Publications by authors named "Fredrik Wiklund"

196 Publications

Identification and Validation of Leucine-rich α-2-glycoprotein 1 as a Noninvasive Biomarker for Improved Precision in Prostate Cancer Risk Stratification.

Eur Urol Open Sci 2020 Oct 13;21:51-60. Epub 2020 Oct 13.

Prostate Cancer Research Group, Centre for Molecular Medicine Norway, University of Oslo and Oslo University Hospital, Oslo, Norway.

Background: More accurate risk assessments are needed to improve prostate cancer management.

Objective: To identify blood-based protein biomarkers that provided prognostic information for risk stratification.

Design Setting And Participants: Mass spectrometry was used to identify biomarker candidates from blood, and validation studies were performed in four independent cohorts retrospectively collected between 1988 and 2015.

Outcome Measurements And Statistical Analysis: The primary outcome objectives were progression-free survival, prostate cancer-specific survival (PCSS), and overall survival. Statistical analyses to assess survival and model performance were performed.

Results And Limitation: Serum leucine-rich α-2-glycoprotein 1 (LRG1) was found to be elevated in fatal prostate cancer. LRG1 provided prognostic information independent of metastasis and increased the accuracy in predicting PCSS, particularly in the first 3 yr. A high LRG1 level is associated with an average of two-fold higher risk of disease-progression and mortality in both high-risk and metastatic patients. However, our study design, with a retrospective analysis of samples spanning several decades back, limits the assessment of the clinical utility of LRG1 in today's clinical practice. Thus, independent prospective studies are needed to establish LRG1 as a clinically useful biomarker for patient management.

Conclusions: High blood levels of LRG1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer, and LRG1 increased the accuracy of risk stratification of prostate cancer patients.

Patient Summary: High blood levels of leucine-rich α-2-glycoprotein 1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer.
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http://dx.doi.org/10.1016/j.euros.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317831PMC
October 2020

Identification of 22 susceptibility loci associated with testicular germ cell tumors.

Nat Commun 2021 07 23;12(1):4487. Epub 2021 Jul 23.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95 percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
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http://dx.doi.org/10.1038/s41467-021-24334-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302763PMC
July 2021

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Sci Rep 2021 04 29;11(1):9264. Epub 2021 Apr 29.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10) and 3145 (P < 1 × 10) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-85169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084951PMC
April 2021

Genetically Inferred Telomere Length and Testicular Germ Cell Tumor Risk.

Cancer Epidemiol Biomarkers Prev 2021 06 18;30(6):1275-1278. Epub 2021 Mar 18.

Division of Cancer Epidemiology and Genetics, NCI, Rockville, Maryland.

Background: Studies evaluating the association between peripheral blood leukocyte telomere length (LTL) and testicular germ cell tumor (TGCT) risk have produced conflicting results.

Methods: Using available genotype data from the Testicular Cancer Consortium (TECAC), polygenic risk score and Mendelian randomization analyses of genetic variants previously associated with LTL were used to assess potential etiologic associations between telomere length and TGCT risk.

Results: Genetically inferred telomere length was not associated with TGCT risk among 2,049 cases and 6,921 controls with individual-level genotype data (OR, 1.02; 95% confidence interval, 0.97-1.07). Mendelian randomization analyses using summary statistic data further indicated no evidence for an association between telomere length and TGCT risk among all available TECAC participants (3,558 cases and 13,971 controls).

Conclusions: Our analyses in the largest molecular genetic testicular cancer study to date provide no evidence for an association between genetically inferred peripheral blood LTL and TGCT risk.

Impact: The lack of evidence for an overall association indicates that peripheral blood LTL is likely not a strong biomarker for TGCT risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172526PMC
June 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

Eur Urol Oncol 2021 Aug 9;4(4):570-579. Epub 2021 Jan 9.

Institute of Biomedicine, University of Turku, Turku, Finland.

Background: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.

Objective: To precisely estimate the contribution of germline ATM mutations to PrCa risk.

Design, Setting, And Participants: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry.

Outcome Measurements And Statistical Analysis: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated.

Results And Limitations: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (p = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).

Conclusions: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families.

