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RESEARCH
Polygenic haza d sco e o guide sc eening o agg essi e p os a e
cance : de elopmen and alida ion in la ge scale
coho s
Tyle M Seibe ,1,2 Chun Chieh Fan,1,3 Yunpeng Wang,4 Ve ena Zube ,4,5 Roshan Ka unamuni,1,2
J Kellogg Pa sons,6 Rosalind A Eeles,7,8 Douglas F Eas on,9 ZSo ia Ko e-Ja ai,7 Ali Amin Al Olama,9,10
Sa a Benlloch Ga cia,9 Kenne h Mui ,11,12 Hen ik G önbe g,13 F ed ik Wiklund,13 Ma kus Aly,13,14,15
Johanna Schleu ke ,16,17,18 Csilla Sipeky,16,17 Teu o LJ Tammela,19 Bø ge G No des gaa d,20,21
Sune F Nielsen,20,21 Ma en Weische ,21 Rasmus Bisbje g,22 M And eas Røde ,23 Pe e I e sen,20,23
Tim J Key,24 Ru h C T a is,24 Da id E Neal,25,26 Jenny L Dono an,27 F eddie C Hamdy,25
Paul Pha oah,28 No a Pashayan,28,29 Kay-Tee Khaw,30 Ch is iane Maie ,31 Wal he Vogel,31
Manuel Luedeke,31 Ka hleen He komme ,32 Adam S Kibel,33 Ceza y Cybulski,34
Dominika Wokolo czyk,34 Wojciech Kluzniak,34 Lisa Cannon-Alb igh ,35,36 He mann B enne ,37,38,39
Ka a ina Cuk,37 Kai-Uwe Saum,37 Jong Y Pa k,40 Thomas A Selle s,41 Cha da Sla o ,42
Radka Kane a,43 Vanio Mi e ,43 Jyo sna Ba a,44 Judi h A Clemen s,44 Amanda Spu dle,44,45,46
Manuel R Teixei a,47,48 Paula Paulo,47 So ia Maia,47 Ha de Pandha,49 Agnieszka Michael,49
And zej Kie zek,49 Da id S Ka ow,1,50 Ian G Mills,4,25,51 Ole A And eassen,4 Ande s M Dale1,50,52;
The PRACTICAL Conso ium*
ABSTRACT
OBJECTIVES
To de elop and alida e a gene ic ool o p edic age
o onse o agg essi e p os a e cance (PCa) and o
guide decisions o who o sc een and a wha age.
DESIGN
Analysis o geno ype, PCa s a us, and age o
selec single nucleo ide polymo phisms (SNPs)
associa ed wi h diagnosis. These polymo phisms
we einco po a ed in o a su i al analysis o es ima e
hei e ec s on age a diagnosis o agg essi e PCa
( ha is, no eligible o su eillance acco ding
o Na ional Comp ehensi e Cance Ne wo k
guidelines; any o Gleason sco e ≥7, s age T3-T4,
PSA (p os a e speci ic an igen) concen a ion ≥10
ng/L, nodal me as asis, dis an me as asis). The
esul ing polygenic haza d sco e is an assessmen o
indi idualgene ic isk. The inal model was applied
o an independen da ase con aining geno ype and
PSAsc eening da a. The haza d sco e was calcula ed
o hese men o es p edic ion o su i al ee
omPCa.
SETTING
Mul iple ins i u ions ha we e membe s o
in e na ional PRACTICAL conso ium.
PARTICIPANTS
All conso ium pa icipan s o Eu opean ances y wi h
known age, PCa s a us, and quali y assu ed cus om
(iCOGS) a ay geno ype da a. The de elopmen
da ase comp ised 31 747 men; he alida ion da ase
comp ised 6411 men.
MAIN OUTCOME MEASURES
P edic ion wi h haza d sco e o age o onse o
agg essi e cance in alida ion se .
RESULTS
In he independen alida ion se , he haza d sco e
calcula ed om 54 single nucleo ide polymo phisms
was a highly signi ican p edic o o age a diagnosis
o agg essi e cance (z=11.2, P<10−16). When men in
he alida ion se wi h high sco es (>98 h cen ile) we e
compa ed wi h hose wi h a e age sco es (30 h-70 h
cen ile), he haza d a io o agg essi e cance was
2.9 (95% con idence in e al 2.4 o 3.4). Inclusion o
amily his o y in a combined model did no imp o e
p edic ion o onse o agg essi e PCa (P=0.59), and
polygenic haza d sco e pe o mance emained high
when amily his o y was accoun ed o . Addi ionally,
he posi i e p edic i e alue o PSA sc eening
o agg essi e PCa was inc eased wi h inc easing
polygenic haza d sco e.
CONCLUSIONS
Polygenic haza d sco es can be used o pe sonalised
gene ic isk es ima es ha can p edic o age a onse
o agg essi e PCa.
In oduc ion
P os a e cance (PCa) is a majo heal h p oblem, wi h
o e a million new cases and o e 300 000 associa ed
dea hs es ima ed wo ldwide in 2012.1 An in e na ional
andomised con olled ial showed ha sc eening
o p os a e speci ic an igen (PSA) esul ed in a 27%
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o: T M Seibe
[email p o ec ed]
A M Dale
[email protected]
Addi ional ma e ial is published
online only. To iew please isi
he jou nal online.
