

MRI

MRI‐targeted biopsy

MRI pathway

Systematic biopsy

Alternative test(s)

Rationale

Objectives

Primary objective

Secondary objectives

Methods

Criteria for considering studies for this review

Types of studies

Participants

Index tests

MRI

MRI‐targeted biopsy

The MRI pathway

Systematic biopsy

Target conditions

Reference standards

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of methodological quality

1. QUADAS‐2 tool for assessing methodological quality of included studies.

Statistical analysis and data synthesis

Investigations of heterogeneity

Sensitivity analyses

Assessment of reporting bias

Certainty of evidence and summary of findings tables

Summary of findings 3. Should MRI be used to diagnose ISUP grade ≥ 2 prostate cancer in men suspected of having clinically significant prostate cancer?

Summary of findings 4. Should MRI‐targeted biopsy be used to diagnose ISUP grade ≥ 2 prostate cancer in men suspected of having clinically significant prostate cancer?

Summary of findings 5. Should an MRI‐pathway be used to diagnose ISUP grade ≥ 2 prostate cancer in men suspected of having clinically significant prostate cancer?

Summary of findings 6. Should systematic biopsy be used to diagnose ISUP grade ≥ 2 prostate cancer in men suspected of having clinically significant prostate cancer?

Results

Results of the search

2.

2. Study characteristics of the diagnostic test accuracy analyses studies.

3. Patient characteristics of the diagnostic test accuracy studies.

4. Study characteristics of the agreement analyses studies.

5. Patient characteristics of the agreement analyses studies.

Methodological quality of included studies

Test accuracy studies

3.

4.

5.

6.

Agreement studies

7.

Findings

Test accuracy: index tests verified by the reference standard, template‐guided biopsy

