Publications by authors named "John Wei"

322 Publications

Preparing Patients with Early Stage Prostate Cancer to Participate in Clinical Appointments Using a Shared Decision Making Training Video.

Med Decis Making 2021 Oct 7:272989X211028563. Epub 2021 Oct 7.

Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.

Background: Rates of shared decision making (SDM) are relatively low in early stage prostate cancer decisions, as patients' values are not well integrated into a preference-sensitive treatment decision. The study objectives were to develop a SDM training video, measure usability and satisfaction, and determine the effect of the intervention on preparing patients to participate in clinical appointments.

Methods: A randomized controlled trial was conducted to compare a plain-language decision aid (DA) to the DA plus a patient SDM training video. Patients with early stage prostate cancer completed survey measures at baseline and after reviewing the intervention materials. Survey items assessed patients' knowledge, beliefs related to SDM, and perceived readiness/intention to participate in their upcoming clinical appointment.

Results: Of those randomized to the DA + SDM video group, most participants (91%) watched the video and 93% would recommend the video to others. Participants in the DA + SDM video group, compared to the DA-only group, reported an increased desire to participate in the decision (mean = 3.65 v. 3.39, < 0.001), less decision urgency (mean = 2.82 v. 3.39, < 0.001), and improved self-efficacy for communicating with physicians (mean = 4.69 v. 4.50, = 0.05). These participants also reported increased intentions to seek a referral from a radiation oncologist (73% v. 51%, = 0.004), to take notes (mean = 3.23 v. 2.86, = 0.004), and to record their upcoming appointments (mean = 1.79 v. 1.43, = 0.008).

Conclusions: A novel SDM training video was accepted by patients and changed several measures associated with SDM. This may be a scalable, cost-effective way to prepare patients with early stage prostate cancer to participate in their clinical appointments.[Box: see text].
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http://dx.doi.org/10.1177/0272989X211028563DOI Listing
October 2021

Characterizing the aggressiveness of prostate cancer using an all-optical needle photoacoustic sensing probe: feasibility study.

Biomed Opt Express 2021 Aug 15;12(8):4873-4888. Epub 2021 Jul 15.

Department of Biomedical Engineering, University of Michigan, 500 S. State St., Ann Arbor, MI 48109, USA.

In our previous studies, we have developed a prototype interstitial needle sensing probe that can acquire broadband A-line photoacoustic (PA) signals encoding both tissue microarchitecture and histochemical information comparable to that accessible by histology. Paving the road toward clinical translation of this technology, we replaced the piezoelectric hydrophone in the needle PA probe with a fiber optic hydrophone that enabled both broader bandwidth and sufficient signal-to-noise ratio (SNR) for PA signal detection. Such an all-optical design also facilitated disposability and significantly reduced the footprint of the needle PA sensing probe. Experiments were performed on well-controlled phantoms and human prostate tissues. The microarchitectures in each sample were quantitatively evaluated by both the nonlinear spectral slope of the PA signal power spectrum and the generalized gamma (GG) parameter by implementing envelope statistics to the PA signal. In the studies on phantoms containing optically absorbing microspheres with various sizes and concentrations, the nonlinear spectral slope showed a strong correlation of r=-0.80 with the microsphere dimensions, and a relatively weak correlation of r=-0.54 with the microsphere concentrations, while the GG parameter showed a strong correlation with the microsphere dimensions (r=0.72) and a moderate correlation with the microsphere concentrations (r=0.63). In the studies on human prostate tissues containing progressive cancer stages, both the nonlinear spectral slope and the GG parameter demonstrated a statistically significant difference between benign and nonaggressive cancer tissues (p<0.01), and between nonaggressive and aggressive cancer tissues (p<0.01). In addition, a multivariate analysis combining the two quantitative measurements demonstrated the boundaries among the different progressive stages of prostate cancer.
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http://dx.doi.org/10.1364/BOE.430085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407826PMC
August 2021

Prospective Multicenter Comparison of Open and Robotic Radical Prostatectomy: The PROST-QA/RP2 Consortium.

J Urol 2021 Aug 26:101097JU0000000000002176. Epub 2021 Aug 26.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

Purpose: To evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study.

Materials And Methods: We evaluated men with localized prostate cancer at 11 high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative outcomes/complications.

Results: Demographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p <0.01) and nerve sparing (94% vs 89%; p <0.01). RALP vs ORP subjects experienced less mean intraoperative blood loss (192 vs 805 mL; p <0.01), shorter mean hospital stay (1.6 vs 2.1 days; p <0.01), and fewer blood transfusions (1% vs 4%; p <0.01), wound infections (2% vs 4%; p=0.02), other infections (1% vs 4%; p <0.01), deep vein thromboses (0.5% vs 2%; p=0.04), and bladder neck contractures requiring dilation (1.6% vs 8.3%; p <0.01). RALP subjects reported less pain (p=0.04), less activity interference (p <0.01) and higher incision satisfaction (p <0.01). Surgical approach (RALP vs ORP) was not a significant predictor of longitudinal HRQOL change in any HRQOL domain.

Conclusions: In high-volume academic centers, RALP and ORP patients may expect similar long-term HRQOL outcomes. Overall, RALP patients have less pain, shorter hospital stays, and fewer post-surgical complications such as blood transfusions, infections, deep venous thromboses, and bladder neck contractures.
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http://dx.doi.org/10.1097/JU.0000000000002176DOI Listing
August 2021

Association of Urinary MyProstateScore, Age, and Prostate Volume in a Longitudinal Cohort of Healthy Men: Long-term Findings from the Olmsted County Study.

Eur Urol Open Sci 2021 Jul 25;29:30-35. Epub 2021 May 25.

Department of Urology, University of Michigan, Ann Arbor, MI, USA.

Background: Serum prostate-specific antigen (PSA), used in prostate cancer screening, is nonspecific for cancer and is affected by age and prostate volume. More specific biomarkers could be more accurate for early detection of prostate cancer and reduce unnecessary prostate biopsies.

Objective: To evaluate the association of age and prostate volume with urinary MyProstateScore (MPS) in a screened, longitudinal cohort without evidence of prostate cancer.