Patient Summary: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
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http://dx.doi.org/10.1016/j.euo.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381233PMC
August 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 06 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

Risk of Rehospitalization and Death in Patients Hospitalized Due to Asthma.

J Allergy Clin Immunol Pract 2021 05 24;9(5):1960-1968.e4. Epub 2020 Dec 24.

Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.

Background: Asthma is a heterogeneous inflammatory airway disease that continues to cause considerable morbidity across the world, with poor asthma control leading to hospitalizations.

Objective: The present study investigated the risk of rehospitalization, mortality, and the management of patients with asthma who had been hospitalized because of an asthma exacerbation.

Methods: National Swedish health registries were linked for patients 6 years or older who were admitted to hospital because of asthma (index date) between January 1, 2006, and December 31, 2015. Exacerbations were defined as asthma-related hospitalization, emergency visits, or collection of oral steroids. Patients were followed for rehospitalizations 12 months after the index date, health care resource utilization and treatment for 36 months, and mortality to study end. Regression models for time-to-event analyses were applied to assess risk factors for rehospitalization and mortality.

Results: A total of 15,691 patients (mean age, 51.5 years; 63% females) were included, of whom 1,892 (12%) were rehospitalized for asthma within 12 months. Rehospitalized patients had a markedly increased risk of subsequent asthma-related mortality (adjusted hazard ratio, 2.80; 95% CI, 1.95-4.01) compared with those not rehospitalized. Two-third of the patients were not followed up by a hospital-based specialist, and 60% did not collect enough inhaled corticosteroid doses to cover daily treatment the year postindex.

Conclusions: In this study, more than 1 in 10 patients were rehospitalized because of asthma within 12 months, and rehospitalizations were associated with asthma-related mortality. Few patients were seen by a hospital-based specialist, and few used inhaled corticosteroid continuously. Closer monitoring after hospitalization is needed.
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http://dx.doi.org/10.1016/j.jaip.2020.12.030DOI Listing
May 2021

The Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
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http://dx.doi.org/10.3390/cancers12113254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694218PMC
November 2020

Management and Risk of Mortality in Patients Hospitalised Due to a First Severe COPD Exacerbation.

Int J Chron Obstruct Pulmon Dis 2020 28;15:2673-2682. Epub 2020 Oct 28.

Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund, Sweden.

Background: Reducing the need for hospitalisation in patients with chronic obstructive pulmonary disease (COPD) is an important goal in COPD management. The aim of this study was to evaluate re-hospitalisation, treatment, comorbidities and mortality in patients with COPD who were hospitalised for the first time due to a COPD exacerbation.

Methods: This was a retrospective, population-based observational cohort study of Swedish patients using linked data from three mandatory national health registries to assess re-hospitalisation rates, medication use and mortality. Rate of hospitalisation was calculated using the number of events divided by the number of person-years at risk; risk of all-cause and COPD-related mortality were assessed using Cox proportional hazard models.

Results: In total, 51,247 patients were identified over 10 years; 35% of patients were not using inhaled corticosteroid, long-acting muscarinic antagonist or long-acting β-agonist treatment prior to hospitalisation, 38% of whom continued without treatment after being discharged. Re-hospitalisation due to a second severe exacerbation occurred in 11.5%, 17.8% and 24% of the patients within 30, 90 and 365 days, respectively. Furthermore, 24% died during the first year following hospitalisation and risk of all-cause and COPD-related mortality increased with every subsequent re-hospitalisation. Comorbidities, including ischaemic heart disease, heart failure and pneumonia, were more common amongst patients who were re-hospitalised than those who were not.

Conclusion: Following hospitalisation for first severe COPD exacerbation, many patients did not collect the treatment recommended by current guidelines. Risk of mortality increased with every subsequent re-hospitalisation. Patients with concurrent comorbidities had an increased risk of being re-hospitalised.
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http://dx.doi.org/10.2147/COPD.S276819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604260PMC
June 2021

Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.

J Natl Cancer Inst 2021 May;113(5):616-625

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease.

Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided.

Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4).

Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
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http://dx.doi.org/10.1093/jnci/djaa132DOI Listing
May 2021

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Nat Commun 2020 07 3;11(1):3353. Epub 2020 Jul 3.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.
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http://dx.doi.org/10.1038/s41467-020-16483-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335068PMC
July 2020

A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data.

Cancer Epidemiol Biomarkers Prev 2020 09 24;29(9):1731-1738. Epub 2020 Jun 24.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.

Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.

Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.

Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.

Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483627PMC
September 2020

The effect of sample size on polygenic hazard models for prostate cancer.

Eur J Hum Genet 2020 10 8;28(10):1467-1475. Epub 2020 Jun 8.

Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.
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http://dx.doi.org/10.1038/s41431-020-0664-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608255PMC
October 2020

Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer.

Genes (Basel) 2020 03 14;11(3). Epub 2020 Mar 14.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.

Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with (4.1%) and (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases ( = 0.030), and the prevalence of 1.6% ( < 0.001) and 5.4% ( = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed ( = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness.
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http://dx.doi.org/10.3390/genes11030314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140841PMC
March 2020

Overuse of short-acting β-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme.

Eur Respir J 2020 04 16;55(4). Epub 2020 Apr 16.

Dept of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.

Background: Overuse of short-acting β-agonists (SABA) may indicate poor asthma control and adverse health outcomes. Contemporary population-based data on use, risk factors and impact of SABA (over)use on asthma exacerbations and mortality are scarce, prompting initiation of the global SABINA (SABA use IN Asthma) programme.

Methods: By linking data from Swedish national registries, asthma patients aged 12-45 years with two or more collections of drugs for obstructive lung disease during 2006-2014 were included. SABA overuse was defined as collection of more than two SABA canisters in a 1-year baseline period following inclusion. SABA use was grouped into 3-5, 6-10 and ≥11 canisters per baseline-year. Cox regression was used to examine associations between SABA use and exacerbation (hospitalisations and/or oral corticosteroid claims) and mortality.

Results: The analysis included 365 324 asthma patients (mean age 27.6 years; 55% female); average follow-up was 85.4 months. 30% overused SABA, with 21% collecting 3-5 canisters per year, 7% collecting 6-10 canisters per year and 2% collecting ≥11 canisters per year. Increasing number of collected SABA canisters was associated with increased risk of exacerbation, as follows. 3-5 canisters: hazard ratio (HR) 1.26 (95% CI 1.24-1.28); 6-10 canisters: 1.44 (1.41-1.46); and ≥11 canisters: 1.77 (1.72-1.83), compared to two or fewer canisters per year. Higher SABA use was associated with incrementally increased mortality risk (2564 deaths observed), as follows. 3-5 canisters: HR 1.26 (95% CI 1.14-1.39); 6-10 canisters 1.67 (1.49-1.87); and ≥11 canisters: 2.35 (2.02-2.72) compared to two or fewer canisters per year.

Conclusion: One-third of asthma patients in Sweden collected three or more SABA canisters annually. SABA overuse was associated with increased risks of exacerbation and mortality. These findings emphasise that monitoring of SABA usage should be key in improving asthma management.
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http://dx.doi.org/10.1183/13993003.01872-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160635PMC
April 2020

Real world utilization of EGFR TKIs and prognostic factors for survival in NSCLC during 2010-2016 in Sweden: A nationwide observational study.

Int J Cancer 2020 05 12;146(9):2510-2517. Epub 2019 Aug 12.

Center for Research & Development, Uppsala University, County Council of Gävleborg, Gävle Hospital, Gävle, Sweden.