Sensitivity and specificity

Detection of grade 2 or higher prostate cancer

Population		Target condition	N participants (studies)	Proportion prostate cancer detected in % (95% CI) ^a			Detection ratio (95% CI) ^b	P‐value	Difference between populations, P value^d
Biopsy status	MRI in % (95% CI) ^c	Target condition	N participants (studies)	MRI pathwayand SBx combined  (total cancer detected)	MRI pathway	SBx	MRI pathwayversus SBx		Difference between populations, P value^d
Mixed population ^e	Positive + negative (100 (100 to 100))	G=1	5442 (21)	26.9 (22.9 to 31.2)	12.9 (10.1 to 16.2)	22.0 (18.9 to 25.4)	0.608 (0.521 to 0.711)	0.000	NA
		G=1^f	5442 (21)	21.2 (17.7 to 25.2)	10.9 (8.2 to 14.4)	18.2 (15.5 to 21.2)	0.622 (0.506 to 0.764)	0.000	NA
		G≥1	6524 (24)	51.7 (47.3 to 56.1)	38.6 (34.0 to 43.4)	43.9 (39.4 to 48.5)	0.877 (0.807 to 0.954)	0.002	NA
		G≥2	6944 (25)	28.5 (24.2 to 33.4)	23.8 (20.1 to 28.0)	20.5 (16.7 to 25.0)	1.120 (1.024 to 1.225)	0.013	NA
		G≥3	5981 (21)	16.4 (13.3 to 20.2)	13.3 (10.5 to 16.7)	11.3 (8.9 to 14.3)	1.201 (1.059 to 1.363)	0.004	NA
	Positive (67.6 (60.2 to 74.3))	G=1	3460 (19)	31.2 (26.4 to 36.4)	19.9 (15.4 to 25.4)	23.9 (19.9 to 28.4)	0.853 (0.753 to 0.967)	0.013	NA
		G=1^f	3460 (19)	22.9 (18.4 to 28.2)	16.8 (12.1 to 22.8)	18.5 (14.9 to 22.7)	0.938 (0.812 to 1.083)	0.381	NA
		G≥1	3998 (20)	69.1 (62.2 to 75.2)	60.7 (52.7 to 68.1)	57.9 (51.9 to 63.7)	1.025 (0.951 to 1.104)	0.522	NA
		G≥2	3998 (20)	43.9 (37.1 to 51.0)	38.2 (32.2 to 44.6)	32.4 (26.4 to 38.9)	1.171 (1.073 to 1.277)	0.000	NA
		G≥3	3902 (18)	25.6 (21.2 to 30.6)	21.5 (17.5 to 26.0)	17.7 (14.3 to 21.7)	1.238 (1.109 to 1.382)	0.000	NA
Biopsy‐naïve men	Positive + negative (100 (100 to 100))	G=1	4079 (17)	28.7 (24.1 to 33.8)	14.3 (10.8 to 18.6)	23.7 (20.1 to 27.8)	0.630 (0.535 to 0.742)	0.000	0.905
		G=1^f	4079 (17)	23.1 (19.1 to 27.7)	11.9 (8.4 to 16.7)	20.1 (17.1 to 23.4)	0.611 (0.485 to 0.769)	0.000
		G≥1	4799 (19)	55.2 (50.1 to 60.1)	40.9 (35.2 to 46.8)	48.5 (43.8 to 53.3)	0.845 (0.767 to 0.930)	0.001	0.121
		G≥2	5219 (20)	29.5 (24.3 to 35.3)	24.0 (19.7 to 29.0)	22.6 (17.9 to 28.2)	1.050 (0.948 to 1.162)	0.349	0.002
		G≥3	4306 (16)	17.1 (13.1 to 21.9)	13.2 (9.8 to 17.5)	13.0 (10.0 to 16.6)	1.087 (0.937 to 1.261)	0.269	0.004
	Positive (67.0 (58.7 to 74.4))	G=1	2682 (16)	32.7 (27.3 to 38.6)	21.4 (16.1 to 28.0)	25.6 (20.9 to 31.0)	0.854 (0.743 to 0.982)	0.026	0.347
		G=1^f	2682 (16)	24.4 (19.1 to 30.7)	17.9 (12.4 to 25.2)	20.5 (16.2 to 25.6)	0.911 (0.782 to 1.062)	0.233
		G≥1	2955 (17)	71.9 (64.8 to 78.1)	63.4 (54.7 to 71.3)	62.5 (56.9 to 67.8)	0.994 (0.915 to 1.079)	0.881	0.053
		G≥2	2955 (17)	45.6 (38.2 to 53.2)	39.5 (33.1 to 46.2)	35.1 (28.5 to 42.4)	1.119 (1.014 to 1.234)	0.025	0.005
		G≥3	2899 (15)	26.4 (21.3 to 32.2)	21.6 (17.1 to 26.9)	19.1 (15.2 to 23.7)	1.158 (1.024 to 1.310)	0.020	0.007
Prior‐negative biopsy men	Positive + negative (100 (100 to 100))	G=1	1202 (8)	24.6 (17.8 to 33.0)	11.2 (7.5 to 16.4)	19.4 (13.3 to 27.3)	0.624 (0.444 to 0.878)	0.007	0.905
		G=1^f	1202 (8)	19.5 (13.2 to 27.9)	10.1 (6.6 to 15.2)	15.5 (10.1 to 22.9)	0.720 (0.507 to 1.023)	0.067
		G≥1	1564 (10)	42.6 (36.5 to 48.9)	30.8 (24.1 to 38.4)	32.5 (27.3 to 38.2)	0.974 (0.854 to 1.111)	0.696	0.121
		G≥2	1564 (10)	24.3 (22.2 to 26.6)	21.2 (18.5 to 24.3)	14.2 (11.5 to 17.4)	1.441 (1.190 to 1.745)	0.000	0.002
		G≥3	1514 (9)	13.7 (11.9 to 15.7)	12.4 (10.5 to 14.4)	7.1 (4.9 to 10.1)	1.637 (1.270 to 2.112)	0.000	0.004
	Positive (69.6 (54.7 to 81.3))	G=1	655 (7)	30.2 (21.0 to 41.5)	19.3 (11.6 to 30.5)	21.0 (13.7 to 30.8)	1.027 (0.892 to 1.183)	0.707	0.347
		G=1^f	655 (7)	23.2 (14.9 to 34.2)	17.5 (9.9 to 29.1)	15.8 (9.9 to 24.2)	1.212 (1.036 to 1.418)	0.016
		G≥1	920 (8)	56.9 (42.3 to 70.5)	49.2 (32.4 to 66.1)	40.2 (32.0 to 49.0)	1.163 (1.023 to 1.322)	0.021	0.053
		G≥2	920 (8)	32.2 (26.0 to 39.1)	28.5 (22.2 to 35.8)	19.3 (16.0 to 23.2)	1.492 (1.223 to 1.822)	0.000	0.005
		G≥3	880 (7)	18.9 (14.5 to 24.3)	17.4 (12.7 to 23.4)	10.4 (7.0 to 15.1)	1.648 (1.298 to 2.093)	0.000	0.007
CI: confidence interval; G: International Society of Urological Pathology grade; MRI: magnetic resonance imaging; MRI pathway: magnetic resonance imaging with or without magnetic resonance imaging‐targeted biopsy; MRI‐TBx: magnetic resonance imaging‐targeted biopsy; N: number; SBx: systematic biopsy