Design Setting And Participants: The Olmsted County Study included men aged 40-79 yr who underwent biennial prostate cancer screening. PSA ≥4.0 ng/ml or abnormal rectal examination triggered prostate biopsy, and patients with cancer were excluded. The remaining men submitted urinary specimens for PCA3 and TMPRSS2:ERG testing.

Outcome Measurements And Statistical Analysis: MPS was calculated using the validated, locked model for grade group ≥2 cancer that includes serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. The associations of age and volume with biomarkers were assessed in multivariable regression models. The statistic was used to quantify the strength of associations independent of the unit of measurement, and values were used to estimate the proportion of biomarker variance explained by each factor.

Results And Limitations: The study included 314 screened men without evidence of cancer. In multivariable models including age and volume, PCA3 score was significantly associated with age ( = 7.51;  < 0.001), while T2:ERG score was not associated with age or volume. MPS was significantly associated with both age ( = 7.45;  < 0.001) and volume ( = 3.56;  < 0.001), but accounting for age alone explained the variability observed (  = 0.29) in a similar way to the model including age and volume (  = 0.31). The variability of PCA3, T2:ERG, and MPS was less dependent on age and volume than the variability for PSA (  = 0.45).

Conclusions: In a cohort of longitudinally screened men without evidence of cancer, we found that MPS demonstrated less variability with noncancer factors (age, prostate volume) than PSA did. These findings support the biology of these markers as more cancer-specific than PSA and highlight their promise in reducing the morbidity associated with PSA-based screening.

Patient Summary: In a group of men with no evidence of prostate cancer, we found that each of three urine-based markers of cancer-PCA3, T2:ERG, and the commercially available MyProstateScore test-showed less variability with noncancer factors (age and prostate volume) than serum PSA (prostate-specific antigen) did. These findings support their proposed use as noninvasive markers of prostate cancer that could improve the accuracy of early detection.
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http://dx.doi.org/10.1016/j.euros.2021.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317796PMC
July 2021

Testing-Related Health Impact of Transrectal and Transperineal Prostate Biopsy as Assessed by Health Utilities.

J Urol 2021 Jul 21:101097JU0000000000002118. Epub 2021 Jul 21.

Michigan Medicine, Department of Radiology, Ann Arbor, Michigan.

Purpose: We sought to assess the temporary health-related quality of life (health utility) of nonmagnetic resonance imaging-guided transrectal and transperineal prostate biopsy.

Materials And Methods: This is a 2-arm, prospectively enrolled, observational, patient-reported outcomes study, performed between June 2019 and November 2020 at a single academic medical center. Inclusion criteria were men undergoing an outpatient ultrasound-guided prostate biopsy (transrectal or transperineal approach, without magnetic resonance imaging guidance). Patients with a history of Gleason 7+ prostate cancer were excluded. Validated survey instruments were utilized to assess baseline (Short Form 12) and testing-related (Testing Morbidities Index [TMI]) health utility states. The primary outcome was the TMI summary testing-related quality-of-life score (summary utility score; scale: 0=death and 1=perfect health). The TMI is comprised of 7 domains, spanning before, during and after testing experiences. Each domain is scored from 1 (no health impact) to 5 (extreme health impact). Testing-related quality-of-life measures were compared with Mann-Whitney test.

Results: Enrollment rates were 80% (60/75; transrectal) and 86% (60/70; transperineal). All patients (120/120) completed the questionnaire. The TMI summary score for transrectal biopsy was not significantly different from transperineal biopsy (0.8, 95% CI 0.84-0.88 vs 0.84, 95% CI 0.81-0.85; p=0.0774). The largest difference in the testing experiences was related to intraprocedural pain (transrectal biopsy: 2.3, 95% CI 2.1-2.4; transperineal biopsy: 2.9, 95% CI 2.6-3.1; p <0.001).

Conclusions: Transperineal and transrectal prostate biopsies have similar effect on temporary health-related quality-of-life. Transient differences relate to intraprocedural pain. These data can inform clinical decision making and future cost-utility models.
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http://dx.doi.org/10.1097/JU.0000000000002118DOI Listing
July 2021

Head to head randomized trial of two decision aids for prostate cancer.

BMC Med Inform Decis Mak 2021 05 12;21(1):154. Epub 2021 May 12.

Sanford School of Public Policy, Duke University, Durham, NC, USA.

Background: While many studies have tested the impact of a decision aid (DA) compared to not receiving any DA, far fewer have tested how different types of DAs affect key outcomes such as treatment choice, patient-provider communication, or decision process/satisfaction. This study tested the impact of a complex medical oriented DA compared to a more simplistic decision aid designed to encourage shared decision making in men with clinically localized prostate cancer.

Methods: 1028 men at 4 VA hospitals were recruited after a scheduled prostate biopsy. Participants completed baseline measures and were randomized to receive either a simple or complex DA. Participants were men with clinically localized cancer (N = 285) by biopsy and who completed a baseline survey. Survey measures: baseline (biopsy); immediately prior to seeing the physician for biopsy results (pre- encounter); one week following the physician visit (post-encounter). Outcome measures included treatment preference and treatment received, knowledge, preference for shared decision making, decision making process, and patients' use and satisfaction with the DA.

Results: Participants who received the simple DA had greater interest in shared decision making after reading the DA (p = 0.03), found the DA more helpful (p's < 0.01) and were more likely to be considering watchful waiting (p = 0.03) compared to those receiving the complex DA at Time 2. While these differences were present before patients saw their urologists, there was no difference between groups in the treatment patients received.

Conclusions: The simple DA led to increased desire for shared decision making and for less aggressive treatment. However, these differences disappeared following the physician visit, which appeared to change patients' treatment preferences. Trial registration This trial was pre-registered prior to recruitment of participants.
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http://dx.doi.org/10.1186/s12911-021-01505-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117645PMC
May 2021

Development of a Whole-urine, Multiplexed, Next-generation RNA-sequencing Assay for Early Detection of Aggressive Prostate Cancer.

Eur Urol Oncol 2021 Mar 31. Epub 2021 Mar 31.

Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:

Background: Despite biomarker development advances, early detection of aggressive prostate cancer (PCa) remains challenging. We previously developed a clinical-grade urine test (Michigan Prostate Score [MiPS]) for individualized aggressive PCa risk prediction. MiPS combines serum prostate-specific antigen (PSA), the TMPRSS2:ERG (T2:ERG) gene fusion, and PCA3 lncRNA in whole urine after digital rectal examination (DRE).