Ci e his as: BMJ 2018;360:j5757
h p://dx.doi.o g/10.1136/bmj.j5757
Accep ed: 4 Decembe 2017
WhAT IS AlReAdy knoWn on ThIS TopIC
Sc eening o p os a e cance (PCa) wi h es s o p os a e speci ic an igen
(PSA) can lead o ea ly de ec ion and allow o cu a i e ea men , bu uni e sal
sc eening also has conside able disad an ages o he men who migh ne e
de elop agg essi e disease
Ideally, physicians would iden i y and sc een pa ien s a high isk o de eloping
agg essi e PCa o PCa a a young age
A p ac ical clinically use ul ool o p edic age o onse is no ye a ailable
WhAT ThIS STudy AddS
This s udy p esen s and alida es a no el polygenic haza d sco e ha is an
indica o o age a onse o agg essi e PCa
The sco e is a ela i ely inexpensi e assessmen o an indi idual man’s age
speci ic isk and p o ides objec i e in o ma ion on whe he a gi en pa ien migh
bene i om PSA sc eening
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educ ion in PCa mo ali y.2 Because o conce ns o e
a high a e o alse posi i e esul s, in addi ion o
agg essi e ea men o appa en ly indolen disease,
howe e , many clinical guidelines do no endo se
uni e sal sc eening and ins ead s ess he impo ance
o aking in o accoun indi idual pa ien isk ac o s
o decide whe he o sc een.3-5 The goal is o a oid
unnecessa y sc eening while s ill iden i ying men a
high isk o whom sc eening and ea ly de ec ion can
educe mo bidi y and mo ali y.
A pa ien ’s gene ic p edisposi ion could be c i ical o he
decision o whe he and when o o e sc eening. Genome-
wide associa ion s udies (GWAS) ha e shown gene ic
a ian s associa ed wi h inc eased isk o PCa.6 7 These
de elopmen s, combined wi h he ecen accessibili y
o geno yping, p o ide an oppo uni y o cance
sc eening in o med by gene ic isk.8 Wi h a combina ion
o isk in o ma ion om an a ay o single nucleo ide
polymo phisms (SNPs), polygenic models can es ima e
an indi idual’s gene ic isk o de eloping he disease.9
P edic ed polygenic isk could imp o e clinical decisions
such as who o sc een o PCa and a wha age.10 11
We used da a om 31 747 men o Eu opean ances y
om he in e na ional PRACTICAL conso ium (h p://
p ac ical.ccge.medschl.cam.ac.uk/) o de elop a
polygenic haza d sco e (PHS) o p edic ing age ela ed
isk o de eloping agg essi e PCa. This is designed
o use be o e he decision o whe he o sc een ( o
example, wi h PSA) by p o iding a isk s a i ica ion
s a egy o maximise sc eening e iciency. The haza d
sco e was es ed in da a om an independen sc eening
s udy (UK P o ecT12), wi h he hypo hesis ha i would
be an indica o o a pa ien ’s inhe en gene ic isk o
de eloping PCa a a ious ages in his li e ime and hus
could guide PSA sc eening.
Me hods
De ini ion o agg essi e disease
Conce ns abou o e diagnosis and o e ea men o
indolen disease ha e in luenced discussion o PCa
sc eening, whe eas he e is consensus ha agg essi e
cance wa an s ea men .13 14 When possible, we
he e o e ocus alida ion in his s udy on p edic ion
o agg essi e disease, de ined as any umou ha
would equi e adical ea men o a ypical heal hy
man acco ding o guidelines om he Na ional
Comp ehensi e Cance Ne wo k (NCCN)— ha is,
no eligible o ac i e su eillance.14 This includes
cance s wi h any o Gleason sco e ≥7, s age T3-T4,
PSA concen a ion ≥10 ng/mL, nodal me as asis, o
dis an me as asis. S age T2 umou s we e classi ied
wi hou a subca ego y in ou da abase, so a pa ien
wi h low Gleason sco e and low PSA concen a ion bu
s age T2b o T2c would be conside ed low isk in his
analysis e en hough NCCN guidelines would indica e
ea men o in e media e isk; his was o ensu e
ha no low isk umou s we e included as cases o
agg essi e cance .
Some addi ional analyses used age o diagnosis
o any PCa ( a he han only agg essi e PCa) as
complemen a y in o ma ion. Ano he seconda y
analysis es ed p edic ion o “ e y agg essi e disease,”
de ined as any o Gleason sco e ≥8, s age T3-4, posi i e
nodes, o dis an me as ases.
Pa icipan s
De elopmen se
To de elop he polygenic haza d sco e model, we
ob ained geno ype and da a on age om 21 s udies om
he PRACTICAL conso ium ( able A in appendix 1),
ep esen ing 31 747 men (18 868 wi h any PCa, 10 635
wi h agg essi e PCa, 5406 wi h e y agg essi e PCa,
12 879 con ols) o geno ypic Eu opean ances y. Age
was ei he a diagnosis o las ollow-up ( o con ols).
Geno yping, pe o med wi h a cus om Illumina a ay
(iCOGS), and quali y con ol s eps ha e been desc ibed
p e iously.6 A o al o 201 043 single nucleo ide
polymo phisms we e a ailable o analysis. We could no
ca ego ise cance as agg essi e o no in 4803 o he men
wi h cance because o incomple e da a on s aging; hese
we e excluded om analyses o agg essi e cance .