Test	No. of studies	No. of participants
1 Diagnostic accuracy of MRI ‐ G = 1	10	1764
2 Diagnostic accuracy of MRI ‐ G ≥ 1	10	1764
3 Diagnostic accuracy of MRI ‐ G ≥ 2	12	3091
4 Diagnostic accuracy of MRI ‐ G ≥ 3	7	1438
5 Diagnostic accuracy of MRI ‐ MRI‐positvity threshold 4/5 ‐ G = 1	4	834
6 Diagnostic accuracy of MRI ‐ MRI‐positvity threshold 4/5 ‐ G ≥ 1	4	834
7 Diagnostic accuracy of MRI ‐ MRI‐positvity threshold 4/5 ‐ G ≥ 2	5	1083
8 Diagnostic accuracy of MRI ‐ MRI‐positvity threshold 4/5 ‐ G ≥ 3	4	834
9 Diagnostic accuracy of MRI ‐ Biopsy‐naïve ‐ G ≥ 1	3	748
10 Diagnostic accuracy of MRI ‐ Biopsy‐naïve ‐ G ≥ 2	3	748
11 Diagnostic accuracy of MRI ‐ Biopsy‐naïve ‐ G ≥ 3	3	748
12 Diagnostic accuracy of MRI ‐ Prior‐negative biopsy ‐ G ≥ 1	8	870
13 Diagnostic accuracy of MRI ‐ Prior‐negative biopsy ‐ G ≥ 2	9	1157
14 Diagnostic accuracy of MRI ‐ Prior‐negative biopsy ‐ G ≥ 3	4	544
15 Diagnostic accuracy of MRI ‐ Sensitivity analysis with composite reference standard (template‐guided biopsy + MRI‐TBx) ‐ G ≥ 2	11	3192
16 Diagnostic accuracy of TBx ‐ G = 1	5	497
17 Diagnostic accuracy of TBx ‐ G ≥ 1	6	611
18 Diagnostic accuracy of TBx ‐ G ≥ 2	8	1553
19 Diagnostic accuracy of TBx ‐ G ≥ 3	3	428
20 Diagnostic accuracy of the MRI‐pathway ‐ G = 1	5	681
21 Diagnostic accuracy of the MRI‐pathway ‐ G ≥ 1	6	844
22 Diagnostic accuracy of the MRI‐pathway ‐ G ≥ 2	8	2257
23 Diagnostic accuracy of the MRI‐pathway ‐ G ≥ 3	3	604
24 Diagnostic accuracy of SBx ‐ G = 1	4	3421
25 Diagnostic accuracy of SBx ‐ G ≥ 1	4	3421
26 Diagnostic accuracy of SBx ‐ G ≥ 2	4	3421
27 Diagnostic accuracy of SBx ‐ G ≥ 3	2	626
28 MRI‐pathway vs SBx ‐ G = 1	21	5442
29 MRI‐pathway vs SBx ‐ G ≥ 1	24	6524
30 MRI‐pathway vs SBx ‐ G ≥ 2	25	6944
31 MRI‐pathway vs SBx ‐ G ≥ 3	21	5981
32 MRI‐pathway vs SBx ‐ Biopsy‐naïve ‐ G = 1	17	4079
33 MRI‐pathway vs SBx ‐ Biopsy‐naïve ‐ G ≥ 1	19	4799
34 MRI‐pathway vs SBx ‐ Biopsy‐naïve ‐ G ≥ 2	20	5219
35 MRI‐pathway vs SBx ‐ Biopsy‐naïve ‐ G ≥ 3	16	4306
36 MRI‐pathway vs SBx ‐ Prior‐negative biopsy ‐ G = 1	8	1202
37 MRI‐pathway vs SBx ‐ Prior‐negative biopsy ‐ G ≥ 1	10	1564
38 MRI‐pathway vs SBx ‐ Prior‐negative biopsy ‐ G ≥ 2	10	1564
39 MRI‐pathway vs SBx ‐ Prior‐negative biopsy ‐ G ≥ 3	9	1514
40 MRI‐pathway vs SBx ‐ Positive MRI ‐ G = 1	19	3460
41 MRI‐pathway vs SBx ‐ Positive MRI ‐ G ≥ 1	20	3998
42 MRI‐pathway vs SBx ‐ Positive MRI ‐ G ≥ 2	20	3998
43 MRI‐pathway vs SBx ‐ Positive MRI ‐ G ≥ 3	18	3902
44 MRI‐pathway vs SBx ‐ Negative MRI ‐ G = 1	19	1666
45 MRI‐pathway vs SBx ‐ Negative MRI ‐ G ≥ 1	20	1781
46 MRI‐pathway vs SBx ‐ Negative MRI ‐ G ≥ 2	20	1781
47 MRI‐pathway vs SBx ‐ Negative MRI ‐ G ≥ 3	18	1725
48 MRI‐pathway vs SBx ‐ Positive MRI ‐ Biopsy‐naïve ‐ G = 1	16	2682
49 MRI‐pathway vs SBx ‐ Positive MRI ‐ Biopsy‐naïve ‐ G ≥ 1	17	2955
50 MRI‐pathway vs SBx ‐ Positive MRI ‐ Biopsy‐naïve ‐ G ≥ 2	17	2955
51 MRI‐pathway vs. SBx ‐ Positive MRI ‐ Biopsy‐naïve ‐ G ≥ 3	15	2899
52 MRI‐pathway vs SBx ‐ Negative MRI ‐ Biopsy‐naïve ‐ G = 1	16	1287
53 MRI‐pathway vs SBx ‐ Negative MRI ‐ Biopsy‐naïve ‐ G ≥ 1	17	1343
54 MRI‐pathway vs SBx ‐ Negative MRI ‐ Biopsy‐naïve ‐ G ≥ 2	17	1343
55 MRI‐pathway vs SBx ‐ Negative MRI ‐ Biopsy‐naïve ‐ G ≥ 3	15	1297
56 MRI‐pathway vs SBx ‐ Positive MRI ‐ Prior‐negative biopsy ‐ G = 1	7	655
57 MRI‐pathway vs SBx ‐ Positive MRI ‐ Prior‐negative biopsy ‐ G ≥ 1	8	920
58 MRI‐pathway vs SBx ‐ Positive MRI ‐ Prior‐negative biopsy ‐ G ≥ 2	8	920
59 MRI‐pathway vs SBx ‐ Positive MRI ‐ Prior‐negative biopsy ‐ G ≥ 3	7	880
60 MRI‐pathway vs SBx ‐ Negative MRI ‐ Prior‐negative biopsy ‐ G = 1	7	341
61 MRI‐pathway vs SBx ‐ Negative MRI ‐ Prior‐negative biopsy ‐ G ≥ 1	8	400
62 MRI‐pathway vs SBx ‐ Negative MRI ‐ Prior‐negative biopsy ‐ G ≥ 2	8	400
63 MRI‐pathway vs SBx ‐ Negative MRI ‐ Prior‐negative biopsy ‐ G ≥ 3	7	390