Objective: To improve on MiPS with a novel next-generation sequencing (NGS) multibiomarker urine assay for early detection of aggressive PCa.

Design, Setting, And Participants: Preclinical development and validation of a post-DRE urine RNA NGS assay (Urine Prostate Seq [UPSeq]) assessing 84 PCa transcriptomic biomarkers, including T2:ERG, PCA3, additional PCa fusions/isoforms, mRNAs, lncRNAs, and expressed mutations. Our UPSeq model was trained on 73 patients and validated on a held-out set of 36 patients representing the spectrum of disease (benign to grade group [GG] 5 PCa).

Outcome Measurements And Statistical Analysis: The area under the receiver operating characteristic curve (AUC) of UPSeq was compared with PSA, MiPS, and other existing models/biomarkers for predicting GG ≥3 PCa.

Results And Limitations: UPSeq demonstrated high analytical accuracy and concordance with MiPS, and was able to detect expressed germline HOXB13 and somatic SPOP mutations. In an extreme design cohort (n = 109; benign/GG 1 vs GG ≥3 PCa, stratified to exclude GG 2 cancer in order to capture signal difference between extreme ends of disease), UPSeq showed differential expression for T2:ERG.T1E4 (1.2 vs 78.8 median normalized reads, p < 0.00001) and PCA3 (1024 vs 2521, p = 0.02), additional T2:ERG splice isoforms, and other candidate biomarkers. Using machine learning, we developed a 15-transcript model on the training set (n = 73) that outperformed serum PSA and sequencing-derived MiPS in predicting GG ≥3 PCa in the held-out validation set (n = 36; AUC 0.82 vs 0.69 and 0.69, respectively).

Conclusions: These results support the potential utility of our novel urine-based RNA NGS assay to supplement PSA for improved early detection of aggressive PCa.

Patient Summary: We have developed a new urine-based test for the detection of aggressive prostate cancer, which promises improvement upon current biomarker tests.
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http://dx.doi.org/10.1016/j.euo.2021.03.002DOI Listing
March 2021

Genomic imbalances in the placenta are associated with poor fetal growth.

Mol Med 2021 01 7;27(1). Epub 2021 Jan 7.

The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, 686 Bay St, Toronto, M5G 0A4, Canada.

Background: Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth.

Methods: We used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR.

Results: Aneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5-107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3.

Conclusions: We conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.
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http://dx.doi.org/10.1186/s10020-020-00253-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792164PMC
January 2021

Photoacoustic spectral analysis at ultraviolet wavelengths for characterizing the Gleason grades of prostate cancer.

Opt Lett 2020 Nov;45(21):6042-6045

The diagnosis of aggressive prostate cancer (PCa) has relied on microscopic architectures, namely Gleason patterns, of tissues extracted through core biopsies. Technology capable of assessing the tissue architecture without tissue extraction will reduce the invasiveness of PCa diagnosis and improve diagnostic accuracy by allowing for more sampling locations. Our recently developed photoacoustic spectral analysis (PASA) has achieved quantification of tissue architectural heterogeneity interstitially. Taking advantage of the unique optical absorption of cell nuclei at ultraviolet (UV) wavelengths, this study investigated PASA at 266 nm for quantifying the tissue architecture heterogeneity in prostates. The results have shown significant differences among the normal, early cancer, and late cancer stages in mouse prostates ex vivo and in vivo (=20, <0.05). The study with human samples ex vivo has shown a correlation of 0.80 (=11, <0.05) between PASA quantification and pathologic diagnosis.
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http://dx.doi.org/10.1364/OL.409249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687867PMC
November 2020

Use of the MyProstateScore Test to Rule Out Clinically Significant Cancer: Validation of a Straightforward Clinical Testing Approach.

J Urol 2021 03 20;205(3):732-739. Epub 2020 Oct 20.

Department of Urology, University of Michigan, Ann Arbor, Michigan.

Purpose: The MyProstateScore test was validated for improved detection of clinically significant (grade group ≥2) prostate cancer relative to prostate specific antigen based risk calculators. We sought to validate an optimal MyProstateScore threshold for clinical use in ruling out grade group ≥2 cancer in men referred for biopsy.

Materials And Methods: Biopsy naïve men provided post-digital rectal examination urine prior to biopsy. MyProstateScore was calculated using the validated, locked multivariable model including only serum prostate specific antigen, urinary prostate cancer antigen 3 and urinary TMPRSS2:ERG. The MyProstateScore threshold approximating 95% sensitivity for grade group ≥2 cancer was identified in a training cohort, and performance was measured in 2 external validation cohorts. We assessed the 1) overall biopsy referral population and 2) population meeting guideline based testing criteria (ie, prostate specific antigen 3-10, or <3 with suspicious digital rectal examination).

Results: Validation cohorts were prospectively enrolled from academic (977 patients, median prostate specific antigen 4.5, IQR 3.1-6.0) and community (548, median prostate specific antigen 4.9, IQR 3.7-6.8) settings. In the overall validation population (1,525 patients), 338 men (22%) had grade group ≥2 cancer on biopsy. The MyProstateScore threshold of 10 provided 97% sensitivity and 98% negative predictive value for grade group ≥2 cancer. MyProstateScore testing would have prevented 387 unnecessary biopsies (33%), while missing only 10 grade group ≥2 cancers (3.0%). In 1,242 patients meeting guideline based criteria, MyProstateScore ≤10 provided 96% sensitivity and 97% negative predictive value, and would have prevented 32% of unnecessary biopsies, missing 3.7% of grade group ≥2 cancers.

Conclusions: In a large, clinically pertinent biopsy referral population, MyProstateScore ≤10 provided exceptional sensitivity and negative predictive value for ruling out grade group ≥2 cancer. This straightforward secondary testing approach would reduce the use of more costly and invasive procedures after screening with prostate specific antigen.
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http://dx.doi.org/10.1097/JU.0000000000001430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189629PMC
March 2021

Health-related quality of life in Japanese patients with bladder cancer measured by a newly developed Japanese version of the Bladder Cancer Index.

Int J Clin Oncol 2020 Dec 24;25(12):2090-2098. Epub 2020 Aug 24.

Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Introduction: We validated a Japanese version of the Bladder Cancer Index (BCI) as a tool for measuring health-related quality of life (HRQOL) in bladder cancer patients treated with various surgical procedures.

Methods: The reliability and validity of the Japanese BCI were examined in 397 Japanese patients with bladder cancer via cross-sectional analysis. The patients simultaneously completed the Short Form (SF)-12, EQ-5D, and the Functional Assessment of Cancer Therapy-General and Bladder (FACT-G and FACT-BL). The differences in BCI subscales among various treatment groups were analyzed.

Results: This study involved 397 patients (301 males and 96 females), with a mean age of 70 years and a median disease duration of 29 months (IQR: 12-66 months). Of these patients, 221 underwent transurethral resection of a bladder tumor, and 176 patients underwent radical cystectomy (ileal conduit: 101 patients, ileal neobladder: 49, and ureterostomy: 26). Cronbach's alpha coefficient was ≥ 0.78 for all subscales, except the bowel bother subscale. Despite moderate correlations being detected between the function and bother score in urinary and bowel domains, the sexual function score was inversely correlated with the sexual bother score (r = - 0.19). A missing value percentage of > 15% was associated with old age (p < 0.05). The mean domain scores differed significantly among distinct clinically relevant treatment groups.

Conclusions: Although revisions are needed to make it easier for elderly patients to comprehend, we confirmed the reliability and validity of the Japanese BCI. The Japanese BCI could be used for cross-cultural assessments of HRQOL in bladder cancer patients.
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http://dx.doi.org/10.1007/s10147-020-01770-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677272PMC
December 2020

Impact of the MyProstateScore (MPS) Test on the Clinical Decision to Undergo Prostate Biopsy: Results From a Contemporary Academic Practice.

Urology 2020 Nov 8;145:204-210. Epub 2020 Aug 8.

Department of Urology, University of Michigan, Ann Arbor, MI; Rogel Cancer Center, University of Michigan, Ann Arbor, MI; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI.

Objective: To evaluate the association of the MyProstateScore (MPS) urine test on the decision to undergo biopsy in men referred for prostate biopsy in urology practice.

Methods: MPS testing was offered as an alternative to immediate biopsy in men referred to the University of Michigan for prostate biopsy from October 2013 through October 2016. The primary endpoint was the decision to perform biopsy. The proportion of patients undergoing biopsy was compared to predicted risk scores from the Prostate Cancer Prevention Trial risk calculator (PCPTrc). Analyses were stratified by the use of multiparametric magnetic resonance imaging (mpMRI). The associations of PCPTrc, MPS, and mpMRI with the decision to undergo biopsy were explored in a multivariable logistic regression model.

Results: Of 248 patients, 134 (54%) proceeded to prostate biopsy. MPS was significantly higher in biopsied patients (median 29 vs14, P < .001). The use of biopsy was strongly associated with MPS, with biopsy rates of 26%, 38%, 58%, 90%, and 85% in the first through fifth quintiles, respectively (P < .001). MPS association with biopsy persisted upon stratification by mpMRI. On multivariable analysis, MPS was strongly associated with the decision to undergo biopsy when modeled as both a continuous (odds ratio [OR] 1.05, 95%; confidence interval [CI] 1.04-1.08; <.001) and binary (OR 7.76, 95%; CI 4.14-14.5; P < .001) variable.

Conclusion: Many patients (46%) undergoing clinical MPS testing as an alternative to immediate prostate biopsy were able to avoid biopsy. Increasing MPS was strongly associated with biopsy rates. These findings were robust to use of mpMRI.
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http://dx.doi.org/10.1016/j.urology.2020.07.042DOI Listing
November 2020

Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees.

Am J Med Genet B Neuropsychiatr Genet 2020 07 6;183(5):268-276. Epub 2020 May 6.

Centre for Addiction and Mental Health, The Hospital for Sick Children & University of Toronto, Toronto, Ontario, Canada.

Autism spectrum disorder (ASD) is a relatively common childhood onset neurodevelopmental disorder with a complex genetic etiology. While progress has been made in identifying the de novo mutational landscape of ASD, the genetic factors that underpin the ASD's tendency to run in families are not well understood. In this study, nine extended pedigrees each with three or more individuals with ASD, and others with a lesser autism phenotype, were phenotyped and genotyped in an attempt to identify heritable copy number variants (CNVs). Although these families have previously generated linkage signals, no rare CNV segregated with these signals in any family. A small number of clinically relevant CNVs were identified. Only one CNV was identified that segregated with ASD phenotype; namely, a duplication overlapping DLGAP2 in three male offspring each with an ASD diagnosis. This gene encodes a synaptic scaffolding protein, part of a group of proteins known to be pathologically implicated in ASD. On the whole, however, the heritable nature of ASD in the families studied remains poorly understood.
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http://dx.doi.org/10.1002/ajmg.b.32785DOI Listing
July 2020

A large data resource of genomic copy number variation across neurodevelopmental disorders.

NPJ Genom Med 2019 7;4:26. Epub 2019 Oct 7.

Hamilton Health Sciences, Ron Joyce Children's Health Centre, Hamilton, On Canada.

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are , , , , , , , , , , and long non-coding RNAs: and . We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
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http://dx.doi.org/10.1038/s41525-019-0098-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779875PMC
October 2019

Genome-wide copy number variant data for inflammatory bowel disease in a caucasian population.

Data Brief 2019 Aug 2;25:104203. Epub 2019 Jul 2.

Department of Biochemistry and Medical Genetics, The George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, MB, Canada.

Genome-wide copy-number association studies offer new opportunities to identify the mechanisms underlying complex diseases, including chronic inflammatory, psychiatric disorders and others. We have used genotyping microarrays to analyse the copy-number variants (CNVs) from 243 Caucasian individuals with Inflammatory Bowel Disease (IBD). The CNV data was obtained by using multiple quality control measures and merging the results of three different CNV detection algorithms: PennCNV, iPattern, and QuantiSNP. The final dataset contains 4,402 CNVs detected by two or three algorithms independently with high confidence. This paper provides a detailed description of the data generation and quality control steps. For further interpretation of the data presented in this article, please see the research article entitled ''.
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http://dx.doi.org/10.1016/j.dib.2019.104203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626884PMC
August 2019

Development of the Japanese version of the health-related quality of life questionnaire for bladder cancer patients using the Bladder Cancer Index: A pilot study.

