• No results found

Clinical and biochemical risk factors for first and recurrent episodes of venous thrombosis Christiansen, S.C.

N/A
N/A
Protected

Academic year: 2021

Share "Clinical and biochemical risk factors for first and recurrent episodes of venous thrombosis Christiansen, S.C."

Copied!
15
0
0

Bezig met laden.... (Bekijk nu de volledige tekst)

Hele tekst

(1)

Clinical and biochemical risk factors for first and recurrent episodes of venous thrombosis

Christiansen, S.C.

Citation

Christiansen, S. C. (2010, September 28). Clinical and biochemical risk factors for first and recurrent episodes of venous thrombosis. Retrieved from https://hdl.handle.net/1887/15992

Version: Corrected Publisher’s Version License:

Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/15992

Note: To cite this publication please use the final published version (if applicable).

(2)

55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55

&KDSWHU

7KHULVNRIYHQRXVWKURPERVLVUHODWHGWRLQFUHDVH

LQERG\PDVVLQGH[LVPHGLDWHGE\IDFWRU

9,,,LQGXFHG$3&UHVLVWDQFH

6&&KULVWLDQVHQ:0/LMIHULQJ,$1 VV-+DPPHUVWU¡P$YDQ+\OFNDPD9OLHJ

)55RVHQGDDO6&&DQQHJLHWHU

(3)



55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

$EVWUDFW

+LJK ERG\ PDVV LQGH[ %0,  LV DVVRFLDWHG ZLWK DQ LQFUHDVHG ULVN RI YHQRXV WKURPERVLV

97 &ORWWLQJIDFWRU ) 9,,,FDQEHUHOHDVHGE\DGLSRVHWLVVXH+LJK)9,,,LQFUHDVHV$3&

UHVLVWDQFH7KLV$3&UHVLVWDQFHFRXOGEHDJJUDYDWHGLQ)9/HLGHQFDUULHUV3UHVHQFHRIKLJK

)9,,, LQ QRQ2 EORRG JURXS LQGLYLGXDOV FRXOG ZRUVHQ WKLV IXUWKHU:H K\SRWKHVL]HG WKDW

DQDVVRFLDWLRQH[LVWVEHWZHHQ%0,DQG$3&UHVLVWDQFHDQGWKDW)9/HLGHQDQGRUEORRG

JURXSQRQ2PRGL¿HVWKHULVNRILQFUHDVLQJ%0,RQ97RFFXUUHQFH7KLVZDVVWXGLHGLQ

D SRROHG DQDO\VLV RI  FDVHFRQWURO VWXGLHV Q   $3&UHVLVWDQFH LQFUHDVHG OLQHDUO\

ZLWKLQFUHDVLQJ%0,SDUWO\H[SODLQHGE\LQFUHDVLQJ)9,,,,QFUHDVLQJ%0,LQGHSHQGHQW

RIH[LVWLQJ$3&UHVLVWDQFHZDVDVVRFLDWHGZLWKIROGDQGIROGLQFUHDVHGULVNRI97

IRUWKRVHZLWKD%0,LQWKHPHGLDQRUXSSHUWHUWLOHFRPSDUHGWRWKHORZHVWWHUWLOH%RWK

ULVNVGHFUHDVHGVOLJKWO\DIWHU)9,,,DQG$3&UHVLVWDQFHDGMXVWPHQWV:KHQ%0,LQFUHDVHG

$3&UHVLVWDQFHIDFWRU9,,,DQGULVNRI97LQFUHDVHGJUDGXDOO\LQ QRQ )9/HLGHQFDUULHUV

ZLWK QRQ 2EORRGJURXSH[FHSWHGIRU)9/HLGHQFDUULHUVZLWKQRQ2EORRGJURXS7KHVH

VKRZHG!IROGLQFUHDVHGULVNVRI97LUUHVSHFWLYHRI%0,:HFRQFOXGHWKDWWKHLQFUHDVHG

ULVNRI97LQLQGLYLGXDOVZLWKKLJK%0,LVPHGLDWHGE\IDFWRU9,,,LQGXFHG$3&UHVLVWDQFH

(4)



55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55

,QWURGXFWLRQ

9HQRXVWKURPERVLVRFFXUVLQSHULQGLYLGXDOVSHU\HDUDQGLVPRUHIUHTXHQWLQ

LQGLYLGXDOV ZLWK RYHUZHLJKW ERG\ PDVV LQGH[ >%0,@ RI  NJP  RU REHVLW\ %0,

!NJP WKDQLQOHDQLQGLYLGXDOV2YHUZHLJKWRUREHVLW\OHDGWRDIROGLQFUHDVHG

ULVNRIYHQRXVWKURPERVLVFRPSDUHGWRQRUPDOZHLJKW,WLVQRWXQGHUVWRRGKRZDKLJK

%0,SUHGLVSRVHVWRYHQRXVWKURPERVLV3HRSOHZLWKRYHUZHLJKWRUREHVLW\WHQGWREHPRUH

LPPRELOH ZKLFK PD\ OHDG WR FORW IRUPDWLRQ WKURXJK VWDVLV ,W LV DOVR SRVVLEOH WKDW WKHVH

LQGLYLGXDOV DFTXLUH D SURWKURPERWLF VWDWH &OLQLFDOO\ DW OHDVW VRPH VWXGLHV KDYH IRXQG D

VWURQJHUHIIHFWRIKLJK%0,RQWKHULVNRI¿UVWYHQRXVWKURPERVLVLQIDFWRU9/HLGHQFDUULHUV 5LVNRIYHQRXVWKURPERVLVLQIDFWRU9/HLGHQFDUULHUVLVH[SODLQHGE\$3&UHVLVWDQFH,W