Study characteristics
Patient sampling	Aim of the study: to assess the performance of mpMRI in men with prior‐negative SBx Type of study: retrospective cohort Selection: unclearly reported Enrolled/eligible: 54/58 Inclusion period: not reported, but before April 2013
Patient characteristics and setting	Inclusion criteria: men who had ≥ 1 negative SBx and underwent mpMRI (index test) followed by TTMB (reference standard). All men included in the study had either increasing or persistently high PSA level Exclusion criteria: 4 men were excluded from the study as they received limited TTMB (< 20 cores were taken) Setting: London, UK. University hospital Age: median 64 years (range 39‐75) PSA: 10 ng/mL (range 2‐23) Prostate volume: 53 mL (range 19‐136) Previous number of negative Bx: 33 men had 1, 16 had 2, 5 had 3
Index tests	Index tests: MRI only, with an MRI‐score 1‐5 with threshold ≥ 3 for positivity. A 1.5 Tesla (Philips Achiva) and 3.0 Tesla (Siemens Avanto) MRI machine, with T2, DWI and DCE sequences were used. Index test performed first, then the reference test.
Target condition and reference standard(s)	Target condition: GS ≥ 3+3, GS ≥ 3+4, GS ≥ 4+3 and others. Pathology grading before ISUP 2005: GS was based upon most frequent pattern instead of highest grade detected. Reference standard: systematic TTMB with the use of a brachytherapy grid under general anaesthesia, as described by Barzell. Basal and apical cores were obtained routinely, and the minimum number of samples was 20. MRI results were available during TTMB.
Flow and timing	All men underwent the same reference test. No men were excluded from analysis
Comparative
Notes	Study authors provided additional data Although MRI‐TBx were taken in a subset of 15 men, their results are not reported nor are they taken into account in our analysis.
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	No
Did the study avoid inappropriate exclusions?	Unclear
		High	Low
DOMAIN 2: Index Test MRI
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Was the reference standard performed independent from the index test?	No
		High	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	Yes
Were all enrolled patients included in the analysis, or were exclusions explained and not leading to a relevant bias?	Yes
		Low