Valida ion se
An independen s udy examined pe o mance o he
model. The alida ion se came om he P o ecT s udy,
which sc eened 82 429 men wi h PSA es ing and
ound 8891 men wi h PSA concen a ion o e han
he speci ied h eshold o 3.0 ng/L o highe , 2896
o whom ecei ed a diagnosis o PCa.12 Among hose
indi iduals, we ob ained da a on geno ype and age o
6411 men (1583 wi h any PCa, 632 wi h agg essi e
PCa, wi h 220 e y agg essi e PCa, 4828 con ols).
S aging da a we e a ailable o all cases. This da ase
was selec ed o alida ion because PSA esul s we e
also a ailable o all pa icipan s a ime o ei he
diagnosis o in e iew. Fu he de ails in appendix 1.
Missing da a
Du ing model de elopmen , we excluded single
nucleo ide polymo phisms wi h call a es less han
95%. We impu ed missing calls o he emaining
polymo phisms wi h he mean geno ype coun o ha
allele ac oss all pa icipan s.
Polygenic haza d sco e
The polygenic haza d sco e was de eloped p e iously
as a pa simonious su i al analysis model o p edic
he ime o e en ou come (in his case, age o onse o
PCa). I has been published elsewhe e,15 and u he
de ails o applica ion he e a e desc ibed in appendix 1.
The sco e is de ined as he ec o p oduc o a
pa ien ’s geno ype (
Xi
) o
n
selec ed single nucleo ide
polymo phisms and he co esponding pa ame e
es ima es (
i
) om a Cox p opo ional haza ds eg ession
(see equa ion).
PHSx = Xiβi
n
i
Σ
Gene ic p edic ion speci ically o agg essi e PCa
has p o ed elusi e, wi h mos single nucleo ide
polymo phisms associa ed wi h agg essi e disease also
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showing associa ion wi h any PCa.16 The e o e, in he
in e es o maximising powe o selec polymo phisms
associa ed wi h age o onse , we decided o ini ially
include all cases om he de elopmen se ( ha is,
any PCa) o gene a ion o he model. We hen es ed
an al e na e s a egy ha limi ed gene a ion o cases o
agg essi e cance o compa ison. The p ima y me ic
o alida ion in bo h ins ances emained p edic ion
o agg essi e cance in he independen alida ion se .
To e i y whe he he polygenic haza d sco e
accu a ely p edic s age a onse o agg essi e PCa, we
calcula ed he sco e o all pa ien s in he alida ion
se and es ed i as he sole p edic i e a iable in a
Cox p opo ional haza ds eg ession model o age
o diagnosis. Pa ien s in he alida ion se wi h a
diagnosis o low isk disease (Gleason sco e ≤6, PSA
concen a ion <10 ng/L, and s age T2N0M0 o lowe )
we e censo ed a ime o diagnosis, e lec ing he
ac ha i is unknown i hey would la e ecei e a
diagnosis o agg essi e disease o a wha age ha
migh ha e occu ed. Signi icance was se a α o 0.01
o his and all subsequen Cox models. As an indica o
o e ec size o he model, we calcula ed a haza d
a io compa ing men wi h high sco es (>98 h cen ile)
wi h hose wi h a e age isk (30 h-70 h cen ile). All
haza d a ios p esen ed he e e e o he same pa e n:
high e sus a e age isk.
Because o e idence ha ini ially low isk disease
o en p og esses o equi e ea men ,17-19 and because
his migh be pa icula ly impo an o men wi h a
diagnosis a a young age, we pe o med a seconda y
analogous analysis o es o p edic ion o age o
diagnosis o any PCa. We did a seconda y analysis o
p edic ion o e y agg essi e disease.
To u he assess he clinical signi icance o he
polygenic haza d sco e, we looked a he posi i e
p edic i e alue (PPV) o PSA es ing wi hin he
alida ion se , wi h clinical diagnosis (including
biopsy esul ) as he ideal. We posi ed ha isk
s a i ica ion by cen iles o he sco e would e lec he
unde lying incidence o PCa and he e o e also a ec
he posi i e p edic i e alue o PSA es ing. De ails
on he calcula ion o posi i e p edic i e alue a e in
appendix 1. Ca ego ies o he sco e we e designa ed by
cen ile compa ed wi h he young heal hy popula ion
wi hin he de elopmen se — ha is, hose con ols
aged <70. All cen iles epo ed in his manusc ip e e
o his popula ion.
To isualize dis ibu ion o he polygenic haza d
sco e among cases o agg essi e PCa in he alida ion
se , we gene a ed a Lo enz cu e.20-22
Compa ison wi h amily his o y
One o he mos impo an isk ac o s used cu en ly
o sc eening decisions is amily his o y.3 We compa ed
amily his o y and polygenic haza d sco e o
p edic ion o onse o agg essi e PCa using he same
Cox model app oach as be o e, wi h he 5703 men
(1405 wi h any PCa, 554 wi h agg essi e PCa, 4298
con ols) om men in he alida ion se wi h known
amily his o y s a us (none o one o mo e a ec ed i s
deg ee ela i es). Models we e cons uc ed wi h amily
his o y alone, haza d sco e alone, o wi h bo h. These
we e compa ed ia log likelihood es s.