ZDVWKHUHIRUHVSHFXODWHGWKDWDMRLQWHIIHFWEHWZHHQIDFWRU9/HLGHQDQGDKLJK%0,OHDGV

WRLQFUHDVHG$3&UHVLVWDQFHZKLFKFRXOGH[SODLQWKHHQKDQFHGULVNRIYHQRXVWKURPERVLV

LQ KHDY\ZHLJKW LQGLYLGXDOV ZLWK IDFWRU9 /HLGHQ 'DWD RQ ZKHWKHU D KLJK %0, OHDGV WR

$3&UHVLVWDQFH LV KRZHYHU OLPLWHG WR RQO\ RQH VWXG\ WKDW IRXQG DQ DVVRFLDWLRQ EHWZHHQ

LQFUHDVLQJ%0,DQGLQFUHDVLQJ$3&UHVLVWDQFH+LJKOHYHOVRIIDFWRU9,,,DUHDOVRDVVRFLDWHG

ZLWKDQLQFUHDVHGULVNRIYHQRXVWKURPERVLV7KLVULVNLVSDUWLDOO\JHQHWLFDOO\GHWHUPLQHG

DVLQGLYLGXDOVZLWKEORRGJURXSQRQ2KDYHKLJKHUOHYHOVRIIDFWRU9,,,WKDQLQGLYLGXDOV

ZLWKEORRGJURXS2+RZHYHUDKLJK%0,LVDOVRDVVRFLDWHGZLWKHOHYDWLRQLQWKHOHYHORI

IDFWRU9,,,ZKLFKPD\EHDUHVXOWRIUHOHDVHRIIDFWRU9,,,E\DGLSRVHWLVVXHWKURXJK

LQÀDPPDWRU\F\WRNLQHV$VIDFWRU9,,,FDQLQGXFH$3&UHVLVWDQFHWKHSDWKZD\RIKLJK

%0,OHDGLQJWRYHQRXVWKURPERVLVFRXOGUXQWKURXJKIDFWRU9,,,LQGXFHG$3&UHVLVWDQFH,I

VRDUHLQIRUFHPHQWLQWKLVULVNLQWKHSUHVHQFHRIIDFWRU9/HLGHQEORRGJURXSQRQ2RUD

FRPELQDWLRQRIERWKJHQHWLFIDFWRUVFRXOGEHH[SHFWHG

:HXVHGWKHGDWDIURPWZRZHOOFKDUDFWHULVHGFDVHFRQWUROVWXGLHVLQWKH1HWKHUODQGV /(76  DQG1RUZD\ 752/ WRVWXG\IRXUK\SRWKHVHVZKLFKZHJUDSKLFDOO\LOOXVWUDWHGLQ)LJXUH

:HVHWRXWWRGHWHUPLQH¿UVWRIDOOZKHWKHUDQDVVRFLDWLRQH[LVWVEHWZHHQ%0,DQG$3&

UHVLVWDQFHLQ/(76DQGZKHWKHUWKLVDVVRFLDWLRQLVPHGLDWHGE\IDFWRU9,,,OHYHOV EODFN

GDVKHG DURZV LQ )LJXUH   6HFRQGO\ ZH VWXGLHG ZKHWKHU WKH ULVN RI YHQRXV WKURPERVLV

DVVRFLDWHGZLWKKLJK%0,ZDVDWWHQXDWHGE\$3&UHVLVWDQFHRUIDFWRU9,,,OHYHOVLQ/(76

EODFNDUURZLQ)LJXUH 7KLUGO\LQDSRROHGDQDO\VLVRI/(76DQG752/ZHYHUL¿HG

LI EORRG JURXS QRQ2 PRGL¿HG WKH ULVN RI LQFUHDVLQJ %0, RQ WKH RFFXUHQFH RI YHQRXV

WKURPERVLV JUH\GDVKHGDUURZVLQ)LJXUH DQGZKHWKHUWKHVHULVNVZHUHIXUWKHULQFUHDVHG

E\WKHSUHVHQFHRIIDFWRU9/HLGHQ JUH\DUURZVLQ)LJXUH 

(5)



55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

)LJXUH+\SRWKHVHVRIWKHVWXG\

7KHEODFNGDVKHGDUURZVLQGLFDWHWKH¿UVWVWXG\TXHVWLRQLHZKHWKHUDQDVVRFLDWLRQH[LVWVEHWZHHQ

%0,DQG$3&UHVLVWDQFHDQGZKHWKHUWKLVDVVRFLDWLRQLVPHGLDWHGE\IDFWRU9,,,OHYHOV7KHEODFNVROLG

DUURZLQGLFDWHVWKHVHFRQGVWXG\TXHVWLRQLHZKHWKHUWKHULVNRIYHQRXVWKURPERVLVDVVRFLDWHGZLWK

KLJK%0,LVDWWHQXDWHGE\$3&UHVLVWDQFHRUIDFWRU9,,,OHYHOV7KHJUH\GDVKHGDUURZVLQGLFDWHWKH

WKLUGVWXG\TXHVWLRQLHLIEORRGJURXSQRQ2PRGL¿HVWKHULVNRILQFUHDVLQJ%0,RQWKHRFFXUHQFH

RIYHQRXVWKURPERVLV7KHJUH\DUURZVLQGLFDWHWKH¿QDOVWXG\TXHVWLRQLHZKHWKHUWKHVHULVNVZHUH

IXUWKHULQFUHDVHGE\WKHSUHVHQFHRIIDFWRU9/HLGHQ

0HWKRGV

/(76SDWLHQWVDQGFRQWUROV

7KHLQFOXVLRQRISDWLHQWVDQGFRQWUROVLQWKH/HLGHQ7URPERSKLOLD6WXG\KDVEHHQH[WHQVLYHO\

GHVFULEHG LQ WKH SDVW ,Q VKRUW FDVHV ZHUHFRQVHFXWLYHSDWLHQWVWUHDWHG IRU GHHS YHLQ

WKURPERVLV '97  DW WKH $QWLFRDJXODWLRQ &OLQLFV LQ /HLGHQ $PVWHUGDP DQG 5RWWHUGDP

GXULQJ WKH SHULRG -DQXDU\   DQG 'HFHPEHU   3DWLHQWV KDG WR EH ZLWKRXW D

GLDJQRVLVRIDFWLYHFDQFHUEHQHDWK\HDUVRIDJHDWHQWU\DQGWRKDYHDGLDJQRVLVRI'97

HVWDEOLVKHG ZLWK REMHFWLYH GLDJQRVWLF PHWKRGV )XO¿OOLQJ WKHVH FULWHULD  SDUWLFLSDWHG

UHVXOWLQJLQDFDVHJURXSZLWKFRQVHFXWLYH'97SDWLHQWV$FRQWUROJURXSZDVDVVHPEOHG

ZKHUHSDWLHQWVZHUHWR¿QGWKHLURZQKHDOWK\FRQWUROVXEMHFWRIWKHVDPHVH[VDPHDJH 

\HDUV QRELRORJLFUHODWLYHDQGZLWKRXWDGLDJQRVLVRIDFWLYHFDQFHUDKLVWRU\RIYHQRXV

WKURPERVLVRUKDYLQJXVHGFRXPDULQWKHUDS\LQWKHODVWWKUHHPRQWKVEHIRUHLQFOXVLRQ7KLV

ZD\FRQWUROVZHUHIRXQG

752/SDWLHQWVDQGFRQWUROV

%HWZHHQ$XJXVWDQG-XQHDOOLQKDELWDQWVROGHUWKDQ\HDUVRIDJH Q   LQ1RUG7U¡QGHODJ&RXQW\ LQ0LGGOH1RUZD\ ZHUHDVNHGWREHSDUWRIDSRSXODWLRQEDVHG