Int J Urol 2019 10 16;26(10):1016-1017. Epub 2019 Jul 16.

Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

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http://dx.doi.org/10.1111/iju.14073DOI Listing
October 2019

Genome-wide analysis identifies rare copy number variations associated with inflammatory bowel disease.

PLoS One 2019 11;14(6):e0217846. Epub 2019 Jun 11.

Department of Biochemistry and Medical Genetics and The George and Fay Yee Centre for Healthcare Innovation, University of Manitoba, Winnipeg, Manitoba, Canada.

Background: Inflammatory bowel disease (IBD) is an idiopathic, chronic disorder of unclear etiology with an underlying genetic predisposition. Recent genome-wide association studies have identified more than 200 IBD susceptibility loci, but the causes of IBD remain poorly defined. We hypothesized that rare (<0.1% population frequency) gene copy number variations (CNVs) could play an important mechanism for risk of IBD. We aimed to examine changes in DNA copy number in a population-based cohort of patients with IBD and search for novel genetic risk factors for IBD.

Methods: DNA samples from 243 individuals with IBD from the Manitoba IBD Cohort Study and 2988 healthy controls were analyzed using genome-wide SNP microarray technology. Three CNV calling algorithms were applied to maximize sensitivity and specificity of CNV detection. We identified IBD-associated genes affected by rare CNV from comparing the number of overlapping CNVs in IBD samples with the number of overlapping CNVs in controls for each gene.

Results: 4,402 CNVs detected by two or three algorithms intersected 7,061 genes, in at least one analyzed sample. Four genes (e.g. DUSP22 and IP6K3) intersected by rare deletions and fourteen genes (e.g. SLC25A10, PSPN, GTF2F1) intersected by rare duplications demonstrated significant association with IBD (FDR-adjusted p-value < 0.01). Of these, ten genes were functionally related to immune response and intracellular signalling pathways. Some of these genes were also identified in other IBD related genome-wide association studies. These suggested that the identified genes may play a role in the risk of IBD.

Conclusion: Our results revealed new genomic loci associated with IBD, which suggested the role of rare CNVs in IBD risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217846PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559655PMC
February 2020

Temporary Health Impact of Prostate MRI and Transrectal Prostate Biopsy in Active Surveillance Prostate Cancer Patients.

J Am Coll Radiol 2019 Oct 4;16(10):1385-1392. Epub 2019 Feb 4.

Department of Radiology, Michigan Medicine, Ann Arbor, Michigan; Michigan Radiology Quality Collaborative, Michigan Medicine, Ann Arbor, Michigan; Department of Urology, Michigan Medicine, Ann Arbor, Michigan.

Purpose: To assess the temporary health impact of prostate multiparametric MRI (mpMRI) and transrectal prostate biopsy in an active surveillance prostate cancer population.

Methods: A two-arm institutional review board-approved HIPAA-compliant prospective observational patient-reported outcomes study was performed from November 2017 to July 2018. Inclusion criteria were men with Gleason 6 prostate cancer in active surveillance undergoing either prostate mpMRI or transrectal prostate biopsy. A survey instrument was constructed using validated metrics in consultation with the local patient- and family-centered care organization. Study subjects were recruited at the time of diagnostic testing and completed the instrument by phone 24 to 72 hours after testing. The primary outcome measure was summary testing-related quality of life (summary utility score), derived from the testing morbidities index (TMI) (scale: 0 = death and 1 = perfect health). TMI is stratified into seven domains, with each domain scored from 1 (no health impact) to 5 (extreme health impact). Testing-related quality-of-life measures in the two cohorts were compared with Mann-Whitney U test.

Results: In all, 122 subjects were recruited, and 90% (110 of 122 [MRI 55 of 60, biopsy 55 of 62]) successfully completed the survey instrument. The temporary quality-of-life impact of transrectal biopsy was significantly greater than that of prostate mpMRI (0.82, 95% confidence interval [CI] 0.79-0.85, versus 0.95, 95% CI 0.94-0.97; P < .001). The largest mean domain-level difference was for intraprocedural pain (transrectal biopsy 2.6, 95% CI 2.4-2.8, versus mpMRI 1.3, 95% CI 1.1-1.5; P < .001).

Conclusion: Transrectal prostate biopsy has greater temporary health impact (lower testing-related quality-of-life measure) than prostate mpMRI.
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http://dx.doi.org/10.1016/j.jacr.2018.11.031DOI Listing
October 2019

Potential Savings in Medicare Part D for Common Urological Conditions.

Urol Pract 2018 Sep;5(5):351-359

Dow Division of Health Services Research, Department of Urology VA Ann Arbor Healthcare System, Ann Arbor, Michigan, VA Health Services Research & Development Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, Michigan.

Introduction: Millions of patients take prescription medications each year for common urological conditions. Generic and brand-name drugs have widely divergent pricing despite similar therapeutic benefit and side effect profiles. We examined prescribing patterns across provider types for generic and brand-name drugs used to treat 3 common urological conditions, and estimated economic implications for Medicare Part D spending.

Methods: We extracted 2014 prescription claims and payments from Medicare Part D and categorized oral medications used to treat 3 urological conditions, namely benign prostatic hyperplasia, erectile dysfunction and overactive bladder. We examined claims and payments for each medication among urologists and nonurologists. Lastly, we estimated potential savings by selecting a low cost or generic drug as a cost comparator for each class.

Results: There were significant differences in prescribing patterns across these conditions, with urologists prescribing more brand-name and expensive medications (p <0.001). The total potential savings related to prescriptions of more expensive and nongeneric drugs in 2014 was $1 billion (benign prostatic hyperplasia $348,454,910, erectile dysfunction $10,211,914 and overactive bladder $698,130,833). These potential savings comprised 53% of the total spending for these medications in 2014.

Conclusions: Within Medicare Part D the potential savings associated with generic substitution for higher cost and nongeneric drugs for 3 common urological conditions surpassed $1 billion, with urologists more likely to prescribe brand-name and more expensive drugs. Increasing low cost and generic drug use where available evidence of efficacy is equivocal represents a promising policy target to optimize prescription drug spending.
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http://dx.doi.org/10.1016/j.urpr.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290920PMC
September 2018

Rare copy number variation in extremely impulsively violent males.