Pa ien in ol emen
No pa ien s we e di ec ly in ol ed in designing he
esea ch ques ion o in conduc ing he esea ch. A
link o he published esul s will be pos ed on he
PRACTICAL conso ium websi e, and he espec i e
p incipal in es iga o s o each con ibu ing s udy will
be p o ided he esul s o dissemina e o indi idual
pa icipan s when possible.
Resul s
Model de elopmen
O he 201 043 single nucleo ide polymo phisms
included in he da ase , 2415 we e associa ed wi h
inc eased isk o PCa in he end es , wi h P<10−6.
The s epwise eg ession amewo k hen iden i ied
54 o hese polymo phisms ha we e inco po a ed
in o he Cox p opo ional haza ds model ( able B
in appendix 1). The 54 pa ame e es ima es ( o
he haza d o de eloping PCa) we e combined wi h
indi idual geno ype o gene a e he polygenic haza d
sco e. Figu e 1 shows Kaplan-Meie and Cox eg ession
es ima es o he inal model. The inal model pe o med
well o p edic ion o age a onse o agg essi e PCa in
he de elopmen se (z=37.5, P<10−16, haza d a io
2.3, 95% con idence in e al 2.2 o 2.4).
We excluded only 43 polymo phisms (0.02%) o
low call a e du ing model de elopmen and used
impu a ion o missing calls o 0.4% o calls in he
inal model. O he 6411 pa icipan s in he alida ion
se , he median indi idual polymo phism call a e was
100%, wi h a minimum o 98%.
Age (yea s)
P obabili y o PCa- ee su i al
Kaplan-Meie
40 45 50 55 60 65 70 75 80 85 90
95
0
0.2
0.4
0.6
0.8
1.0
PHS 0-20 h cen ile
PHS 30-70 h cen ile
PHS 80-97 h cen ile
PHS 98-100 h cen ile
Cox
Fig1 | Kaplan-Meie and Cox es ima es o p os a e
cance - ee su i al o pa ien s in de elopmen se by
cen ile anges o polygenic haza d sco e. Cen iles a e in
e e ence o dis ibu ion o sco e wi hin 11 190 con ols
aged unde 70 in de elopmen se . Time o “ ailu e”
is age a any diagnosis o p os a e cance . Con ols
we e censo ed a age o obse a ion. Fo mal es ing o
p opo ionali y is desc ibed in appendix 1
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Risk p edic ion wi h polygenic haza d sco e
In he independen alida ion se om he P o ecT
s udy, a Cox p opo ional haza ds model showed
ha he polygenic haza d sco e was a signi ican
p edic o o age a onse o agg essi e PCa (z=11.2,
P<10−16). Compa ed wi h a e age isk, he haza d
a io o men wi h a high sco e (>98 h cen ile) was 2.9
(95% con idence in e al 2.4 o 3.4). The sco e was
also p edic i e o any PCa (z=15.4, P<10−16; haza d
a io 2.5, 2.2 o 2.8) and e y agg essi e PCa (z=6.8,
P<10−11; 3.0, 2.2 o 4.0).
An al e na e model used only cases o agg essi e PCa
om he de elopmen se o selec polymo phisms.
P edic ion o onse o agg essi e PCa was s ill
signi ican (z=9.4, P<10−16, 2.6; 2.1 o 3.1) bu did no
ou pe o m he o iginal model, so we used he o iginal
o all subsequen analyses as planned.
As he polygenic haza d sco e was p edic i e o
isk o PCa, we expec ed i o modula e he posi i e
p edic i e alue o PSA es ing in he alida ion se .
Indeed, he posi i e p edic i e alue o PSA was lowe
among pa ien s wi h a low sco e and highe among
pa ien s wi h p og essi ely highe sco es ( ig 2). This
pa e n held o he posi i e p edic i e alue o any
PCa, as well ( ig B in appendix 1).
The Lo enz cu e in igu e C in appendix 1 shows he
dis ibu ion o he polygenic haza d sco e among cases
o agg essi e PCa in he alida ion se . Pa ien s wi h
sco es abo e he 50 h cen ile accoun ed o 76% o
cases o agg essi e PCa, and he uppe i h accoun ed
o 42%.
Family his o y
Wi h he subse o he alida ion se wi h known
amily his o y s a us (1405 cases, 4298 con ols),
we epea ed he Cox es wi h adjus men o amily
his o y. Family his o y alone was no p edic i e o
age o onse o agg essi e PCa (z=0.9, P=0.37; haza d
a io 1.1, 95% con idence in e al 0.9 o 1.4), hough
he e was a end owa d p edic ion o any PCa (z=2.0,
P=0.05; 1.2, 1.0 o 1.3). Inclusion o amily his o y did
no imp o e p edic ion o e he polygenic haza d sco e
alone o agg essi e PCa (P=0.59) o any PCa (P=0.14),
and he sco e emained p edic i e when adjus ed o
amily his o y.
discussion
PCa isk p edic ion wi h polygenic haza d sco e
Gene ic in o ma ion can guide he decision o
whe he an indi idual pa ien needs PCa sc eening.8
The polygenic haza d sco e desc ibed he e ep esen s
a pe sonalised gene ic assessmen o a man’s age
ela ed isk ha could in o m bo h whe he and when
o o de sc eening es s. When applied o da a om
an independen clinical ial, he sco e was a highly
signi ican p edic o o age a diagnosis o agg essi e
PCa. Men in he op 2% o he sco e had a haza d a io
o 2.9 o agg essi e PCa compa ed wi h men wi h
a e age isk. As he sco e is ep esen a i e o a man’s
ixed gene ic isk, i can be calcula ed once, long be o e
onse o PCa, and subs an ially in o m he decision o
whe he he should unde go PCa sc eening.