KHDOWK VXUYH\ FDOOHG ³+HOVHXQGHUV¡NHOVHQ L 1RUG7U¡QGHODJ´ +817 $OO SDUWLFLSDQWV



























,QFUHDVH%0,

,QFUHDVHIDFWRU9,,,

,QFUHDVH$3&UHVLVWDQFH

,QFUHDVHGYHQRXVWKURPERWLFULVN

%ORRGJURXSQRQ2

)DFWRU9/HLGHQ

(6)



55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 Q  SDUWLFLSDWLRQ UDWH   XQGHUZHQW D SK\VLFDO H[DPLQDWLRQ GRQDWHG  PO RI

EORRGDQG¿OOHGLQDTXHVWLRQQDLUH3DUWLFLSDQWVKDGDPHGLDQDJHRI\HDUV UDQJH

 7KHIROORZXSRI+817KDVEHHQGHVFULEHGEHIRUH,QEULHIFDVHVZLWKYHQRXV

WKURPERVLVZHUHLGHQWL¿HGVFUHHQLQJWKHFRPSXWHUL]HGGLDJQRVLVUHJLVWULHVRIDOOGHSDUWPHQWV

LQWKHRQO\WZRORFDOKRVSLWDOVLQWKHUHJLRQ /HYDQJHUDQG1DPVRVKRVSLWDOV XQWLO-DQXDU\

7KHVHDUFKZDVVXSSOHPHQWHGE\FURVVOLQNLQJZLWKDOOSRVLWLYHGLDJQRVWLFSURFHGXUHV

IRU YHQRJUDSK\ GXSOH[ DQG 'RSSOHU XOWUDVRXQG ZLWKLQ WKH UHJLVWULHV RI WKH UDGLRORJ\

GHSDUWPHQWVDWWKHWZRKRVSLWDOV)LQDOO\SDWLHQWVIURP1RUG7U¡QGHODJ&RXQW\GLVFKDUJHG

IURP6W2ODY8QLYHUVLW\+RVSLWDOZLWKGLDJQRVWLFFRGHVRIYHQRXVWKURPERVLVZHUHLQFOXGHG

7KLVVHDUFKLGHQWL¿HGFDVHVZLWKDGLDJQRVWLFFRGHRIYHQRXVWKURPERVLVDQGWKHLU

KRVSLWDOUHFRUGVZHUHUHYLHZHGWRREWDLQLQIRUPDWLRQIRUYDOLGDWLRQRIWKHGLDJQRVLV

:H XVHG WKH IROORZLQJ FULWHULD DV D FRQ¿UPDWLRQ RI WKH GLDJQRVLV UHVSHFWLYHO\ IRU '97

DQ LQWUDOXPLQDO ¿OOLQJ GHIHFW RU QR YHQRXV ¿OOLQJ RQ DVFHQGLQJ FRQWUDVW YHQRJUDSK\ RU

QRFRPSUHVVLEOHYHQRXVVHJPHQWRUQRYHQRXVÀRZLQSRSOLWHDOIHPRUDORUD[LOODU\YHLQV

RQGXSOH[XOWUDVRXQGRUDSRVLWLYHFRPSXWHGWRPRJUDSK\VFDQRUDSRVLWLYHDXWRSV\IRU

SXOPRQDU\HPEROXV 3( DYHQWLODWLRQSHUIXVLRQVFDQZLWKRQHRUPRUHVHJPHQWDORUVXE

VHJPHQWDO SHUIXVLRQ GHIHFWV ZLWK QRUPDO YHQWLODWLRQ RU D FRQWUDVW GHIHFW RQ SXOPRQDU\

FRPSXWHGWRPRJUDSK\VFDQRUDSRVLWLYHDXWRSV\

:H IRXQG  FDVHV ZLWK D YDOLGDWHG GLDJQRVLV RI ZKRP    ZHUH ZLWKLQ WKH

+817FRKRUW:HH[FOXGHGSDWLHQWVZLWKSUHYLRXVYHQRXVWKURPERVLVHQUROOPHQWLQ

WKH+817FRKRUWDIWHUWKHHYHQWOHDYLQJFDVHVZLWKDGH¿QLWHGLDJQRVLVRIYHQRXV

WKURPERVLV 6XEVHTXHQWO\ ZH VDPSOHG  FRQWUROV IURP WKH EDVHOLQH RI WKH +817

FRKRUWIUHTXHQF\PDWFKHGWRWKHFDVHVE\VH[DQG\HDUDJHVWUDWD

/DERUDWRU\PHDVXUHPHQWV

/(76

%ORRGGUDZQIURPWKHSDUWLFLSDQWVZDVSODFHGLQ0RIWULVRGLXPFLWUDWHFHQWULIXJDWHG

DWJIRUPLQXWHVEHIRUHVWRUDJHDW±ƒ&LQDP/FRQWDLQHU$VWDQGDUG

VDOWLQJRXWPHWKRGZDVXVHGWRH[WUDFW'1$  

$FWLYDWHG3URWHLQ&5HVLVWDQFHDQGWKH)DFWRU9 *→$ YDULDQW IDFWRU9/HLGHQ ZHUH

PHDVXUHGDFFRUGLQJWRPHWKRGVGHVFULEHGHDUOLHULQWKH/(76

7KHPHWKRGRIPHDVXULQJSODVPD¶V$377VHQVLWLYLW\WRDFWLYDWHGSURWHLQ&ZDVDFFRUGLQJ

WRWKHWHFKQLTXHXVHGE\'DKOElFNHWDODQGLVH[SUHVVHGDVQRUPDOL]HG$3&UDWLR$3&

UHVLVWDQFHPHDVXUHPHQWVZHUHPLVVLQJRUIDLOLQJLQFDVHVDQGFRQWUROV'1$VDPSOHV

ZHUHPLVVLQJRUPHDVXUHPHQWIDLOHGLQFDVHVEXWLQQRQRIWKHFRQWUROV)DFWRU9,,,DFWLYLW\

ZDVPHDVXUHGE\DVWDJHFRDJXODWLRQDVVD\DQGEORRGJURXSE\SRO\PHUDVHFKDLQUHDFWLRQV 752/

$YDLODEOH'1$GHVFHQGHGIURPSHULSKHUDOEORRGOHXNRF\WHV ZKROHEORRGRUEORRGFORWV DQG

ZDVH[WUDFWHGXVLQJWKH3XUHJHQHNLW *HQWUD6\VWHPV,QF PDQXDOO\RUZLWKDQ$XWRSXUH/6

*HQWUD6\VWHPV,QF )DFWRU9/HLGHQDQGEORRGJURXSZHUHPHDVXUHGXVLQJSRO\PHUDVH

FKDLQUHDFWLRQDFFRUGLQJWRWKH7DTPDQPHWKRG,QFDVHV  DQGFRQWUROV  

'1$VDPSOHVZHUHHLWKHUPLVVLQJRUWKHPHDVXUHPHQWVIDLOHG7HFKQLFLDQVZHUHQRWDZDUHRI

WKHVWDWXVRIFDVHVRUFRQWUROVVLQFHDOOVDPSOHVZHUHVWRUHGDQRQ\PRXVO\EHIRUHWKHVHOHFWLRQ

(7)