Study characteristics
Patient sampling	Aim of the study: to test diagnostic accuracy of mpMRI and SBx against a reference test, TTMB Type of study: multicentre, paired‐cohort, prospective study Selection: consecutive Enrolled/eligible: 576/740 Inclusion period: May 2012‐November 2015
Patient characteristics and setting	Inclusion criteria: PSA ≤ 15 ng/mL within previous 3 months, organ confined disease on DRE Exclusion criteria: previous history of PBx, prostate surgery or treatment for PCa (interventions for benign prostatic hyperplasia/bladder outflow obstruction were accepted. Evidence of a urinary tract infection or history of acute prostatitis within the last 3 months. Contraindication to MRI (e.g. claustrophobia, pacemaker, estimated GFR = 50). Previous history of hip replacement surgery, metallic hip replacement or extensive pelvic orthopedic metal work. Treated using 5‐alpha‐reductase inhibitors at time of registration or during the prior 6 months. Setting: London, UK. University and peripheral hospitals Age: mean 63.4 years (SD 7.6) PSA: mean 7.1 ng/mL (SD 2.9) Prostate volume: not reported
Index tests	Index test 1: MRI only: at multiple sites, 1.5 Tesla MRI scanners (T1, T2, DWI and DCE sequences) were used. Radiologists were provided with clinical details. A 5‐point Likert radiology reporting scale was used, with score of ≥ 3 designated a suspicious scan. Radiologist had undergone additional centralised training. Index test 2: 10–12 core transrectal SBx. Participants and physicians remained blinded to the mpMRI images and report. Participants first underwent the TTMB, followed by the SBx
Target condition and reference standard(s)	Target condition: GS ≥ 3+3, GS ≥ 3+4, GS ≥ 4+3 and others Reference standard: TTMB, blinded for MRI report, with cores taken from every hole in the 5‐mm sampling frame.
Flow and timing	All men underwent the same reference test. Participants left the study for various reasons: 4 were ineligible, 2 were unblinded, 69 had large prostates (> 100 mL), 5 had T4 or nodal disease, 21 had clinical reasons, 52 did not want to proceed, 11 had other reasons
Comparative
Notes	Study authors provided additional data. Number of TTMB cores not reported but estimated
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test SBx
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?	Yes
		Low	Low
DOMAIN 2: Index Test MRI
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Was the reference standard performed independent from the index test?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	Yes
Were all enrolled patients included in the analysis, or were exclusions explained and not leading to a relevant bias?	No
		High