Genes Brain Behav 2019 07 3;18(6):e12536. Epub 2018 Dec 3.

Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic.

The genetic correlates of extreme impulsive violence are poorly understood, and there have been no studies that have systematically characterized a large group of affected individuals both clinically and genetically. We performed a genome-wide rare copy number variant (CNV) analysis in 281 males from four Czech prisons who met strict clinical criteria for extreme impulsive violence. Inclusion criteria included age ≥ 18 years, an ICD-10 diagnosis of Dissocial Personality Disorder, and the absence of an organic brain disorder. Participants underwent a structured psychiatric assessment to diagnose extreme impulsive violence and then provided a blood sample for genetic analysis. DNA was genotyped and CNVs were identified using Illumina HumanOmni2.5 single-nucleotide polymorphism array platform. Comparing with 10851 external population controls, we identified 828 rare CNVs (frequency ≤ 0.1% among control samples) in 264 participants. The CNVs impacted 754 genes, with 124 genes impacted more than once (2-25 times). Many of these genes are associated with autosomal dominant or X-linked disorders affecting adult behavior, cognition, learning, intelligence, specifically expressed in the brain and relevant to synapses, neurodevelopment, neurodegeneration, obesity and neuropsychiatric phenotypes. Specifically, we identified 31 CNVs of clinical relevance in 31 individuals, 59 likely clinically relevant CNVs in 49 individuals, and 17 recurrent CNVs in 65 individuals. Thus, 123 of 281 (44%) individuals had one to several rare CNVs that were indirectly or directly relevant to impulsive violence. Extreme impulsive violence is genetically heterogeneous and genomic analysis is likely required to identify, further research and specifically treat the causes in affected individuals.
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http://dx.doi.org/10.1111/gbb.12536DOI Listing
July 2019

Association of ERG/PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer.

Med Oncol 2018 Oct 5;35(12):152. Epub 2018 Oct 5.

Department of Pathology, University of Michigan Health System, Ann Arbor, MI, USA.

We have previously demonstrated a significant correlative relationship between PTEN deletion and ERG rearrangement, both in the development of clinically localized prostate cancers and metastases. Herein, we evaluate the cooperative role of ERG and PTEN in oncological outcomes after radical prostatectomy for clinically localized prostate cancer. We evaluated ERG and PTEN status using three previously described cohorts. The first cohort included 235 clinically localized prostate cancer cases represented on tissue microarrays (TMA), evaluated using previously validated FISH assays for ERG and PTEN. The second cohort included 167 cases of clinically localized prostate cancer on TMAs evaluated for PTEN by FISH, and for PTEN and ERG by dual IHC. The third cohort comprised 59 clinically localized prostate cancer cases assessed by array comparative genomic hybridization (aCGH). Kaplan-Meir plots and long rank tests were used to assess the association of ERG and PTEN status with biochemical recurrence after radical prostatectomy for clinically localized prostate cancer. Of the 317 cases eligible for analyses with evaluable ERG and PTEN status, 88 (27.8%) patients developed biochemical recurrence over a median follow-up of 5.7 years. Overall, 45% (142/317) of cases demonstrated ERG rearrangement and 20% (62/317) of cases demonstrated PTEN loss. Hemizygous and homozygous deletion of PTEN was seen in 10% (18/175) and 3% (5/175) of ERG-negative cases, respectively. In contrast, hemizygous and homozygous deletion of PTEN was seen in 11% (15/142) and 17% (24/123) of ERG-positive cases, respectively. PTEN loss (heterozygous or homozygous) was significantly associated with shorter time to biochemical recurrence compared to no PTEN loss (p < 0.001). However, ERG rearrangement versus no rearrangement was not associated with time to PSA recurrence (p = 0.15). Patients who exhibited ERG rearrangement and loss of PTEN had no significant difference in time to recurrence compared to patients with wild-type ERG and loss of PTEN (p = 0.30). Our findings confirm a mutual cooperative role of ERG and PTEN in the pathogenesis of prostate cancer, particularly for homozygous PTEN deletion. ERG did not stratify outcome either alone or in combination with PTEN in this cohort.
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http://dx.doi.org/10.1007/s12032-018-1212-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601345PMC
October 2018

Interstitial assessment of aggressive prostate cancer by physio-chemical photoacoustics: An ex vivo study with intact human prostates.

Med Phys 2018 Jun 23. Epub 2018 Jun 23.

Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.

Purpose: Transrectal ultrasound (TRUS)-guided biopsy is the standard procedure for evaluating the presence and aggressiveness of prostate cancer. TRUS biopsy involves tissue removal, and suffers from low core yield as well as high false negative rate. A less invasive and more accurate diagnostic procedure for prostate cancer is therefore highly desired. Combining the optical sensitivity and ultrasonic resolution to resolve the spatial distribution of the major molecular components in tissue, photoacoustic (PA) technology could be an alternative approach for the diagnosis of prostate cancer. The purpose of this study was to examine the feasibility of identifying aggressive prostate cancer using interstitial PA measurements.

Methods: Seventeen patients with prebiopsy magnetic resonance imaging (MRI), TRUS biopsies, and planned prostatectomies were enrolled in this study. The interstitial PA measurements were achieved using our recently developed needle PA probe, which was inserted into the ex vivo prostates in the fashion of a biopsy needle. A total of 70 interstitial PA measurements were acquired. The PA measurements were quantified by a previously established PA physio-chemical analysis (PAPCA) method. The histology has confirmed the nonaggressive and aggressive cancerous conditions at the insertion locations. The diagnostic accuracy was also compared to that provided by the prebiopsy MRI.

Results: The quantitative study shows significant differences between the individual parameters of the nonaggressive and the aggressive cancerous regions (P < 0.005). Multivariate analysis of the quantitative features achieved a diagnostic accuracy of 78.6% for differentiating nonaggressive and aggressive prostate cancer tissues.

Conclusions: The proposed procedure has shown promises in the diagnosis of aggressive prostate cancer.
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http://dx.doi.org/10.1002/mp.13061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629517PMC
June 2018

Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression.

Nat Genet 2018 06 28;50(6):814-824. Epub 2018 May 28.

School of Informatics and Computing, Indiana University, Bloomington, IN, USA.