55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

RIDFRQWUROJURXSIURPWKHEDVHOLQHFRKRUW,QWKH752/VWXG\SODVPDZDVQRWREWDLQHGDQG

WKHUHIRUHIDFWRU9,,,OHYHOVDQG$3&UHVLVWDQFHFRXOGQRWEHGHWHUPLQHGLQ752/

6WDWLVWLFDODQDO\VLV

/LQHDU UHJUHVVLRQ ZDV XVHG WR GHWHUPLQH WKH UHODWLRQ EHWZHHQ LQFUHDVLQJ$3&UHVLVWDQFH

DQG%0,LQFUHDVLQJIDFWRU9,,,OHYHOVDQG%0,LQFUHDVLQJ$3&UHVLVWDQFHDQGIDFWRU9,,,

OHYHOVDQGEHWZHHQLQFUHDVLQJ$3&UHVLVWDQFHDQG%0,DGMXVWHGIRUIDFWRU9,,,OHYHOV

&XWRIISRLQWVQHHGHGWRFUHDWHWHUWLOHFDWHJRULHVRI$3&UHVLVWDQFHZHUHGHULYHGIURPWKH

FRQWUROJURXSRIWKH/(76SRSXODWLRQDIWHUWKHH[FOXVLRQRIIDFWRU9/HLGHQFDUULHUVDQG

LQGLYLGXDOV ZKR XVHG RUDO FRQWUDFHSWLYHV DW WLPH RI EORRG GUDZ &XWRII SRLQWV WR FUHDWH

WHUWLOHFDWHJRULHVIRU%0,ZHUHGHULYHGIURPWKHFRQWUROJURXSVRIWKH/(76DQGWKH752/

SRSXODWLRQ VHSDUDWHO\ LUUHVSHFWLYH RI IDFWRU 9 /HLGHQ RU RUDO FRQWUDFHSWLYH XVH /RJLVWLF

UHJUHVVLRQZDVXVHGWRFDOFXODWHRGGVUDWLRVDQGWKHLUFRQ¿GHQFHLQWHUYDOV &,V 

DGMXVWHGIRUDJHDQGVH[

7KHHIIHFWRIIDFWRU9/HLGHQRUEORRGJURXSLQFRPELQDWLRQZLWKDKLJK%0,ZDVFDOFXODWHG

LQWKH /(76DQGWKH752/ SRSXODWLRQERWKVHSDUDWHO\DQGFRPELQHG7R KDYH DQDO\VHV

GLUHFWHGDWVLPLODUJURXSVLQWKH752/DQG/(76SRSXODWLRQVZHUHVWULFWHGWKHDQDO\VLVLQ

WKH752/VXEMHFWVWRWKRVHZKRZHUH\RXQJHUWKDQDQGWRWKRVHZKRKDGD'97RQO\LQ

WKHFXUUHQWVWXG\ Q FDVHVDQGQ FRQWUROV 

7KHVWDWLVWLFDOVRIWZDUHXVHGZDV6366YHUVLRQ 6366&KLFDJR,OO8QLWHG6WDWHV 

5HVXOWV

/(76DQG752/VWXG\SRSXODWLRQV

7KHGHVFULSWLYHFKDUDFWHULVWLFVRIWKHSDWLHQWVDQGFRQWUROLQGLYLGXDOVRIERWKVWXG\SRSXODWLRQV

DUHOLVWHGLQ7DEOH7KH752/SRSXODWLRQLVDQROGHUSRSXODWLRQVLQFHWKHXSSHUOLPLWRI

LQFOXVLRQLQ/(76ZDV\HDUVZKHUHDVWKHUHZDVQRDJHOLPLWLQWKH752/VWXG\+HQFH

/(76FDVHVDQGFRQWUROVKDGDPHGLDQDJHRI\HDUVZKLOHWKLVZDV\HDUVLQWKH752/

FDVHVDQG\HDUVLQWKHFRQWUROV7KHUHZHUHVOLJKWO\PRUHZRPHQWKDQPHQLQERWKVWXGLHV

7DEOH%DVHOLQHFKDUDFWHULVWLFVRIWKH/(76DQGWKH752/VWXG\

/(76 752/

&DWHJRU\ &DVHV

Q  &RQWUROV

Q  &DVHV

Q  &RQWUROV Q 

7RWDO    

6H[ 0HQ        

:RPHQ        

$JHJURXSV\HDUV       

        

        

        

        

        

      

!      

(8)



55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55

%0,$3&UHVLVWDQFHDQG)9,,,

)LJXUH$VKRZVWKDWLQWKH/(76FRQWUROLQGLYLGXDOVWKHQRUPDOLVHG$3&UDWLRGHFUHDVHG

OLQHDUO\ ZLWK LQFUHDVLQJ %0, LH $3&UHVLVWDQFH LQFUHDVHG ZKHQ %0, LQFUHDVHG 7KLV

DVVRFLDWLRQ ZDV IRXQG LQ ERWK PHQ DQG ZRPHQ EXW DSSHDUHG WR EH VOLJKWO\ VWURQJHU LQ

PHQ %HWD&,WRIRUPHQDQG&,WR

IRUZRPHQ $VDPHSURWKURPERWLFSKHQRPHQRQZDVREVHUYHGIRUIDFWRU9,,,LH

DQLQFUHDVHLQ%0,ZDVDVVRFLDWHGZLWKLQFUHDVHGIDFWRU9,,,OHYHOVERWKLQPHQDQGZRPHQ

ZKLFKUHODWLRQZDVDJDLQVRPHZKDWVWURQJHULQPHQWKDQLQZRPHQ )LJXUH% ,QFUHDVHG

$3&UHVLVWDQFHZDVWKHUHIRUHDOVRDVVRFLDWHGZLWKDQLQFUHDVHRIIDFWRU9,,,OHYHOV )LJXUH

& DQGIDFWRU9,,,OHYHOVH[SODLQHGSDUWRIWKHUHODWLRQEHWZHHQ%0,DQG$3&UHVLVWDQFHDV

WKHVORSHRIWKHUHJUHVVLRQOLQHRI$3&UHVLVWDQFHRQ%0,OHYHOVGHFUHDVHGDIWHUDGMXVWPHQW

IRUIDFWRU9,,,ERWKLQPHQDQGLQZRPHQ DGMXVWHGEHWD&,WR

IRUPHQDQG&,WRIRUZRPHQ 



(9)