Study characteristics
Patient sampling	Aim of the study: to assess the potential of a risk‐based strategy including MRI to selectively identify men aged ≥ 70 years with high‐grade PCa Type of study: prospective, 2‐arm, PSA‐screening study: 179 men received 6 core SBx only; 158 received MRI+/‐MRI‐TBx and SBx Selection: consecutive selection based on invitation to participate in a population‐based PSA screening trial Enrolled/eligible: 337/406 (69 participants refused Bx) In the current analysis, only the 158 men in the group receiving MRI and MRI‐TBx are included, of which 85 had a prior‐negative Bx and 74 were Bx‐naïve Inclusion period: Octobr 2013‐April 2016
Patient characteristics and setting	Inclusion criteria: PSA ≥ 3.0 ng/mL Exclusion criteria: none Setting: PSA‐screening study. Rotterdam, the Netherlands. University hospital Age: median 73.1 years (IQR 72.4‐73.8)* PSA: median 4.2 ng/mL (IQR 3.4–5.8)* Prostate volume: median 52.9 (IQR 36.8‐70.9)* DRE positive: 14 participants* *of the 158 prior‐negative‐ and Bx‐naïve participants taken together
Index tests	Index test 1: MRI‐pathway: a 3 Tesla MRI machine (Discovery MR750, General Electric Healthcare) was used, with T2, DWI, and DCE sequences. PI‐RADS version 2 was used, with score 1‐5 and score ≥ 3 for positivity. The Koelis Urostation was used for software fused transrectal MRI‐TBx from all MRI‐positive lesions Index test 2: transrectal extended sextant SBx were taken, blinded for MRI results, before taking the MRI‐TBx
Target condition and reference standard(s)	No reference standard is used in this agreement analyses (MRI‐pathway vs SBx) study, therefore the reference standard domain is not applicable and disregarded
Flow and timing	All participants underwent the same reference test. During the study, 69 participants refused Bx.
Comparative
Notes	Only the 158 participants in the group receiving MRI and MRI‐TBx are included in the current analysis; the 179 participants with sextant Bx only are excluded from our analysis.
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	High
DOMAIN 2: Index Test SBx
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?	Yes
		Low	Low
DOMAIN 2: Index Test MRI‐pathway
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?	Yes
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Was the reference standard performed independent from the index test?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	Yes
Were all enrolled patients included in the analysis, or were exclusions explained and not leading to a relevant bias?	No
		High

Study characteristics
Patient sampling	Aim of the study: to compare the PCa detection rate of SBx and mpMRI‐TBx Type of study: prospective cohort Selection: unclear Enrolled/eligible: 206/213 Inclusion period: September 2012‐September 2013
Patient characteristics and setting	Inclusion criteria: ≥ 1 prior‐negative SBx session (10–12 cores) and a persistent clinical suspicion of PCa (elevated PSA, an abnormal DRE, or a previous abnormal TRUS image) that warranted a repeat SBx Exclusion criteria: a prior PCa diagnosis, prior prostate mpMRI, or presence of general contraindications for MRI Setting: Herlev, Denmark. University hospital Age: median 65 years (IQR 58‐68) PSA: median 12.8 ng/mL (IQR 8.9‐19.6) Prostate volume: not reported. Instead, PSA‐density: median 0.20 (IQR 0.13‐0.29) DRE positive: 18 men
Index tests	Index test 1: MRI‐pathway: a 3 Tesla MRI (Ingenia, Philips) was used, with T2, DWI and DCE sequencing. PI‐RADS version 1 with a Likert 1‐5 score and threshold for positivity of ≥ 2 was used*. Software fusion (Hitachi Ltd, HI‐RVS‐system) MRI‐TBx were taken of all MRI‐positive lesions Index test 2: a 10‐core transrectal SBx. Abnormalities on TRUS were sampled using the standard core for the relevant segment. This was performed first and blinded for MRI results, afterwards the MRI‐TBx were taken
Target condition and reference standard(s)	No reference standard is used in this agreement analyses study (MRI‐pathway vs SBx), therefore the reference standard domain is not applicable and disregarded
Flow and timing	All participants underwent the same reference test. During the study, 7 participants were excluded because of technical problems or claustrophobia
Comparative
Notes	*Although MRI‐TBx scores 2‐5 were taken, the results for a threshold of ≥ 3 can be distinguished. In our analysis, therefore, we used the threshold of ≥ 3 for a positive MRI and MRI‐TBx. We contacted study authors but they could not provide additional data. Other comparisons were not possible to the lack of detailed data.
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Did the study avoid inappropriate exclusions?	Yes
		Unclear	Low
DOMAIN 2: Index Test SBx
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?	Yes
		Low	Low
DOMAIN 2: Index Test MRI‐pathway
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?	Yes
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Was the reference standard performed independent from the index test?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	Yes
Were all enrolled patients included in the analysis, or were exclusions explained and not leading to a relevant bias?	Yes
		Low