Posi i e p edic i e alue is di ec ly dependen on
p e alence, so i he polygenic haza d sco e p edic s
age o onse o PCa, he posi i e p edic i e alue o
PSA should a y wi h he sco e. Figu e 2 shows ha
his was ue in he alida ion se . Nea ly a qua e o
he posi i e PSA es esul s in men wi h a high sco e
po ended a diagnosis o agg essi e PCa. The isk was
much lowe o men wi h low sco es wi h a aised PSA
concen a ion. The sco e is an indica o o he u ili y o
PSA sc eening and could be in luen ial in he decision
whe he o o de a PSA es o a gi en pa ien .
These esul s also add o exis ing da a as u he
e idence ha gene ic ea u es can p edic isk o
PCa.6-8 11 23-25 In es iga ion in o he geno ypic ea u es
desc ibed he e and elsewhe e could gi e addi ional
insigh in o biological a ionales o he associa ion
wi h PCa.
The polygenic haza d sco e is based on haza d a ios
and is he e o e an es ima e o ela i e isk. Absolu e
isk can be es ima ed wi hin a gi en popula ion
i he unde lying a e age haza d a e is known.
This echnique would hen allow es ima ion o an
indi idual PCa- ee su i al cu e o any PHS. An
example o hese indi idual cu es has been published
o Alzheime ’s disease.15
Compa ison wi h amily his o y
Family his o y o PCa is one o he mos commonly
used isk ac o s in clinic o de e mine sc eening
decisions.3 Family his o y, howe e , was no p edic i e
o age o onse o agg essi e PCa in he alida ion se ,
and i did no imp o e p edic ion o e he haza d sco e
alone. This could e lec a lack o powe o de ec an
associa ion o amily his o y in he ela i ely small
alida ion se .
Conce n o o e ea men
A conce n wi h PSA sc eening is o e diagnosis and
o e ea men o indolen disease. As wi h o he gene ic
p edic ion ools, he polygenic haza d sco e is no
speci ic o agg essi e PCa alone,16 hough he haza d
PHS cen ile
Posi i e p edic i e alue (PPV)
0
0.10
0.15
0.20
0.25
0.30
0.05
<20 h All >50 h >80 h >95 h
Fig2 | Posi i e p edic i e alue o PSA es ing o
agg essi e PCa in alida ion se . Cen iles e e o
dis ibu ion o polygenic haza d sco e among young
con ols in de elopmen se . 95% con idence in e als
a e om andom samples o cases in alida ion se (see
me hods)
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a io was sligh ly highe o agg essi e PCa han o
any PCa. The p oblem o o e diagnosis is compounded
by he obse a ion ha many men wi h an ini ial
diagnosis o low isk disease la e ecei e a diagnosis
o agg essi e disease.17 19 Ac i e su eillance is one
answe o o e ea men ha a oids up on ea men
bu s ill allows o moni o ing o de elopmen o
indica ions ha ea men is necessa y. Indeed,
mos umou s e en ually equi e ea men ,17 18 and
ea lie ea men p e en s de elopmen o me as a ic
disease.18 Hence, a oiding sc eening al oge he in
pa ien s who migh de elop PCa a a young age does
ca y isk o conside able mo bidi y. The p esen
esul s show ha he polygenic haza d sco e can help
o a ge sc eening e o s owa d hose men a highes
isk o ea ly onse PCa o agg essi e PCa equi ing
ea men .
As he sco e is p edic i e o agg essi e PCa in gene al,
i migh also be use ul o p edic ing ou comes o men
wi h a diagnosis o low isk PCa in P o ecT. The clinical
da a necessa y o answe his in e es ing ques ion
ha e no ye been made a ailable o he PRACTICAL
conso ium, so i will ha e o be explo ed in u u e
analyses.
P e ious ools
P e ious s udies ha e used GWAS-associa ed
polymo phisms o p edic isk o PCa wi h a case-
con ol design.23-25 Epidemiological da a, howe e ,
show ha isk o PCa is no a simple dicho omy o
cases and con ols bu a he is highly dependen
on inc easing age. We he e o e op ed o a su i al
analysis app oach op imised o gene ic p edic ion o
age o onse o PCa. The polygenic haza d sco e can
hen be used in clinical decisions, when age plays
a c i ical ole. I a man has a high isk o de eloping
PCa a age 95, his is a di e en clinical si ua ion om
a man a high isk a age 55. A compa ison o he
polygenic haza d sco e wi h a adi ional polygenic
isk sco e is desc ibed in appendix 2.
