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@ARTICLE{Seibert:131811,
      author       = {T. M. Seibert and C. C. Fan and Y. Wang and V. Zuber and R.
                      Karunamuni and J. K. Parsons and R. A. Eeles and D. F.
                      Easton and Z. Kote-Jarai and A. A. Al Olama and S. B. Garcia
                      and K. Muir and H. Grönberg and F. Wiklund and M. Aly and
                      J. Schleutker and C. Sipeky and T. L. Tammela and B. G.
                      Nordestgaard and S. F. Nielsen and M. Weischer and R.
                      Bisbjerg and M. A. Røder and P. Iversen and T. J. Key and
                      R. C. Travis and D. E. Neal and J. L. Donovan and F. C.
                      Hamdy and P. Pharoah and N. Pashayan and K.-T. Khaw and C.
                      Maier and W. Vogel and M. Luedeke and K. Herkommer and A. S.
                      Kibel and C. Cybulski and D. Wokolorczyk and W. Kluzniak and
                      L. Cannon-Albright and H. Brenner$^*$ and K. Cuk$^*$ and
                      K.-U. Saum$^*$ and J. Y. Park and T. A. Sellers and C.
                      Slavov and R. Kaneva and V. Mitev and J. Batra and J. A.
                      Clements and A. Spurdle and M. R. Teixeira and P. Paulo and
                      S. Maia and H. Pandha and A. Michael and A. Kierzek and D.
                      S. Karow and I. G. Mills and O. A. Andreassen and A. M.
                      Dale},
      collaboration = {P. Consortium},
      title        = {{P}olygenic hazard score to guide screening for aggressive
                      prostate cancer: development and validation in large scale
                      cohorts.},
      journal      = {The BMJ},
      volume       = {360},
      issn         = {0007-1447},
      address      = {Malden},
      publisher    = {BMJ Publishing Group},
      reportid     = {DKFZ-2018-00106},
      pages        = {j5757},
      year         = {2018},
      abstract     = {To develop and validate a genetic tool to predict age of
                      onset of aggressive prostate cancer (PCa) and to guide
                      decisions of who to screen and at what age.Analysis of
                      genotype, PCa status, and age to select single nucleotide
                      polymorphisms (SNPs) associated with diagnosis. These
                      polymorphisms were incorporated into a survival analysis to
                      estimate their effects on age at diagnosis of aggressive PCa
                      (that is, not eligible for surveillance according to
                      National Comprehensive Cancer Network guidelines; any of
                      Gleason score ≥7, stage T3-T4, PSA (prostate specific
                      antigen) concentration ≥10 ng/L, nodal metastasis, distant
                      metastasis). The resulting polygenic hazard score is an
                      assessment of individual genetic risk. The final model was
                      applied to an independent dataset containing genotype and
                      PSA screening data. The hazard score was calculated for
                      these men to test prediction of survival free from
                      PCa.Multiple institutions that were members of international
                      PRACTICAL consortium.All consortium participants of European
                      ancestry with known age, PCa status, and quality assured
                      custom (iCOGS) array genotype data. The development dataset
                      comprised 31 747 men; the validation dataset comprised
                      6411 men.Prediction with hazard score of age of onset of
                      aggressive cancer in validation set.In the independent
                      validation set, the hazard score calculated from 54 single
                      nucleotide polymorphisms was a highly significant predictor
                      of age at diagnosis of aggressive cancer (z=11.2, P<10-16).
                      When men in the validation set with high scores (>98th
                      centile) were compared with those with average scores
                      (30th-70th centile), the hazard ratio for aggressive cancer
                      was 2.9 $(95\%$ confidence interval 2.4 to 3.4). Inclusion
                      of family history in a combined model did not improve
                      prediction of onset of aggressive PCa (P=0.59), and
                      polygenic hazard score performance remained high when family
                      history was accounted for. Additionally, the positive
                      predictive value of PSA screening for aggressive PCa was
                      increased with increasing polygenic hazard score.Polygenic
                      hazard scores can be used for personalised genetic risk
                      estimates that can predict for age at onset of aggressive
                      PCa.},
      cin          = {C070 / G110 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)C070-20160331 / I:(DE-He78)G110-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {313 - Cancer risk factors and prevention (POF3-313)},
      pid          = {G:(DE-HGF)POF3-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29321194},
      pmc          = {pmc:PMC5759091},
      doi          = {10.1136/bmj.j5757 },
      url          = {https://inrepo02.dkfz.de/record/131811},
}