Study characteristics
Patient sampling	Aim of the study: to assess the diagnostic accuracy and negative predictive value of a novel bpMRI method in Bx‐naïve men in detecting and ruling out significant PCa. Type of study: prospective, single‐institutional, paired diagnostic study Selection: consecutive selection Enrolled/eligible: 1020/1063 (43 participants were excluded for various reasons) Inclusion period: November 2015–June 2017
Patient characteristics and setting	Inclusion criteria: Bx‐naïve men with a clinical suspicion of PCa (PSA ≥ 4 ng/mL and/or abnormal DRE results) Exclusion criteria: prior PBx, evidence of acute urinary tract infections, acute prostatitis, general contraindications for MRI, and prior hip replacement surgery or other metallic implants in the pelvic area Setting: Herlev, Denmark, University Hospital Age: median 67 years (IQR 61‐71) PSA: median 8 ng/mL (IQR 5.7‐13) Prostate volume: median 53 mL (IQR 40‐72) DRE positive: 377/1020 (37%) participants
Index tests	Index test 1: MRI‐pathway: a 3 Tesla MRI machine (Philips) with a pelvic‐phased‐array coil was used with T2, DWI sequences, without DCE (bpMRI). An in‐house modified PI‐RADS version 2 was used with score 1‐5 and score ≥ 3 for positivity. Transrectal software fused MRI‐TBx were performed from all MRI‐positive lesions, using Hitachi (n = 877) and Invivo (n = 143) systems. Index test 2: transrectal 10‐core SBx were taken before the MRI‐TBx, the performers were blinded for the MRI results
Target condition and reference standard(s)	No reference standard is used in this agreement analyses study (MRI‐pathway vs SBx), therefore the reference standard domain is not applicable and disregarded.
Flow and timing	All participants underwent the same type of tests. The minimal exclusions were sufficiently explained not leading to relevant bias.
Comparative
Notes	Study authors provided additional data.
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test SBx
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 2: Index Test MRI‐pathway
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?	Yes
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Was the reference standard performed independent from the index test?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	Yes
Were all enrolled patients included in the analysis, or were exclusions explained and not leading to a relevant bias?	Yes
		Low

Study characteristics
Patient sampling	Aim of the study: to evaluate the diagnostic efficacy of cognitive mpMRI‐TBx compared to SBx in Bx‐naïve men Type of study: prospective single‐centre cohort study Selection: consecutive Enrolled/eligible: 168/168 Inclusion period: July 2011‐July 2014
Patient characteristics and setting	Inclusion criteria: Bx‐naïve men, with a clinical suspicion of PCa because of elevated PSA levels and/or an abnormal DRE Setting: Madrid, Spain. University Hospital Age: mean 61.4 years (± 7.6) PSA: mean 8.3 ng/mL (± 6.1) Prostate volume: mean 48.9 mL (± 6.7)
Index tests	Index test 1: MRI‐pathway: mpMRI was performed with a 1.5 Tesla machine (Achieva, Philips Healtcare, Best, the Netherlands) with surface coil, using T1, T2 and DWI. PI‐RADS version 1 was used to assess the MRI by 2 readers independently, with a 1‐5 score and score ≥ 3 for positivity. All PI‐RADS ≥ 3 lesions were targeted cognitively with 2 MRI‐TBx cores. Index test 2: all men underwent transrectal SBx based on the Vienna nomogram (8‐19 biopsy cores depended on age and prostate volume), before MRI‐TBx were taken, by the same urologist. Blinding of MRI results during SBx was not reported
Target condition and reference standard(s)	No reference standard is used in this agreement analyses study (MRI‐pathway vs SBx), therefore the reference standard domain is not applicable and disregarded
Flow and timing	All participants underwent the same type of tests No participants were excluded
Comparative
Notes	Study authors provided additional data
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test SBx
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Unclear
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Unclear	Low
DOMAIN 2: Index Test MRI‐pathway
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?	Yes
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Was the reference standard performed independent from the index test?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	Yes
Were all enrolled patients included in the analysis, or were exclusions explained and not leading to a relevant bias?	Yes
		Low