55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

)LJXUH6FDWWHUGLDJUDPVDQGOLQHDUUHJUHVVLRQPRGHOVRIQRUPDOL]HG$3&UDWLRDVVRFLDWHGZLWKERG\

PDVVLQGH[DQGIDFWRU9,,,

0HQZLWKRXWIDFWRU9/HLGHQ EODFNGRWVDQGVROLGUHJUHVVLRQOLQHQ 

1RUPDOL]HG$3&UDWLR  [%0,  &,VORSH   )LJXUH$

)DFWRU9,,, ,8G/   [%0,  &,VORSH   )LJXUH%

1RUPDOL]HG$3&UDWLR  [)9,,,  &,VORSH   )LJXUH&

1RUPDOL]HG$3&UDWLR  [%0,  &, VORSH    )9,,, DGMXVWHG

GDWDQRWVKRZQ



:RPHQZLWKRXWIDFWRU9/HLGHQ ZKLWHGRWVDQGGDVKHGUHJUHVVLRQOLQHQ 

1RUPDOL]HG$3&UDWLR  [%0,  &,VORSH   )LJXUH$ 

)DFWRU9,,, ,8G/   [%0,  &,VORSH   )LJXUH%

1RUPDOL]HG$3&UDWLR  [)9,,,  &,VORSH   )LJXUH&

1RUPDOL]HG$3&UDWLR  [%0,  &, VORSH     )9,,, DGMXVWHG

GDWDQRWVKRZQ

'DWDVXEWUDFWHGIURPFRQWUROLQGLYLGXDOVLQ/(76ZLWKRXWIDFWRU9/HLGHQ

&,GHQRWHVFRQ¿FHQFHLQWHUYDO)9,,,IDFWRU9,,,

7KHULVNRIYHQRXVWKURPERVLVZLWKLQFUHDVLQJ%0,DQG$3&UHVLVWDQFH

7RH[DPLQHWKHHIIHFWRILQFUHDVLQJ%0,RQWKHULVNRIYHQRXVWKURPERVLVVHSDUDWHIURP

$3&UHVLVWDQFHGXHWRRWKHUIDFWRUVZHUHVWULFWHGWKHDQDO\VLVWRLQGLYLGXDOVIURPWKH/(76

ZLWKRXWIDFWRU9/HLGHQRURUDOFRQWUDFHSWLYHXVH,QWKHVHLQGLYLGXDOVWKHULVNRIYHQRXV

WKURPERVLVLQFUHDVHGIROGIRUWKRVHZLWKD%0,LQWKHPHGLDQWHUWLOH RGGVUDWLR

&, DQGIROGIRUWKRVHLQWKHXSSHUWHUWLOH RGGVUDWLR&, 

DVFRPSDUHGWRLQGLYLGXDOVLQWKHORZHVWWHUWLOH 7DEOH $GMXVWPHQWIRU$3&UHVLVWDQFHRU

IDFWRU9,,,OHYHOVLQDORJLVWLFUHJUHVVLRQPRGHOOHGWRDVOLJKWGHFUHDVHLQWKHVHUHODWLYHULVN

HVWLPDWHVVXJJHVWLQJWKDWWKHHIIHFWRQULVNLVDWOHDVWSDUWO\PHGLDWHGWKURXJK)9,,,OHYHOV

RU$3&UHVLVWDQFH

(10)



55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 7DEOH5LVNRIYHQRXVWKURPERVLVDFFRUGLQJWR%0,WHUWLOHVDQG$3&UHVLVWDQFH

%0, NJP &DVH &RQWURO 2GGVUDWLR

&,  2GGVUDWLR

&, 2GGVUDWLR

&,

Q  Q  DGMXVWHGIRU$3& DGMXVWHGIRU)9,,, /RZHUWHUWLOH      5HIHUHQFH 5HIHUHQFH 5HIHUHQFH 0HGLDQWHUWLOH           

8SSHUWHUWLOH !          

7RWDO  

%0,GHQRWHVERG\PDVVLQGH[ NJP &,FRQ¿GHQFHLQWHUYDO)9,,,IDFWRU9,,,

'DWDVXEWUDFWHGIURP/(76H[FOXGLQJLQGLYLGXDOVZLWKIDFWRU9/HLGHQDQGZRPHQZKRXVHGRUDO

FRQWUDFHSWLYHV

7KHULVNRIYHQRXVWKURPERVLVZLWKLQFUHDVLQJ%0,IDFWRU9/HLGHQDQGQRQ2EORRGJURXS

7DEOHVKRZVWKHFRPELQHGHIIHFWVRIIDFWRU9/HLGHQDQGEORRGJURXSZLWKLQLQFUHDVLQJ

%0,FDWHJRULHVRQWKHULVNRIYHQRXVWKURPERVLVLQWKH/(76DQG752/SRSXODWLRQV:KHQ

%0,LQFUHDVHG$3&UHVLVWDQFHDQGIDFWRU9,,,OHYHOVDOVRLQFUHDVHGLQDGRVHUHVSRQVHZD\

LQQRQIDFWRU9/HLGHQFDUULHUVZLWKEORRGJURXS27KHVHLQGLYLGXDOVZHUHDWULVNRIYHQRXV

WKURPERVLVZKHQWKH\KDGD%0,LQWKHXSSHUWHUWLOHFRPSDUHGWRWKHORZHVWWHUWLOHDGMXVWHG

RGGVUDWLR &, $VLPLODUEXWVOLJKWO\VWURQJHUGRVHUHVSRQVHSDWWHUQIRU

LQFUHDVHLQ$3&UHVLVWDQFHDQGLQFUHDVHRIIDFWRU9,,,OHYHOVZKHQ%0,OHYHOLQFUHDVHGZDV

REVHUYHGLQQRQIDFWRU9/HLGHQFDUULHUVZLWKEORRGJURXSQRQ29HQRXVWKURPERWLFULVN

ZDV PRGHVWO\ LQFUHDVHG LQ D GRVHUHVSRQVH ZD\ ZKHQ WKHVH LQGLYLGXDOV ZHUH FRPSDUHG

ZLWKWKHUHIHUHQFHJURXS)DFWRU9/HLGHQFDUULHUVZLWKEORRGJURXS2DOVRVKRZHGDGRVH

UHVSRQVH LQFUHDVH RI$3&UHVLVWDQFH DQG IDFWRU 9,,, ZKHQ %0, OHYHO LQFUHDVHG 5LVN RI

YHQRXVWKURPERVLVZDVVWURQJO\LQFUHDVHGDJDLQLQDGRVHUHVSRQVHZD\ZLWKLQWKH%0,

WHUWLOHVFRPSDUHGWRWKHUHIHUHQFHJURXS&DUULHUVRIIDFWRU9/HLGHQZLWKEORRGJURXSQRQ2

KDGKLJKHVWIDFWRU9,,,OHYHOVEHWZHHQWKH%0,WHUWLOHV7KH\VKRZHGWKHKLJKHVWULVNRI

YHQRXVWKURPERVLVFRPSDUHGWRWKHUHIHUHQFHJURXSQRORQJHULQDGRVHUHVSRQVHZD\ZLWK

DGMXVWHGRGGVUDWLRVRI &,  &, DQG &,

 UHVSHFWLYHO\ZLWKLQWKH%0,WHUWLOHV

(11)