O he PCa isk calcula o s use clinical a iables and
a e mos use ul o a man who migh al eady ha e
PCa.26-28 PSA concen a ion is o en included, meaning
he decision o whe he o sc een has necessa ily
al eady been made when he ools a e o be used. These
a e less use ul o p edic ing his li e ime isk be o e he
eaches an age a which he and his physician ha e o
decide whe he he should ollow some p og amme o
PCa sc eening.
The isk s a i ica ion me ic wi h bes suppo i e
e idence desc ibed in he li e a u e is an ea ly midli e
PSA concen a ion measu ed a a ela i ely young age
( o example, <50). While no cu en ly ecommended
in many majo clinical guidelines,3-5 ea ly midli e PSA
has been shown o be p edic i e o u u e isk o PCa
and le hal PCa.22 29-31 One nes ed case-con ol s udy
showed ha jus he op 10% o he dis ibu ion o
concen a ions o PSA in es s done in men aged unde
50 accoun ed o 40% o cases o me as a ic PCa.22 This
has led o a ecommenda ion o conside PSA es ing as
ea ly as age 45 in men hough by hei physician o
be a high isk.32 A di ec compa ison o he polygenic
haza d sco e and ea ly midli e PSA o p edic ion o
age a onse o agg essi e PCa would be wo hwhile.
The e migh also be an ad an age o combining he
wo p edic o s. Un o una ely, ea ly midli e PSA
concen a ion was no a ailable in he da ase s used in
he p esen s udy so he ques ion is le o u u e wo k.
Limi a ions
The de elopmen se was a he e ogeneous composi e
o se e al s udies o a ied design ( able A in appendix
1), which p o ides su icien powe o s udy single
nucleo ide polymo phisms wi h ela i ely small e ec
sizes bu also aises he conce n o unde ec ed bias in
a e ospec i e analysis. The alida ion se , howe e ,
came om an independen la ge p ospec i e ial, and
wha e e p oblems migh exis in he de elopmen
se , he mos pe inen ques ion is whe he he model
allows use ul p edic ions.
The sco e was applied he e o PSA sc eening alone.
PSA is he mos p e alen sc eening es cu en ly o
PCa, bu he haza d sco e could also be expec ed o
add alue o o he sc eening s a egies, by p edic ing
unde lying isk o PCa o a gi en age and he e o e
in luencing p e es p obabili y (and, by ex ension,
posi i e p edic i e alue). This migh include PSA
eloci y, PSA densi y, o some sc eening ool comple ely
independen o PSA.
The e idence p esen ed he e sugges s ha he
polygenic haza d sco e can help a physician decide
whe he o o de PSA, based on he p e es p obabili y
and posi i e p edic i e alue o PSA o a gi en pa ien .
Ou s udy does no , howe e , deal wi h an al e na e
ques ion: how he haza d sco e migh compa e o
diagnos ic ools (including isk calcula o s) ha a e
pa o he clinical in es iga ions a e a aised PSA
concen a ion has been ound. Adequa e da a a e
no a ailable in he p esen da ase o answe his
ques ion, bu i could be ied in u u e wo k as an
addi ional applica ion o he polygenic haza d sco e.
The age ange o he alida ion se was limi ed o
50-70; o una ely, his includes he age a which
sc eening is belie ed o ha e he mos bene i .33-36
Finally, e hnici y in his model was limi ed o
Eu opean ances y. Valida ion o he sco e in o he
e hnic g oups—and, i necessa y, cus om models o
each—is needed. We plan o in es iga e his impo an
ques ion.
Conclusions
In conclusion, we desc ibe he e he de elopmen o a
new polygenic haza d sco e o pe sonalised gene ic
assessmen o indi idual age associa ed isk o PCa.
This sco e has been alida ed in an independen
da ase , showing accu a e p edic ion o onse o
agg essi e PCa. Mo eo e , he sco e can p edic he
u ili y o PSA es ing o an indi idual man. This gene ic
isk model migh play a ole in guiding decisions abou
whe he and when o sc een o PCa. In es iga ion in o
he ela ion be ween he sco e and ea ly midli e PSA
es ing is wa an ed.