Study characteristics
Patient sampling	Aim of the study: to investigate the overall and clinically significant PCa detection rates of MRI‐TBx and SBx in prior‐negative Bx men Type of study: retrospective study Selection: consecutive selection, but performance of MRI according to the physicians’ clinical considerations Enrolled/eligible: 185/185 (65 men underwent MRI and Bx, 120 men underwent only Bx without prior MRI) Inclusion period: March 2012–December 2014
Patient characteristics and setting	Inclusion criteria: men with prior‐negative Bx, persistently elevated serum PSA level and normal DRE Exclusion criteria: positive DRE Setting: Taichung, Taiwan. University hospital Age: median 64 years (IQR 60.3‐67.8) PSA: median 10.9 ng/mL (IQR 7.2‐14.7) Prostate volume: median 48 mL (IQR 33.5‐62.5) DRE positive: none
Index tests	Index test 1: MRI‐pathway: a 3 Tesla MRI machine (Signa HDx, General Electric Healthcare) was used with T2, DWI, and DCE sequences. PI‐RADS version 1 was converted to PI‐RADS version 2, with score 1‐5 and score ≥ 3 for positivity. Transrectal cognitive MRI‐TBx were performed from all MRI‐positive lesions with ≥ 2 cores Index test 2: transrectal SBx were taken with ≥ 16 cores from the peripheral zone and transitional zone, after the MRI‐TBx were taken by the same operator.
Target condition and reference standard(s)	No reference standard is used in this agreement analyses study (MRI‐pathway vs SBx), therefore the reference standard domain is not applicable and disregarded.
Flow and timing	All participants underwent the same reference test. No participants were excluded.
Comparative
Notes	The 120 participants in the control group who underwent only SBx without prior MRI were excluded from our analysis. Study authors provided additional data.
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	No
Did the study avoid inappropriate exclusions?	No
		High	Low
DOMAIN 2: Index Test SBx
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	No
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		High	Low
DOMAIN 2: Index Test MRI‐pathway
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?	Yes
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Was the reference standard performed independent from the index test?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	Yes
Were all enrolled patients included in the analysis, or were exclusions explained and not leading to a relevant bias?	Yes
		Low

Study characteristics
Patient sampling	Aim of the study: to determine the detection rate of 3‐Tesla MRI and MRI‐TBx compared to SBx Type of study: prospective cohort Selection: consecutive selection of participants who presented with a suspicion of PCa Enrolled/eligible: 420/429 Inclusion period: June 2008‐December 2013
Patient characteristics and setting	Inclusion criteria: abnormal DRE findings and/or persistently elevated PSA levels Exclusion criteria: not reported Setting: Shanghai, China. University hospital Age: median 67 years (range 45‐91) PSA: median 9.7 ng/mL (range 2.4‐35.7) Prostate volume: median 44.8 mL (range 21.2‐83.2) DRE positive: 52 participants
Index tests	Index test 1: MRI‐pathway: a 3 Tesla MRI machine (Philips Achieva) was used, with T1, T2, T2 spectral presaturation attenuated inversion recovery (SPAIR) and DWI sequences. An in‐house MRI score 1‐5 with threshold ≥ 3 for positivity were used. Cognitive transperineal MRI‐TBx were performed from all MRI‐positive lesions. Index test 2: a 10‐core fan‐shaped transperineal SBx from the peripheral zone with 2‐cores from transition zone was performed, blinded for MRI results, before taking the MRI‐TBx
Target condition and reference standard(s)	No reference standard is used in this agreement analyses study (MRI‐pathway vs SBx), therefore the reference standard domain is not applicable and disregarded.
Flow and timing	All participants underwent the same reference test Except for the 9 excluded participants (DWI artifacts due to movement of the participant) all participants were included in the analysis.
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test SBx
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	High
DOMAIN 2: Index Test MRI‐pathway
Was the MRI assessed without knowledge of the results of the (reference or other index) biopsies?	Yes
Were the MRI‐TBx performed independent of the (reference or other index) biopsies?	Yes
Was the performance of the SBx not influenced by the performance of the (reference or other index) biopsies?
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Was the reference standard performed independent from the index test?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Did all patients receive the same reference standard?	Yes
Were all enrolled patients included in the analysis, or were exclusions explained and not leading to a relevant bias?	Yes
		Low