55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55 7DEOH

/(76DQG752/FRPELQHG5LVNRIYHQRXVWKURPERVLVDFFRUGLQJWRWKHFRPELQDWLRQVRIIDFWRU9/HLGHQ%0,WHUWLOHVDQG EORRGJURXS  %0,)DFWRU9 /HLGHQ%ORRGJURXS0HDQ QRUPDOL]HG $3&UDWLR

‚

0HDQIDFWRU 9,,, ,8G/

‚

&DVH Q 

&RQWURO Q 

25 &, 25Á &, /RZHVWWHUWLOH2    5HIHUHQFH5HIHUHQFH 0HGLDQWHUWLOH2        8SSHUWHUWLOH2        /RZHVWWHUWLOHQRQ2        0HGLDQWHUWLOHQRQ2        8SSHUWHUWLOHQRQ2        /RZHVWWHUWLOH2        0HGLDQWHUWLOH2        8SSHUWHUWLOH2        /RZHVWWHUWLOHQRQ2        0HGLDQWHUWLOHQRQ2        8SSHUWHUWLOHQRQ2        7RWDO %0,GHQRWHVERG\PDVVLQGH[ NJP &,FRQ¿GHQFHLQWHUYDO25RGGVUDWLR 7HUWLOHVGHULYHGIURP/(76DQG752/FRQWUROSRSXODWLRQUHVSHFWLYHO\ &DVHVDQGFRQWUROV\HDUVRIDJHDQG'97FDVHVRQO\ 3(H[FOXGHG  /(768SSHUWHUWLOH%0,!0HGLDQWHUWLOH%0,!/RZHVWWHUWLOH%0, 752/8SSHUWHUWLOH%0,!0HGLDQWHUWLOH%0,!/RZHVWWHUWLOH%0,

‚'DWDVXEWUDFWHGIURP/(76 Á2GGVUDWLRDGMXVWHGIRUDJHDQGVH[

(12)



55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55

'LVFXVVLRQ

,QWKLVVWXG\ZHKDYHVKRZQWKDWDQLQFUHDVHLQ%0,LVUHODWHGWRDQLQFUHDVHLQ$3&UHVLVWDQFH

3DUWRIWKLVUHODWLRQFRXOGEHH[SODLQHGE\IDFWRU9,,,OHYHODVWKHVORSHRIWKHUHJUHVVLRQOLQH

RI$3&UHVLVWDQFHRQ%0,OHYHOVGHFUHDVHGDIWHUDGMXVWPHQWIRUIDFWRU9,,,7KHUHZDVDGRVH

UHVSRQVHUHODWLRQEHWZHHQLQFUHDVHRI%0,DQGLQFUHDVLQJYHQRXVWKURPERWLFULVN IROG

DQGIROGLQFUHDVHGULVNZKHQPHGLDQ%0,WHUWLOHRUXSSHU%0,WHUWLOHUHVSHFWLYHO\ZDV

FRPSDUHGZLWKWKHORZHVW%0,WHUWLOH 7KLVZDVSDUWO\DUHVXOWRI$3&UHVLVWDQFHDQGIDFWRU

9,,,DVRGGVUDWLRVDWWHQXDWHGDIWHUZHDGMXVWHGIRU$3&UHVLVWDQFHRUIRUIDFWRU9,,,7KHVH

ODWWHU¿QGLQJVVXSSRUWHYLGHQFHIURPRWKHUVWXGLHVWKDWDOVRVKRZHGWKDWLQFUHDVHRI%0,LV

DVVRFLDWHGZLWK$3&UHVLVWDQFHDQGHOHYDWLRQRIIDFWRU9,,,OHYHOV

:KHQLQGLYLGXDOVKDGRWKHUFDXVHVRI$3&UHVLVWDQFHVXFKDVEORRGJURXSQRQ2RUIDFWRU

9/HLGHQZHVDZDJUDGXDOLQFUHDVHLQ$3&UHVLVWDQFHDQGIDFWRU9,,,OHYHOVZLWKLQFUHDVLQJ

%0,DQGDMRLQWHIIHFWRQWKHYHQRXVWKURPERWLFULVNZLWKLQFUHDVLQJ%0,7KLVFRQ¿UPHG

RXUK\SRWKHVLVWKDWIDFWRU9/HLGHQDQGRUEORRGJURXSQRQ2PRGL¿HVWKHULVNRILQFUHDVLQJ

%0, RQ YHQRXV WKURPERVLV RFFXUUHQFH WKURXJK IDFWRU9,,, LQGXFHG$3&UHVLVWDQFH7KLV

FRQFOXVLRQ LV RQO\ H[FHSWHG IRU LQGLYLGXDOV ZKR KDG ERWK EORRG JURXS QRQ2 DQG IDFWRU

9/HLGHQDVWKHVHLQGLYLGXDOVKDGWKHKLJKHVWULVNRIYHQRXVWKURPERVLV RGGVUDWLRV!  LUUHVSHFWLYH RI WKHLU %0, WHUWLOH $SSDUDQWO\ WKH FRPELQDWLRQ RI VWURQJ $3&UHVLVWDQFH