The purpose of our study was to investigate time trends in treatment pattern and prognostic factors for overall survival (OS) in epidermal growth factor receptor (EGFR) targeting tyrosine kinase inhibitors (TKIs) treated nonsmall cell lung cancer (NSCLC) patients. Utilizing Swedish nationwide registers, we identified all Stage IIIB-IV NSCLC patients treated with EGFR TKIs and followed them from diagnosis (2010-2015) until death or end of observation (2016). Multivariable Cox regression analyses were performed to test associations of patient-, tumor-related factors with OS. Of 9,992 Stage IIIB-IV NSCLC patients, the 1,419 (14%) who initiated EGFR TKI treatment during observation were younger (median age 68 vs. 71 years), less ≥1 comorbidities (34% vs. 46%), more often female (59% vs. 47%), Stage IV (89% vs. 85%) and adenocarcinoma (85% vs. 66%) compared to non-TKI treated patients. After TKI initiation, 7% (n = 100) of the patients switched, 4% (n = 62) rechallenged a TKI treatment, 65% (n = 919) discontinued and 24% (n = 338) had died. A more recent diagnosis demonstrated shorter time to EGFR TKI initiation, prolonged treatment length and longer median OS (15.3 months 2010-2011; 14.4 months 2012-2013; 18.6 months 2014-2015). Prognostic factors for longer OS when treated with EGFR TKIs were younger age, adenocarcinoma, less advanced clinical stage and less comorbid disease. In conclusion, during the observation period, survival improved for EGFR TKI treated NSCLC patients, as did the accessibility for targeted therapies for these patients.
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http://dx.doi.org/10.1002/ijc.32596DOI Listing
May 2020

Oral corticosteroid use, morbidity and mortality in asthma: A nationwide prospective cohort study in Sweden.

Allergy 2019 11 11;74(11):2181-2190. Epub 2019 Jun 11.

Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.

Background: Patterns and determinants of long-term oral corticosteroid (OCS) use in asthma and related morbidity and mortality are not well-described. In a nationwide asthma cohort in Sweden, we evaluated the patterns and determinants of OCS use and risks of OCS-related morbidities and mortality.

Methods: Data for 217 993 asthma patients (aged ≥ 6 years) in secondary care were identified between 2007 and 2014 using Swedish national health registries. OCS use at baseline was categorized: regular users (≥5 mg/d/y; n = 3299; 1.5%); periodic users (>0 but <5 mg/d/y; n = 49 930; 22.9%); and nonusers (0 mg/d/y; n = 164 765; 75.6%). Relative risks of becoming a regular OCS user and for morbidity and mortality were analysed using multivariable Cox regression.

Results: At baseline, 24% of asthma patients had used OCS during the last year and 1.5% were regular users. Of those not using OCS at baseline, 26% collected at least one OCS prescription and 1.3% became regular OCS users for at least 1 year during the median follow-up of 5.3 years. Age at asthma diagnosis, increasing GINA severity and Charlson Comorbidity Index were associated with regular OCS use. Compared to periodic and non-OCS use, regular use was associated with increased incidence of OCS-related morbidities and greater all-cause mortality, adjusted HR 1.34 (95% CI 1.24-1.45).

Conclusions: Oral corticosteroids use is frequent for asthma patients, and many are regular users. Regular OCS use is associated with increased risk of morbidity and mortality. These findings indicate that there is a need of other treatment options for patients with severe asthma who are using regular OCS.
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http://dx.doi.org/10.1111/all.13874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899917PMC
November 2019

Shared heritability and functional enrichment across six solid cancers.

Nat Commun 2019 01 25;10(1):431. Epub 2019 Jan 25.

Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández Almagro, 3, 28029, Madrid, Spain.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r = 0.57, p = 4.6 × 10), breast and ovarian cancer (r = 0.24, p = 7 × 10), breast and lung cancer (r = 0.18, p =1.5 × 10) and breast and colorectal cancer (r = 0.15, p = 1.1 × 10). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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http://dx.doi.org/10.1038/s41467-018-08054-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347624PMC
January 2019

Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Nat Commun 2019 01 17;10(1):382. Epub 2019 Jan 17.

Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-08293-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336778PMC
January 2019

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Nat Genet 2019 02;51(2):363

Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0330-6DOI Listing
February 2019

Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Nat Commun 2018 11 5;9(1):4616. Epub 2018 Nov 5.

Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
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http://dx.doi.org/10.1038/s41467-018-06863-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218483PMC
November 2018

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

Cancer Epidemiol Biomarkers Prev 2019 01 23;28(1):208-216. Epub 2018 Oct 23.

Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

Background: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).

Methods: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.

Results: Thirty-five metabolites were strongly associated with prostate cancer ( < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.

Conclusions: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.

Impact: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746173PMC
January 2019

Synergistic Interaction of and Predisposes to Aggressive Prostate Cancer.