The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.
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http://dx.doi.org/10.1038/s41588-018-0120-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980762PMC
June 2018

Copy number variation in fetal alcohol spectrum disorder.

Biochem Cell Biol 2018 04 13;96(2):161-166. Epub 2018 Mar 13.

a The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 04A, Canada.

Fetal alcohol spectrum disorder (FASD) is characterized by a combination of neurological, developmental, and congenital defects that may occur as a consequence of prenatal alcohol exposure. Earlier reports showed that large chromosomal anomalies may link to FASD. Here, we examined the prevalence and types of copy number variations (CNVs) in FASD cases previously diagnosed by a multidisciplinary FASD team in sites across Canada. We genotyped 95 children with FASD and 87 age-matched, typically developing controls on the Illumina Human Omni2.5 SNP (single nucleotide polymorphisms) array platform. We compared their CNVs with those of 10 851 population controls to identify rare CNVs (<0.1% frequency), which may include large unbalanced chromosomal abnormalities, that might be relevant to FASD. In 12/95 (13%) of the FASD cases, rare CNVs were found that impact potentially clinically relevant developmental genes, including the CACNA1H involved in epilepsy and autism, the 3q29 deletion disorder, and others. Our results show that a subset of children diagnosed with FASD have chromosomal deletions and duplications that may co-occur or explain the neurodevelopmental impairments in a diagnosed cohort of FASD individuals. Children suspected to have FASD with or without sentinel facial features of fetal alcohol syndrome and neurodevelopmental delays should potentially be evaluated by a clinical geneticist and possibly have genetic investigations as appropriate to exclude other etiologies.
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http://dx.doi.org/10.1139/bcb-2017-0241DOI Listing
April 2018

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.

CMAJ 2018 02;190(5):E126-E136

The Centre for Applied Genomics (Reuter, Walker, Thiruvahindrapuram, Whitney, Yuen, Trost, Paton, Pereira, Herbrick, Wintle, Merico, Howe, MacDonald, Lu, Nalpathamkalam, Sung, Wang, Patel, Pellecchia, J. Wei, Strug, Bell, Kellam, Mahtani, Hosseini, Fiume, Marshall, Buchanan, Scherer); Divisions of Clinical Pharmacology and Toxicology (I. Cohn), or Clinical, and Metabolic Genetics (Sondheimer, Weksberg, Shuman, Bowdin, Meyn, Monfared), The Hospital for Sick Children; Departments of Paediatrics (Sondheimer, R. Cohn) and Molecular Genetics (Yuen, Weksberg, Shuman, R. Cohn, Ellis, Meyn), University of Toronto; Deep Genomics Inc. (Merico); Department of Psychiatry (Bassett), University Health Network and Centre for Addiction and Mental Health, University of Toronto; Li Ka Shing Knowledge Institute (Bombard), St. Michael's Hospital; Institute of Health Policy, Management and Evaluation (Bombard), University of Toronto; Centre for Genetic Medicine (Stavropoulos, Bowdin, Ray, Monfared); Molecular Genetics Laboratory (Stavropoulos, Ray, Marshall), Division of Genome Diagnostics, Paediatric Laboratory Medicine; Developmental and Stem Cell Biology (Hildebrandt, W. Wei, Romm, Pasceri, Ellis); Ted Rogers Cardiac Genome Clinic (Hosseini); Cytogenetics Laboratory (Joseph-George), Division of Genome Diagnostics, Paediatric Laboratory Medicine, The Hospital for Sick Children; Departments of Biochemistry and Laboratory Medicine, and Pathobiology (Keeley), University of Toronto; DNAstack (Cook, Fiume); McLaughlin Centre (Lee, Scherer), University of Toronto; Medcan Health Management Inc. (Davies, Hazell); Dalla Lana School of Public Health (Szego), Department of Family and Community Medicine, and The Joint Centre for Bioethics, University of Toronto; Centre for Clinical Ethics (Szego), St. Joseph's Health Centre, Toronto, Ont.

Background: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers.

Methods: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant.

Results: Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set ( = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants - associated with cancer, cardiac or neurodegenerative phenotypes - remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual.

Interpretation: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care.
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http://dx.doi.org/10.1503/cmaj.171151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798982PMC
February 2018

Incorporation of Urinary Prostate Cancer Antigen 3 and TMPRSS2:ERG into Prostate Cancer Prevention Trial Risk Calculator.

Eur Urol Focus 2019 01 13;5(1):54-61. Epub 2018 Feb 13.

Department of Urology, University of Texas Health at San Antonio, San Antonio, TX, USA. Electronic address:

Background: The Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) is a commonly used risk tool for predicting the outcome on biopsy based on the established risk factors.

Objective: To determine whether incorporation of the novel urinary markers prostate cancer antigen 3 (PCA3) and TMPRSS2:ERG (T2:ERG) into the PCPTRC improves its discrimination, accuracy, and clinical net benefit.

Design, Setting, And Participants: Since PCA3 and T2:ERG were not measured as part of the PCPTRC, a Bayesian modeling approach was used to combine data where the markers were measured in a Michigan cohort with the PCPTRC as prior probabilities to form an updated PCPTRC. This update was compared to the existing PCPTRC on an independent Early Detection Research Network cohort in terms of discrimination, calibration, and decision curve analysis.

Results And Limitations: Among the 1225 Michigan biopsies, 57.7%, 24.0%, and 18.3% were negative, with low- and high-grade (Gleason grade≥7) prostate cancer, respectively. Evaluated on the Early Detection Research Network validation set comprising 854 biopsies, areas under the curve (95% confidence interval) for predicting high-grade cancer in the 854 biopsies comprising the validation set were 70.0% (66.0-74.0%), 76.4% (72.8-80.0%), and 77.1% (73.6-80.6%) for the PCPTRC alone, with PCA3 added, and PCA3 and T2:ERG added, respectively. Net benefit was improved for the updated PCPTRC, while calibration was not. Limitations are that the updated PCPTRC is based on two different cohorts, the PCPT and Michigan, and that 20% of the validation set came from the Michigan center. More validation is required; hence, the updated risk tool is posted online.

Conclusions: Incorporation of PCA3 into the PCPTRC improved validation on an independent cohort, whereas T2:ERG offered negligible utility in addition to PCA3.