FRPELQHGZLWKKLJKIDFWRU9,,,OHYHOVZDVVXI¿FLHQWHQRXJKWRJHQHUDWHYHU\KLJKWKURPERWLF

ULVNVLUUHVSHFWLYHRI%0,LQWKHVHLQGLYLGXDOV7KDWIDFWRU9/HLGHQFDUULHUVZLWKEORRG

JURXSQRQ2DUHDWYHU\KLJKULVNRIYHQRXVWKURPERVLVKDVEHHQUHSRUWHGEHIRUHDQG

PD\GHVHUYHDWWHQWLRQLQWKHPDQDJHPHQWRISULPDU\RUVHFRQGDU\SUHYHQWLRQIRUYHQRXV

WKURPERVLVLQWKHVHLQGLYLGXDOVDOWKRXJKWKLVLPSOLFDWLRQVKRXOGEHKDQGOHGZLWKFDXWLRQDV

QXPEHUVSDUWLFXODUO\LQWKHFRQWUROJURXSZHUHVPDOO

3UHYDOHQFHRIRYHUZHLJKWDQGREHVLW\LQWKHZHVWHUQZRUOGLV,WKDVEHHQFDOFXODWHG

WKDWDOPRVWRQHWKLUGRIDOOHYHQWVRIYHQRXVWKURPERVLVFRXOGEHSUHYHQWHGE\ZHLJKWORVV

DVVXPLQJWKDWZHLJKWORVVUHGXFHVYHQRXVWKURPERWLFULVN)RUWKLVUHDVRQHQFRXUDJHPHQW

WRPDQDJHZHLJKWFRQWUROLQLQGLYLGXDOVZLWKRYHUZHLJKWRUREHVLW\VHHPVUHDVRQDEOH

6RPHOLPLWDWLRQVRIRXUGDWDPHULWFRQVLGHUDWLRQ)LUVWKHLJKWDQGZHLJKWZHUHVHOIUHSRUWHG

ERWKLQWKH/(76DQGLQWKH752/VWXG\$VLQJHQHUDOLQGLYLGXDOVZLWKXQGHUZHLJKWWHQG

WRRYHUUHSRUWWKHLUERG\ZHLJKWZKLOHLQGLYLGXDOVZLWKRYHUZHLJKWWHQGWRXQGHUUHSRUWWKHLU

ERG\ZHLJKWDFWXDOULVNVVKRXOGEHVRPHZKDWKLJKHULIWKLVSKHQRPHQRQKDVRFFXUUHG

6HFRQGFRQWUROLQGLYLGXDOVLQ/(76ZHUHLQWURGXFHGE\WKHFDVHV IULHQGVDFTXDLQWDQFHV 

,W LV WKHUHIRUH SRVVLEOH WKDW LQ /(76 FDVHV DQG FRQWUROV KDG VLPLODU OLIH VW\OHV WKDW PD\

KDYHUHVXOWHGLQVLPLODU%0,V:KHQWKLVZHUHWKHFDVHLWDOVRZRXOGKDYHOHGWRORZHUULVN

HVWLPDWHVLQRXUVWXG\WKDQDFWXDOULVNV

:HFRQFOXGHWKDWWKHLQFUHDVHGULVNRIYHQRXVWKURPERVLVLQLQGLYLGXDOVZLWKKLJK%0,LV

PHGLDWHGE\IDFWRU9,,,LQGXFHG$3&UHVLVWDQFH,QGLYLGXDOVZLWKIDFWRU9/HLGHQRUEORRG

JURXSQRQ2KDGDKLJKHUULVNRIYHQRXVWKURPERVLVFRPSDUHGWRQRQFDUULHUVZKLFKZDV

HQIRUFHGWRIROGE\LQFUHDVHRI%0,)XWXUHVWXGLHVDUHQHHGHGWRVKRZLIWKHVHULVNVFDQ

EHGRZQJUDGHGE\ZHLJKWORVV

(13)



55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

(14)



55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55 55

5HIHUHQFHV

  1DHVV,$&KULVWLDQVHQ6&5RPXQGVWDG3&DQQHJLHWHU6&5RVHQGDDO)5+DPPHUVWU¡P-

,QFLGHQFHDQGPRUWDOLW\RIYHQRXVWKURPERVLVDSRSXODWLRQEDVHGVWXG\-7KURPE+DHPRVW

  

  1RUGVWU|P0/LQGEODG%%HUJTYLVW'.MHOOVWU|P7$SURVSHFWLYHVWXG\RIWKHLQFLGHQFHRI

GHHSYHLQWKURPERVLVZLWKLQDGH¿QHGXUEDQSRSXODWLRQ-,QWHUQ0HG  

  :+22EHVLW\SUHYHQWLQJDQGPDQDJLQJWKHJOREDOHSLGHPLF5HSRUWRQD:+2&RQVXOWDWLRQ

RQ2EHVLW\*HQHYD±-XQH:+21871&'7HFKQLFDO5HSRUW6HULHV1XPEHU

:RUOG+HDOWK2UJDQL]DWLRQ*HQHYD  

  $EGROODKL0&XVKPDQ05RVHQGDDO)52EHVLW\ULVNRIYHQRXVWKURPERVLVDQGWKHLQWHUDFWLRQ

ZLWKFRDJXODWLRQIDFWRUOHYHOVDQGRUDOFRQWUDFHSWLYHXVH7KURPE+DHPRVW  

  3RPS(5OH&HVVLH65RVHQGDDO)5'RJJHQ&-5LVNRIYHQRXVWKURPERVLVREHVLW\DQG

LWV MRLQW HIIHFW ZLWK RUDO FRQWUDFHSWLYH XVH DQG SURWKURPERWLF PXWDWLRQV %U - +DHPDWRO

  

  -XXO.7\EMDHUJ+DQVHQ$6FKQRKU31RUGHVWJDDUG%*)DFWRU9/HLGHQDQGWKHULVNIRU

YHQRXVWKURPERHPEROLVPLQWKHDGXOW'DQLVKSRSXODWLRQ$QQ,QWHUQ0HG  

  %HUWLQD50.RHOHPDQ%3.RVWHU7HWDO0XWDWLRQLQEORRGFRDJXODWLRQIDFWRU9DVVRFLDWHG

ZLWKUHVLVWDQFHWRDFWLYDWHGSURWHLQ&1DWXUH  

  /RZH*'5XPOH\$:RRGZDUG05HLG(5XPOH\-$FWLYDWHGSURWHLQ&UHVLVWDQFHDQG

WKH)954PXWDWLRQLQDUDQGRPSRSXODWLRQVDPSOHDVVRFLDWLRQVZLWKFDUGLRYDVFXODUULVN

IDFWRUVDQGFRDJXODWLRQYDULDEOHV7KURPE+DHPRVW  

  .RVWHU 7 %ODQQ $' %ULsW ( 9DQGHQEURXFNH -3 5RVHQGDDO )5 5ROH RI FORWWLQJ IDFWRU

9,,, LQ HIIHFW RI YRQ :LOOHEUDQG IDFWRU RQ RFFXUUHQFH RI GHHSYHLQ WKURPERVLV /DQFHW

  