Clin Cancer Res 2018 12 4;24(24):6265-6276. Epub 2018 Sep 4.

Institute of Biomedicine, University of Turku, Turku, Finland.

Purpose: Distinguishing aggressive prostate cancer from indolent disease improves personalized treatment. Although only few genetic variants are known to predispose to aggressive prostate cancer, synergistic interactions of G84E high-risk prostate cancer susceptibility mutation with other genetic loci remain unknown. The purpose of this study was to examine the interplay of rs138213197 (G84E) and rs2278911 (R229Q) germline variants on prostate cancer risk.

Experimental Design: Genotyping was done in Finnish discovery cohort ( = 2,738) and validated in Swedish ( = 3,132) and independent Finnish ( = 1,155) prostate cancer cohorts. Expression pattern analysis was followed by functional studies in prostate cancer cell models.

Results: Interplay of (G84E) and (R229Q) variants results in highest observed inherited prostate cancer risk (OR, 21.1; = 0.000024). In addition, this synergism indicates a significant association of T and T dual carriers with elevated risk for high Gleason score (OR, 2.3; = 0.025) and worse prostate cancer-specific life expectancy (HR, 3.9; = 0.048), and it is linked with high PSA at diagnosis (OR, 3.30; = 0.028). Furthermore, combined high expression of correlates with earlier biochemical recurrence. Finally, functional experiments showed that ectopic expression of variants stimulates prostate cancer cell growth and migration. In addition, we observed strong chromatin binding of HOXB13 at locus and revealed that functionally promotes transcription. The study is limited to retrospective Nordic cohorts.

Conclusions: Simultaneous presence of T and T alleles confers for high prostate cancer risk and aggressiveness of disease, earlier biochemical relapse, and lower disease-specific life expectancy. HOXB13 protein binds to gene and functionally promotes transcription.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719560PMC
December 2018

ANO7 is associated with aggressive prostate cancer.

Int J Cancer 2018 11 22;143(10):2479-2487. Epub 2018 Sep 22.

Institute of Biomedicine, University of Turku, Turku, Finland.

Prostate cancer is one of the most common and heritable human cancers. Our aim was to find germline biomarkers that can predict disease outcome. We previously detected predisposing signals at 2q37, the location of the prostate specific ANO7 gene. To investigate, in detail, the associations between the ANO7 gene and PrCa risk and disease aggressiveness, ANO7 was sequenced in castration resistant tumors together with samples from unselected PrCa patients and unaffected males. Two pathogenic variants were discovered and genotyped in 1769 patients and 1711 unaffected males. Expression of ANO7 vs. PrCa aggressiveness was investigated. Different databases along with Swedish and Norwegian cohorts were used for validation. Case-control and aggressive vs. nonaggressive association analyses were performed against risk and/or cancer aggressiveness. The ANO7 mRNA level and patient survival were analyzed using expression data from databases. Variant rs77559646 showed both risk (OR 1.40; p = 0.009, 95% CI 1.09-1.78) and association with aggressive PrCa (Genotype test p = 0.04). It was found to be an eQTL for ANO7 (Linear model p-values for Finnish patients p = 0.009; Camcap prostate tumor p = 2.53E-06; Stockholm prostate tumor cohort p = 1.53E-13). rs148609049 was not associated with risk, but was related to shorter survival (HR 1.56; 95% CI 1.03-2.36). High ANO7 expression was independently linked to poor survival (HR 18.4; 95% CI 1.43-237). ANO7 genotypes correlate with expression and biochemical relapse, suggesting that ANO7 is a potential PrCa susceptibility gene and that its elevated expression correlates with disease severity and outcome.
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http://dx.doi.org/10.1002/ijc.31746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589920PMC
November 2018

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

Nat Commun 2018 06 11;9(1):2256. Epub 2018 Jun 11.

Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
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http://dx.doi.org/10.1038/s41467-018-04109-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995836PMC
June 2018

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Nat Genet 2018 07 11;50(7):928-936. Epub 2018 Jun 11.

Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa.
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http://dx.doi.org/10.1038/s41588-018-0142-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568012PMC
July 2018
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