Patient Summary: After passing external validation, prostate cancer antigen 3 has been added to the online Prostate Cancer Prevention Trial Risk Calculator for use by patients in deciding whether to proceed to biopsy. TMPRSS2:ERG did not improve prediction on the external validation set, but is included for further validation.
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http://dx.doi.org/10.1016/j.euf.2018.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077104PMC
January 2019

OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome.

Am J Hum Genet 2018 02;102(2):278-295

Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address:

Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development.
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http://dx.doi.org/10.1016/j.ajhg.2018.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985537PMC
February 2018

Cost-effectiveness of magnetic resonance imaging and targeted fusion biopsy for early detection of prostate cancer.

BJU Int 2018 07 8;122(1):50-58. Epub 2018 Mar 8.

Department of Industrial and Operations Engineering, University of Michigan, Ann Arbor, MI, USA.

Objective: To determine how best to use magnetic resonance imaging (MRI) and targeted MRI/ultrasonography fusion biopsy for early detection of prostate cancer (PCa) in men with elevated prostate-specific antigen (PSA) concentrations and whether it can be cost-effective.

Methods: A Markov model of PCa onset and progression was developed to estimate the health and economic consequences of PCa screening with MRI. Patients underwent PSA screening from ages 55 to 69 years. Patients with elevated PSA concentrations (>4 ng/mL) underwent MRI, followed by targeted fusion or combined (standard + targeted fusion) biopsy on positive MRI, and standard or no biopsy on negative MRI. Prostate Imaging Reporting and Data System (PI-RADS) score on MRI was used to determine biopsy decisions. Deaths averted, quality-adjusted life-years (QALYs), cost and incremental cost-effectiveness ratio (ICER) were estimated for each strategy.

Results: With a negative MRI, standard biopsy was more expensive and had lower QALYs than performing no biopsy. The optimum screening strategy (ICER $23 483/QALY) recommended combined biopsy for patients with PI-RADS score ≥3 and no biopsy for patients with PI-RADS score <3, and reduced the number of screening biopsies by 15%. Threshold analysis suggests MRI continues to be cost-effective when the sensitivity and specificity of MRI and combined biopsy are simultaneously reduced by 19 percentage points.

Conclusions: Our analysis suggests MRI followed by targeted MRI/ultrasonography fusion biopsy can be a cost-effective approach to the early detection of PCa.
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http://dx.doi.org/10.1111/bju.14151DOI Listing
July 2018

Histotripsy Treatment of Benign Prostatic Enlargement Using the Vortx R System: Initial Human Safety and Efficacy Outcomes.

Urology 2018 Apr 9;114:184-187. Epub 2018 Jan 9.

University of Michigan, Ann Arbor, MI. Electronic address:

Objective: To assess clinical safety (primary) and efficacy (secondary) of histotripsy for treatment of symptomatic benign prostatic enlargement in a first-in human study.

Methods: Twenty-five male subjects with moderate to severe lower urinary tract symptoms, prostate size between 30 and 80 g, and no evidence of prostate cancer were enrolled at 2 sites in a prospective, single-arm study. Treatment consisted of acoustic energy delivery through the perineum with integrated real-time transrectal ultrasound monitoring using the Vortx R system. Follow-up evaluations were performed on postoperative day 1 and 1, 3, and 6 months.

Results: Twenty-five men underwent histotripsy treatment with no serious intraoperative adverse events. Postoperatively, 3 cases of transient urinary retention (<3 days), 1 case of urinary retention (8 days in duration, defined as serious), a minor anal abrasion, and microscopic hematuria were considered device-related adverse events. Debulking of targeted prostate tissue was not observed with transrectal ultrasound imaging or with endoscopic visualization, and clinically meaningful improvement in uroflow or postvoid residual urine (PVR) did not occur. However, International Prostate Symptom Score improvement at 1 month was 12.5 (52.4%) ± 6.6 points (n = 25), at 3 months was 11.9 (50.8%) ± 7.6 points (n = 24), and at 6 months was 10.4 (44.0%) ± 7.6 points (n = 24) (P <.001).

Conclusion: Prostate histotripsy was safe and well tolerated in this pilot human trial with improvement in lower urinary tract symptoms.
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http://dx.doi.org/10.1016/j.urology.2017.12.033DOI Listing
April 2018

Development of a Nationally Representative Coordinated Registry Network for Prostate Ablation Technologies.

J Urol 2018 06 4;199(6):1488-1493. Epub 2018 Jan 4.

Department of Urology, New York Presbyterian-Weill Cornell Medical College, New York, New York. Electronic address:

Purpose: The accumulation of data through a prospective, multicenter coordinated registry network is a practical way to gather real world evidence on the performance of novel prostate ablation technologies. Urological oncologists, targeted biopsy experts, industry representatives and representatives of the FDA (Food and Drug Administration) convened to discuss the role, feasibility and important data elements of a coordinated registry network to assess new and existing prostate ablation technologies.

Materials And Methods: A multiround Delphi consensus approach was performed which included the opinion of 15 expert urologists, representatives of the FDA and leadership from high intensity focused ultrasound device manufacturers. Stakeholders provided input in 3 consecutive rounds with conference calls following each round to obtain consensus on remaining items. Participants agreed that these elements initially developed for high intensity focused ultrasound are compatible with other prostate ablation technologies. Coordinated registry network elements were reviewed and supplemented with data elements from the FDA common study metrics.

Results: The working group reached consensus on capturing specific patient demographics, treatment details, oncologic outcomes, functional outcomes and complications. Validated health related quality of life questionnaires were selected to capture patient reported outcomes, including the IIEF-5 (International Index of Erectile Function-5), the I-PSS (International Prostate Symptom Score), the EPIC-26 (Expanded Prostate Cancer Index Composite-26) and the MSHQ-EjD (Male Sexual Health Questionnaire for Ejaculatory Dysfunction). Group consensus was to obtain followup multiparametric magnetic resonance imaging and prostate biopsy approximately 12 months after ablation with additional imaging or biopsy performed as clinically indicated.

Conclusions: A national prostate ablation coordinated registry network brings forth vital practice pattern and outcomes data for this emerging treatment paradigm in the United States. Our multiple stakeholder consensus identifies critical elements to evaluate new and existing energy modalities and devices.
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http://dx.doi.org/10.1016/j.juro.2017.12.058DOI Listing
June 2018
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