RESEARCH
6 doi: 10.1136/bmj.j5757 |
BMJ
2018;360:j5757 | he bmj
AUTHOR AFFILIATIONS
1Cen e o Mul imodal Imaging and Gene ics, Uni e si y o
Cali o nia, San Diego, La Jolla, CA, USA
2Depa men o Radia ion Medicine and Applied Sciences,
Uni e si y o Cali o nia, San Diego, La Jolla, CA, USA
3Depa men o Cogni i e Science, Uni e si y o Cali o nia, San
Diego, La Jolla, CA, USA
4NORMENT, KG Jebsen Cen e, Oslo Uni e si y Hospi al and
Uni e si y o Oslo, Oslo, No way
5MRC Bios a is ics Uni , Camb idge Biomedical Campus, Camb idge
CB2 0SR, UK
6Depa men o Su ge y, Uni e si y o Cali o nia, San Diego, La Jolla,
CA, USA
7Ins i u e o Cance Resea ch, London, SM2 5NG, UK
8Royal Ma sden NHS Founda ion T us , London, SW3 6JJ, UK
9Cen e o Cance Gene ic Epidemiology, Depa men o Public
Heal h and P ima y Ca e, Uni e si y o Camb idge, S angeways
Resea ch Labo a o y, Camb idge CB1 8RN, UK
10Depa men o Clinical Neu osciences, S oke Resea ch G oup,
Uni e si y o Camb idge, R3, Box 83, Camb idge Biomedical
Campus, Camb idge CB2 0QQ, UK
11Ins i u e o Popula ion Heal h, Uni e si y o Manches e ,
Manches e , UK
12Wa wick Medical School, Uni e si y o Wa wick, Co en y, UK
13Depa men o Medical Epidemiology and Bios a is ics, Ka olinska
Ins i u e , S ockholm, Sweden
14Depa men o Molecula Medicine and Su ge y, Solna, 171 76
S ockholm, Sweden
15Depa men o U ology, Ka olinska Uni e si y Hospi al, Solna, 171
76 S ockholm, Sweden
16Depa men o Medical Biochemis y and Gene ics, Ins i u e o
Biomedicine, Kiinamyllynka u 10, FI-20014 Uni e si y o Tu ku,
Finland
17Tyks Mic obiology and Gene ics, Depa men o Medical Gene ics,
Tu ku Uni e si y Hospi al, Tu ku, Finland
18BioMediTech, 30014 Uni e si y o Tampe e, Tampe e, Finland
19Depa men o U ology, Tampe e Uni e si y Hospi al and Medical
School, Uni e si y o Tampe e, Finland
20Facul y o Heal h and Medical Sciences, Uni e si y o Copenhagen,
Denma k
21Depa men o Clinical Biochemis y, He le and Gen o e Hospi al,
Copenhagen Uni e si y Hospi al, He le , Denma k
22Depa men o U ology, He le and Gen o e Hospi al,
Copenhagen Uni e si y Hospi al, He le , Denma k
23Copenhagen P os a e Cance Cen e, Depa men o U ology,
Rigshospi ale , Copenhagen Uni e si y Hospi al, Copenhagen,
Denma k
24Cance Epidemiology Uni , Nu ield Depa men o Popula ion
Heal h Uni e si y o Ox o d, Ox o d OX3 7LF, UK
25Nu ield Depa men o Su gical Sciences, Facul y o Medical
Science, Uni e si y o Ox o d, John Radcli e Hospi al, Ox o d, UK
26Uni e si y o Camb idge, Depa men o Oncology, Box 279,
Addenb ooke’s Hospi al, Camb idge CB2 0QQ, UK
27School o Social and Communi y Medicine, Uni e si y o B is ol,
B is ol BS8 2PS, UK
28Cen e o Cance Gene ic Epidemiology, Depa men o Oncology,
Uni e si y o Camb idge, S angeways Resea ch Labo a o y,
Camb idge, UK
29Uni e si y College London, Depa men o Applied Heal h
Resea ch, London WC1E 7HB, UK
30Clinical Ge on ology Uni , Uni e si y o Camb idge, Camb idge UK
31Ins i u e o Human Gene ics, Uni e si y Hospi al o Ulm, Ulm,
Ge many
32Depa men o U ology, Klinikum ech s de Isa de Technischen
Uni e si ae Muenchen, Munich, Ge many
33Di ision o U ologic Su ge y, B igham and Women’s Hospi al,
Dana-Fa be Cance Ins i u e, 75 F ancis S ee , Bos on, MA 02115,
USA
34In e na ional He edi a y Cance Cen e, Depa men o Gene ics
and Pa hology, Pome anian Medical Uni e si y, Szczecin, Poland
35Di ision o Gene ic Epidemiology, Depa men o Medicine,
Uni e si y o U ah School o Medicine, Sal Lake Ci y, U ah, USA
36Geo ge E. Wahlen Depa men o Ve e ans A ai s Medical Cen e ,
Sal Lake Ci y, U ah, USA
37Di ision o Clinical Epidemiology and Aging Resea ch, Ge man
Cance Resea ch Cen e (DKFZ), Heidelbe g, Ge many
38Di ision o P e en i e Oncology, Ge man Cance Resea ch Cen e
(DKFZ) and Na ional Cen e o Tumo Diseases (NCT), Heidelbe g,
Ge many
39Ge man Cance Conso ium (DKTK), Ge man Cance Resea ch
Cen e (DKFZ), Heidelbe g, Ge many
40Depa men o Cance Epidemiology, Mo i Cance Cen e ,
12902 Magnolia D i e, Tampa, FL 33612, USA
41O ice o he Cen e Di ec o , Mo i Cance Cen e , 12902
Magnolia D i e, Tampa, FL 33612, USA
42Depa men o U ology and Alexand o ska Uni e si y Hospi al,
Medical Uni e si y, So ia, Bulga ia
43Depa men o Medical Chemis y and Biochemis y, Molecula
Medicine Cen e , Medical Uni e si y, So ia, 2 Zd a e S , 1431 So ia,
Bulga ia
44Aus alian P os a e Cance Resea ch Cen e-Qld, Ins i u e o
Heal h and Biomedical Inno a ion and School o Biomedical
Science, Queensland Uni e si y o Technology, B isbane, Aus alia
45Molecula Cance Epidemiology Labo a o y, Queensland Ins i u e
o Medical Resea ch, B isbane, Aus alia
46Aus alian P os a e Cance BioResou ce, Ins i u e o Heal h
and Biomedical Inno a ion and School o Biomedical Science,
Queensland Uni e si y o Technology, B isbane, Aus alia
47Depa men o Gene ics, Po uguese Oncology Ins i u e, Po o,
Po ugal
48Biomedical Sciences Ins i u e (ICBAS), Uni e si y o Po o, Po o,
Po ugal
49Uni e si y o Su ey, Guild o d, Su ey, GU2 7XH
50Depa men o Radiology, Uni e si y o Cali o nia, San Diego, La
Jolla, CA, USA
51Cen e o Cance Resea ch and Cell Biology, Queens Uni e si y
Bel as , Bel as , UK
52Depa men o Neu osciences, Uni e si y o Cali o nia, San Diego,
La Jolla, CA, USA
*De ails o addi ional membe s om he P os a e Cance
Associa ionG oup o In es iga e Cance Associa ed Al e a ions in
heGenome conso ium (PRACTICAL, h p://p ac ical.ccge.medschl.
cam.ac.uk/), acknowledgmen s, and unding a e p o ided in
appendix2.
Con ibu o s: TMS, CCF, VZ, DSK, IGM, OAA, and AMD designed he
s udy. RAE, DFE, ZSKJ, AAAO, SBG, KM, HG, FW, MA, JS, CSi, TLJT, BGN,
SFN, MW, RB, MAR, PI, TJK, RCT, DEN, JLD, FCH, PPh, NP, KTK, CM, WV,
ML, KH, ASK, CC, DW, WK, LCA, HB, KC, KUS, JYP, TAS, CSI, RKan, VM,
B, JAC, AS, APCBR, MRT, PPa, SM, HP, AM, and AK collec ed he da a.
TMS, CCF, IGM, OAA, and AMD pe o med he li e a u e sea ch. TMS,
CCF, YW, VZ, RKa , DSK, and AMD pe o med he da a analysis. TMS,
CCF, RKa , JKP, DSK, OAA, and AMD in e p e ed he da a. TMS, RKa ,
JKP, DSK, OAA, and AMD c ea ed he igu es. TMS, CCF, OAA, and AMD
w o e he manusc ip . All au ho s e iewed he manusc ip , added
app op ia e e isions, ag eed o submission o publica ion, and
app o ed he inal e sion. TMS and AMD a e gua an o s.
Compe ing in e es s: All au ho s ha e comple ed he ICMJE uni o m
disclosu e o m a www.icmje.o g/coi_disclosu e.pd and decla e
no suppo om any o ganisa ion o he submi ed wo k excep as
ollows: DSK and AMD epo a esea ch g an om he US Depa men
o De ense, OAA epo s esea ch g an s om KG Jebsen S i elsen,
Resea ch Council o No way, and Sou h Eas No way Heal h Au ho i y,
TMS epo s hono a ia om WebMD o educa ional con en , as well
as a esea ch g an om Va ian Medical Sys ems, ASK epo s ad iso y
boa d membe ships o Sano i-A en is, Dend eon, and P o ound, AK
epo s paid wo k o Ce a a Quan i a i e Sys ems Pha macology, DSK
epo s paid wo k o Human Longe i y, OAA has a pa en applica ion
(US 20150356243) pending, AMD also applied o his pa en
applica ion and assigned i o UC San Diego. AMD has addi ional
disclosu es ou side he p esen wo k: ounde , equi y holde , and
ad iso y boa d membe o Co Techs Labs, ad iso y boa d membe
o Human Longe i y, ecipien o non- inancial esea ch suppo
om Gene al Elec ic Heal hca e; no inancial ela ionships wi h any
companies ha migh ha e an in e es in he submi ed wo k in he
RESEARCH
No comme cial euse: See igh s and ep in s h p://www.bmj.com/pe missions Subsc ibe: h p://www.bmj.com/subsc ibe
p e ious 3 yea s; no o he ela ionships o ac i i ies ha could appea
o ha e in luenced he submi ed wo k.
E hics app o al: No equi ed.
Funding: This s udy was unded in pa by g an s om he US
Depa men o De ense (W81XWH-13-1-0391), P os a e Cance
Founda ion, he Resea ch Council o No way (223273), KG Jebsen
S i elsen, and Sou h Eas No way Heal h Au ho i y. Funding o he
PRACTICAL conso ium membe s udies is de ailed in appendix 2.
T anspa ency: The lead au ho a i ms ha he manusc ip is
an hones , accu a e, and anspa en accoun o he s udy being
epo ed; ha no impo an aspec s o he s udy ha e been omi ed;
and ha any disc epancies om he s udy as planned ha e been
explained.
Da a sha ing: No addi ional da a a ailable.
This is an Open Access a icle dis ibu ed in acco dance wi h he
C ea i e Commons A ibu ion Non Comme cial (CC BY-NC 4.0) license,
which pe mi s o he s o dis ibu e, emix, adap , build upon his wo k
non-comme cially, and license hei de i a i e wo ks on di e en
e ms, p o ided he o iginal wo k is p ope ly ci ed and he use is non-
comme cial. See: h p://c ea i ecommons.o g/licenses/by-nc/4.0/.
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Appendix 1: Supplemen a y me hods, ables, and
igu es
Appendix 2: De ails o addi ional conso ium
membe s, acknowledgemen s, and unding