  'DUYDOO.$6DP5&6LOYHUPDQ6+%UDGEXU\$:$GDP'-2EHVLW\DQGWKURPERVLV(XU-

9DVF(QGRYDVF6XUJ  

  )ROVRP$5 &RQODQ 0* 'DYLV &( :X .. 5HODWLRQV EHWZHHQ KHPRVWDVLV YDULDEOHV DQG

FDUGLRYDVFXODUULVNIDFWRUVLQPLGGOHDJHGDGXOWV$WKHURVFOHURVLV5LVNLQ&RPPXQLWLHV $5,&  6WXG\,QYHVWLJDWRUV$QQ(SLGHPLRO  

  :RRGZDUG05XPOH\$/RZH*'7XQVWDOO3HGRH+&UHDFWLYHSURWHLQDVVRFLDWLRQVZLWK

KDHPDWRORJLFDOYDULDEOHVFDUGLRYDVFXODUULVNIDFWRUVDQGSUHYDOHQWFDUGLRYDVFXODUGLVHDVH%U-

+DHPDWRO  

  .RVWHU 7 5RVHQGDDO )5 GH 5RQGH + %ULsW ( 9DQGHQEURXFNH -3 %HUWLQD 50 9HQRXV

WKURPERVLVGXHWRSRRUDQWLFRDJXODQWUHVSRQVHWRDFWLYDWHGSURWHLQ&/HLGHQ7KURPERSKLOLD

6WXG\/DQFHW  

  9DQGHQEURXFNH-3.RVWHU7%ULsW(5HLWVPD3+%HUWLQD505RVHQGDDO)5,QFUHDVHGULVN

RIYHQRXVWKURPERVLVLQRUDOFRQWUDFHSWLYHXVHUVZKRDUHFDUULHUVRIIDFWRU9/HLGHQPXWDWLRQ

/DQFHW1RY  

  +ROPHQ-0LGWKMHOO..UXJHU‘HWDO7KH1RUG7U¡QGHODJ+HDOWK6WXG\ +817

  2EMHFWLYHV FRQWHQWV PHWKRGV DQG SDUWLFLSDWLRQ 1RUZHJLDQ -RXUQDO RI (SLGHPLRORJ\



  1DHVV,$&KULVWLDQVHQ6&&DQQHJLHWHU6&5RVHQGDDO)5+DPPHUVWURHP-$SURVSHFWLYH

VWXG\RIDQWLFDUGLROLSLQDQWLERGLHVDVDULVNIDFWRUIRUYHQRXVWKURPERVLVLQDJHQHUDOSRSXODWLRQ

WKH+817VWXG\ -7KURPE+DHPRVW  

  'DKOElFN%&DUOVVRQ06YHQVVRQ3-)DPLOLDOWKURPERSKLOLDGXHWRDSUHYLRXVO\XQUHFRJQL]HG

PHFKDQLVPFKDUDFWHUL]HGE\SRRUDQWLFRDJXODQWUHVSRQVHWRDFWLYDWHGSURWHLQ&SUHGLFWLRQRID

FRIDFWRUWRDFWLYDWHGSURWHLQ&3URF1DWO$FDG6FL86$  

  +ROODQG30$EUDPVRQ5':DWVRQ5*HOIDQG'+'HWHFWLRQRIVSHFL¿FSRO\PHUDVHFKDLQ

UHDFWLRQ SURGXFW E\ XWLOL]LQJ WKH µµ H[RQXFOHDVH DFWLYLW\ RI 7KHUPXV DTXDWLFXV '1$

SRO\PHUDVH3URF1DWO$FDG6FL86$  

(15)



55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

55

  &XVKPDQ 0 <DQH] ' 3VDW\ %0 HW DO$VVRFLDWLRQ RI ¿EULQRJHQ DQG FRDJXODWLRQ IDFWRUV

9,,DQG9,,,ZLWKFDUGLRYDVFXODUULVNIDFWRUVLQWKHHOGHUO\WKH&DUGLRYDVFXODU+HDOWK6WXG\

&DUGLRYDVFXODU+HDOWK6WXG\,QYHVWLJDWRUV$P-(SLGHPLRO  

  'H /RUHQ]R ) 0XNKHUMHH 0 .DG]LROD = 6XOHLPDQ 6 .DNNDU 99$VVRFLDWLRQ RI RYHUDOO

DGLSRVLW\UDWKHUWKDQERG\PDVVLQGH[ZLWKOLSLGVDQGSURFRDJXODQWIDFWRUV7KURPE+DHPRVW

  

  0LxDQR$2UGyxH]$(VSDxD)HWDO$%EORRGJURXSDQGULVNRIYHQRXVRUDUWHULDOWKURPERVLV

LQ FDUULHUV RI IDFWRU 9 /HLGHQ RU SURWKURPELQ *$ SRO\PRUSKLVPV +DHPDWRORJLFD

  

  0RUHOOL90'H9LVVHU0&9RV+/%HUWLQD505RVHQGDDO)5$%2EORRGJURXSJHQRW\SHV

DQGWKHULVNRIYHQRXVWKURPERVLVHIIHFWRIIDFWRU9/HLGHQ-7KURPE+DHPRVW  

  2KLUD7&XVKPDQ07VDL0<HWDO$%2EORRGJURXSRWKHUULVNIDFWRUVDQGLQFLGHQFHRI

YHQRXV WKURPERHPEROLVP WKH /RQJLWXGLQDO ,QYHVWLJDWLRQ RI 7KURPERHPEROLVP (WLRORJ\

/,7( -7KURPE+DHPRVW  

  0RNGDG$+)RUG(6%RZPDQ%$HWDO3UHYDOHQFHRIREHVLW\GLDEHWHVDQGREHVLW\UHODWHG

KHDOWKULVNIDFWRUV-$0$  

  (LFKLQJHU6+URQ*%LDORQF]\N&HWDO2YHUZHLJKWREHVLW\DQGWKHULVNRIUHFXUUHQWYHQRXV

WKURPERHPEROLVP$UFK,QWHUQ0HG  

  *XQQHOO'%HUQH\/+ROODQG3HWDO+RZDFFXUDWHO\DUHKHLJKWZHLJKWDQGOHJOHQJWKUHSRUWHG

E\WKHHOGHUO\DQGKRZFORVHO\DUHWKH\UHODWHGWRPHDVXUHPHQWVUHFRUGHGLQFKLOGKRRG",QW-

(SLGHPLRO  

Referenties

GERELATEERDE DOCUMENTEN

,GLRSDWKLF ZDV GH¿QHG DV DQ LQLWLDO WKURPERWLF HYHQW WKDW RFFXUUHG LQ WKH DEVHQFH RI   SUHJQDQF\  SXHUSHULXP  RUDOFRQWUDFHSWLYHXVHZLWKLQGD\V

,W KDV EHHQ VXJJHVWHG WKDW WKH GLVFUHSDQF\ LQ UHFXUUHQFH ULVN EHWZHHQ WKH VH[HV FRXOG. EH H[SODLQHG E\ DQ DJH GLIIHUHQFH DW WKH WLPH RI WKH ¿UVW HYHQW

XVH $Q LGLRSDWKLF WKURPERWLF HYHQW ZDV GH¿QHG DV DQ LQLWLDO HYHQW WKDW RFFXUUHG LQ WKH. DEVHQFH RI SUHJQDQF\ SXHUSHULXP RUDO FRQWUDFHSWLYH XVH ZLWKLQ 

Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded

WKDW WKHVH SKHQRW\SHV GR QRW FDXVDOO\ DIIHFW WKH ULVN RI WKURPERVLV DQG UHÀHFW

Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded

JHYRQGHQ DVVRFLDWLH KHW UHVXOWDDW ZDV YDQ HHQ RQWVWHNLQJVUHDFWLH GLH GRRU GH WURPERVH. ]HOIZDVWHZHHJJHEUDFKW0HWRQ]HSURVSHFWLHYHRS]HW

Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded