Allogeneic haematopoietic stem cell donation and transplantation across the MHC class I barrier: "Faster is better than more. More is better than less".

Allogeneic haematopoietic stem cell donation and transplantation

across the MHC class I barrier: "Faster is better than more. More is

better than less".

Heemskerk, M.B.A.

Citation

Heemskerk, M. B. A. (2006, September 28). Allogeneic haematopoietic stem cell donation and transplantation across the MHC class I barrier: "Faster is better than more. More is better than less". Retrieved from https://hdl.handle.net/1887/4578

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/1887/4578

3

The importance of identifying a back-up donor for

unrelated stem cell transplantation

60YDQ:DOUDYHQ0%$+HHPVNHUN-/:7M/LH50<%DUJH--&RUQHOLVVHQ 50(JHOHU/)9HUGRQFN1:XOIIUDDW02XGVKRRUQ

54

Abstract

7KH LPSRUWDQFH RI LGHQWLI\LQJ D EDFNXS GRQRU RQFH D SULPDU\ VXLWDEOH XQUHODWHG VWHP FHOOGRQRUKDVEHHQIRXQGLVRIWHQXQGHUHVWLPDWHG7UDQVSODQWFHQWUHVHUURQHRXVO\FRXQWRQ WKHXQUHODWHGYROXQWHHUGRQRUVWREHZLOOLQJDYDLODEOHDQGPHGLFDO¿WIRUDFWXDOGRQDWLRQ $FFRUGLQJWRRXUGDWDZKLFKLQFOXGHVXQUHODWHGGRQRUZRUNXSSURFHGXUHVSHUIRUPHG IRU'XWFKSDWLHQWVEHWZHHQDQGRQHRXWRIHOHYHQZRUNXSVHQGHGLQWKH SULPDU\UHTXHVWHGGRQRUIDLOLQJWRGRQDWH2IDOOGRQRUUHODWHGFDQFHOODWLRQV1 RI WKHSURFHGXUHVZHUHGHIHUUHGGXHWRPHGLFDOUHDVRQVDQGGXHWRQRQPHGLFDOUHDVRQV 0RVWRIWKHGRQRUVGHIHUUHGIRUPHGLFDOUHDVRQVZHUHIHPDOHS ,QRIWKHFDVHV IRUZKLFKDEDFNXSGRQRUZDVDOUHDG\LGHQWL¿HGWKHSDWLHQWVZHUHWUDQVSODQWHGZLWKDGHOD\ RIOHVVWKHQWZRZHHNVZKHQQREDFNXSGRQRUZDVDYDLODEOHWKHPHGLDQGHOD\LQFUHDVHG WRZHHNV :HVWURQJO\HQFRXUDJHLPSOHPHQWLQJDVHDUFKIRUDWOHDVWRQHEDFNXSGRQRULQWKHSULPDU\ VHDUFK ,GHQWLI\LQJ D EDFNXS GRQRU FDQ VDYH SUHFLRXV WLPH DQG FRPSOLFDWHG ORJLVWLF UHVFKHGXOLQJ

Introduction

55

Materials and methods

7KHDQDO\VLVFRQFHUQHGWKHZRUNXSSURFHGXUHVIROORZLQJXQUHODWHGGRQRUVHDUFKHVIRU 'XWFKSDWLHQWVIDFLOLWDWHGE\WKH(XURSGRQRU)RXQGDWLRQLQWKH1HWKHUODQGVIURP WR  3DWLHQWV RULJLQDWHG IURP WKH IROORZLQJ WUDQVSODQW FHQWUHV WKH /HLGHQ 8QLYHUVLW\ 0HGLFDO&HQWUHQ DGXOWVFKLOGUHQ(UDVPXV0HGLFDO&HQWUH'DQLHO5RWWHUGDP Q DQGWKH8QLYHUVLW\0HGLFDO&HQWUH8WUHFKWQ DGXOWVFKLOGUHQ6WDWLVWLFDO DQDO\VLVZDVSHUIRUPHGLQ6366XVLQJ&KLVTXDUHWHVWDQG0DQQ:KLWQH\8WHVW 2XUVHDUFKFULWHULDLQFOXGH+/$PDWFKJUDGH&09VWDWXVGRQRUJHQGHUGRQRUDJHDQG $%2EORRGJURXSV\VWHP1_{&RQ¿UPDWRU\+/$W\SLQJDQGDGGLWLRQDOLPPXQRJHQHWLFWHVWLQJ} VXFKDV0L[HG/\PSKRF\WH&XOWXUH0/&DQG&\WR[LF/\PSKRF\WHSUHFXUVRUWHVW&7/S DUHSHUIRUPHGZLWKSRWHQWLDOGRQRUVDQGWKHEHVWPDWFKHGGRQRULVUHTXHVWHGIRUZRUNXS $ZRUNXSSURFHGXUHLQYROYHVWKHIRUPDOUHTXHVWIRUSK\VLFDOH[DPLQDWLRQDQGSUHSDUDWLRQ RIDGRQRUIRUVWHPFHOOKDUYHVW7KHWUDQVSODQWFHQWUHFDQH[SUHVVWKHSUHIHUHQFHIRUERQH PDUURZ RU VWLPXODWHG SHULSKHUDO EORRG VWHP FHOOV ZLWK WKH GHFLVLRQ EHLQJ GULYHQ ODUJHO\ E\WKHSDWLHQWFRQGLWLRQDQGGLVHDVHVWDJHRUFXUUHQWWUDQVSODQWSURWRFRO,WGHSHQGVRQWKH SROLF\RIWKHGRQRUUHJLVWU\DQGWKHZLOOLQJQHVVRIWKHGRQRUWRGHWHUPLQHLIWKLVUHTXHVWFDQ DQGZLOOEHIXO¿OOHG7KHWUDQVSODQWFHQWUHGHWHUPLQHVDWHQWDWLYHGDWHIRUWUDQVSODQWDWLRQ 7KHGRQRUFHQWUHFRQWDFWVWKHFKRVHQGRQRUIRUFRXQVHOOLQJDQGSK\VLFDOH[DPLQDWLRQDQG DUUDQJHVWKHGH¿QLWLYHGDWHIRUWKHVWHPFHOOKDUYHVW$WWLPHRIWKHZRUNXSUHTXHVWRIWKH EHVWPDWFKHGGRQRUWKHVHFRQGEHVWGRQRULVVHOHFWHGWREHWKHEDFNXSGRQRULQFDVHWKH¿UVW GRQRUIDLOVWRGRQDWH7KLVGRQRULVUHOHDVHGZLWKWKHUHPDLQLQJGRQRUVLQIRUPLQJWKHGRQRU UHJLVWU\WKDWKHVKHLVWKHEDFNXSGRQRU7KHGHWHUPLQDWLRQWRUHOHDVHWKLVEDFNXSGRQRUWR WKHZRUOGZLGHGRQRUSRROLVEDVHGRQWKHSROLFLHVRIHDFKLQGLYLGXDOGRQRUUHJLVWU\UDQJLQJ IURPLPPHGLDWHUHOHDVHWRDWHPSRUDU\UHPRYDOIURPWKHGRQRUSRROWRDZDLWWKHRXWFRPHRI WKHSULPDU\GRQRU¶VHYDOXDWLRQDQGFRQVHQW

Results

%HWZHHQDQGZRUNXSSURFHGXUHVZLWKXQUHODWHGVWHPFHOOGRQRUVIRU 'XWFKSDWLHQWVZHUHLQLWLDWHG2YHUDOOZRUNXSSURFHGXUHVZHUHFDQFHOOHG,QWRWDO ¿UVWWUDQVSODQWDWLRQVWZHQW\RQHVHFRQGWUDQVSODQWDWLRQVDQGWZRWKLUGWUDQVSODQWDWLRQVZHUH SHUIRUPHG,QWKLUW\VL[RIWKH¿UVWWUDQVSODQWDWLRQVDQGHOHYHQRIWKHVHFRQGWUDQVSODQWDWLRQV DEDFNXSGRQRUZDVDVNHGWRGRQDWHVWHPFHOOV7KHUHDVRQWRUHTXHVWWKHEDFNXSGRQRUDW WLPHRIVHFRQGWUDQVSODQWDWLRQZDVGHIHUUDORIWKH¿UVWGRQRULQRQHFDVHDQGSUHIHUHQFHRI WKHWUDQVSODQWFHQWUHLQWKHRWKHUFDVHV,QWRWDOGRQRUVZHUHLQYROYHGPDOHV IHPDOHVRIQLQHGRQRUVWKHJHQGHUZDVQRWUHSRUWHG

56

Cancellations

,Q   WKH ZRUN XS SURFHGXUH ZDV FDQFHOOHG GXH WR SDWLHQW UHODWHG UHDVRQV SULPDULO\ EHFDXVH WKH SDWLHQW ZDV QR ORQJHU HOLJLEOH IRU WUDQVSODQWDWLRQ ,Q   WKH GRQRU ZDV GHIHUUHG7DEOH  VKRZV WKH JURXQGV IRU GRQRU GHIHUUDO7KH\ ZHUH HLWKHU SHUVRQDOQ ¿YHPDOHDQG¿YHIHPDOHGRQRUVRUPHGLFDOQ PDOHDQGIHPDOH GRQRUV7KHSURSRUWLRQRIIHPDOHGRQRUVLQWKHODWWHUJURXSLVKLJKHUWKDQLQWKHJURXSRIDOO UHTXHVWHGGRQRUVS 5HDVRQVIRUGRQRUV¶PHGLFDOGHIHUUDOZHUHLQDQXPEHURIFDVHV VSHFL¿HG E\ WKH GRQRU FHQWUH DOWKRXJK WKH\ KDYH QR REOLJDWLRQ WR GR VR )HPDOH GRQRUV KDYHDQLQFUHDVHGUDWHRIGHIHUUDOIRUPHGLFDOUHDVRQVFRPSDUHGWRPDOHGRQRUVS  ,QWKLVVWXG\SUHJQDQF\LVFRQVLGHUHGDPHGLFDOUHDVRQIRUXQDYDLODELOLW\ZLWKUHJDUGVWR LQWHUQDWLRQDOUHJXODWLRQVIRUGRQRUHOLJLELOLW\

Table 1. Reasons for donor cancellation at time of work up

Reasons for cancellation VSHFL¿FDWLRQV PDOH IHPDOH

57 Back-up donor &RQIURQWDWLRQZLWKGRQRUGHIHUUDOGXULQJWKHZRUNXSVWDJHKDVOHGWRRXUFXUUHQWSROLF\WR DWWHPSWWRLGHQWLI\DGRQRUDQGDEDFNXSGRQRUIRUHDFKSDWLHQW2YHUDOOLQRI DOOH[DPLQHGZRUNXSSURFHGXUHVDSRWHQWLDOEDFNXSGRQRUZDVLGHQWL¿HGLQWKHLQLWLDOGRQRU VHDUFK7KHQXPEHURISDWLHQWVIRUZKRPDEDFNXSGRQRUZDVLGHQWL¿HGKDVLPSURYHGGXULQJ WKHSDVW\HDUV,QWKH¿UVW\HDUVDEDFNXSGRQRUZDVIRXQGIRURQO\RIWKH SDWLHQWV,QWKHODVWWKUHH\HDUVDEDFNXSGRQRUZDVLGHQWL¿HGIRURIDOO SDWLHQWV&XUUHQWO\RIRXUXQUHODWHGGRQRUVHDUFKHVUHVXOWLQWKHLGHQWL¿FDWLRQRIDEDFNXS GRQRUWDEOH,QWKHVHFDVHVDOORWKHUGRQRUVWHVWHGKDGWRRPDQ\PLVPDWFKHVWREHDFFHSWDEOH 7DEOH,PSURYHPHQWRIEDFNXSGRQRULGHQWL¿FDWLRQRYHUWLPH SHULRGLQWLPH SDWLHQWVZLWKDEDFNXSGRQRUZRUNXSV  1987-1989         WKHZRUNXSSURFHGXUHVXQWLOWKH-XQHDUHLQFOXGHG &KLVTXDUHWHVWS -7 ,QRIDOOFDVHVWKHEHVWGRQRUZDVGHIHUUHGDIWHUWKHIRUPDOUHTXHVWIRUSK\VLFDOH[DPLQDWLRQ DQGSUHSDUDWLRQIRUVWHPFHOOKDUYHVW)RUSDWLHQWVDQXQUHODWHGVWHPFHOOGRQRUVHDUFK KDG WR EH UHRSHQHG ,Q  RI WKH  FDQFHOOHGZRUN XS SURFHGXUHV D EDFNXS GRQRU KDG SUHYLRXVO\EHHQLGHQWL¿HG,QRIWKHVHFDVHVWKHEDFNXSGRQRUZDVUHTXHVWHGWRGRQDWH VWHPFHOOV7ZHQW\QLQHSDWLHQWVZHUHWUDQVSODQWHGZLWKWKLVEDFNXSGRQRUPRVWO\ZLWKRXW PDMRUGHOD\)RURQHSDWLHQWVWHPFHOOWUDQVSODQWDWLRQZDVQRORQJHUDQRSWLRQ)LYHRIWKH UHTXHVWHGEDFNXSGRQRUVZHUHQRWHOLJLEOHIRUVWHPFHOOGRQDWLRQGXHWRPHGLFDOUHDVRQV 7KH DEVHQFH RI D EDFNXS GRQRU FDQ FDXVH GHOD\ RU HYHQ FDQFHOODWLRQ RI WKH SUHIHUUHG WKHUDS\7KHUHJXODUWLPHGHOD\LQDZRUNXSSURFHGXUHLVGH¿QHGDVWKHGLIIHUHQFHLQGD\V EHWZHHQWKHWHQWDWLYHGDWHIRUWUDQVSODQWDWLRQDWWLPHRIWKHZRUNXSUHTXHVWDQGWKH¿QDO WUDQVSODQWDWLRQ GDWH7KH WUDQVSODQW FHQWUH SURSRVHV WKH WHQWDWLYH GDWH IRU WUDQVSODQWDWLRQ GHSHQGLQJRQWKHDYDLODELOLW\RIERWKWKHGRQRUDQGWKHFROOHFWLRQFHQWUHWKH¿QDOGDWHIRU FROOHFWLRQZLOOEHGHWHUPLQHGLQFRQVXOWDWLRQZLWKWKHWUDQVSODQWFHQWUH7KHPHGLDQGHOD\ RISDWLHQWVWUDQVSODQWHGZLWKWKHEHVWGRQRULVGD\VUDQJH2YHURIWKH¿UVW

58

WUDQVSODQWDWLRQVWRRNSODFHZLWKLQDSHULRGRIOHVVWKHQGD\VIURPWKHWHQWDWLYHGDWH7R LQYHVWLJDWHWKHGHOD\FDXVHGE\WKHGHIHUUDORIDGRQRUGXULQJWKHZRUNXSSURFHGXUHZH GHWHUPLQHG WKH GLIIHUHQFH LQ WKH ¿UVW WHQWDWLYH KDUYHVW GDWH DQG ¿QDO KDUYHVW GDWH ,Q  SDWLHQWVWUDQVSODQWHGZLWKDEDFNXSGRQRUDPHGLDQGHOD\RIGD\VUDQJHGD\V RFFXUUHG

,QFDQFHOOHGZRUNXSSURFHGXUHVQREDFNXSGRQRUKDGEHHQLGHQWL¿HGDQGDQHZXQUHODWHG GRQRUVHDUFKKDGWREHVWDUWHG6L[SDWLHQWVZHUHWUDQVSODQWHGZLWKDPHGLDQGHOD\RI GD\VUDQJHGD\V7KHRWKHUIRXUSDWLHQWVZHUHQRORQJHUHOLJLEOHIRUWUDQVSODQWDWLRQ $Q RYHUYLHZ RI WKH DGYDQWDJH LQ WLPH RI DQ LQLWLDOO\ LGHQWL¿HG EDFNXS GRQRU LV JLYHQ LQ 7DEOH

7DEOH7KHDGYDQWDJHLQWLPHRIDQLQLWLDOO\LGHQWL¿HGEDFNXSGRQRU7KHGHOD\LVGH¿QHGDVWKH GLIIHUHQFHEHWZHHQWHQWDWLYHDQG¿QDOKDUYHVWGDWH

PHGLDQGHOD\ range WUDQVSODQWHG best donor available

Q  GD\V GD\V 

best donor deferred:

EDFNXSGRQRUDYDLODEOHQ  GD\V GD\V  best donor deferred:

QREDFNXSGRQRUDYDLODEOHQ  GD\V GD\V 

Discussion

$VXFFHVVIXOXQUHODWHGGRQRUVHDUFKGRHVQRWJXDUDQWHHWKHDYDLODELOLW\RIWKHLGHQWL¿HGGRQRU IRUVWHPFHOOKDUYHVW'XULQJWKHLQLWLDOVHDUFK+/$W\SLQJDQGDGGLWLRQDOODERUDWRU\WHVWV DUHSHUIRUPHG7KHEHVWGRQRULVFKRVHQDQGUHTXHVWHGIRUVWHPFHOOGRQDWLRQWKHVHFRQG EHVWRUVRFDOOHGEDFNXSGRQRULVUHOHDVHG,WLVRXUH[SHULHQFHWKDWPRUHSDWLHQWVDUHQRZ UHIHUUHGWRXVIRUDQXUJHQWVHDUFKZLWKDQLQLWLDOSURSRVHGWLPHIUDPHIRUWUDQVSODQWDWLRQ ZLWKLQWRZHHNV7KLVLVOLNHO\DUHVXOWRIRXUVXFFHVVLQEHLQJDEOHWRORFDWHGRQRUVLQ DYHU\VKRUWQRWLFH_{DQGFKDQJHVLQFXUUHQWWUDQVSODQWDWLRQSUDFWLFH$YDULDWLRQEHWZHHQ}  GD\V LQ WKH SURSRVHG DQG ¿QDO KDUYHVW GDWH LV FRQVLGHUHG DFFHSWDEOH7KH SROLF\ WR VWUXFWXUDOO\LGHQWLI\DEDFNXSGRQRUZDVLQWURGXFHGLQLQRXUVHDUFKSURFHVV6LQFH WKHQWKHWRWDOQXPEHURILGHQWL¿HGEDFNXSGRQRUVIRU'XWFKSDWLHQWVKDVWULSOHGRYHUWKH \HDUV7KLVFRXOGEHDWWULEXWHGWRWKHLQFUHDVLQJQXPEHURIUHJLVWHUHGGRQRUVZRUOGZLGH7 _in FRPELQDWLRQZLWKRXUHYLGHQFHEDVHGVHDUFKVWUDWHJ\

59 ,Q  FDVHV WKH GRQRU FHQWUH FDQFHOOHG WKH ZRUN XS SURFHGXUH 7KH UHDVRQV IRU GRQRU FDQFHOODWLRQ ZHUH GLYLGHG LQ PHGLFDO DQG QRQPHGLFDO UHDVRQV $ VLJQL¿FDQW QXPEHU RI IHPDOH GRQRUV ZHUH GHIHUUHG GXH WR PHGLFDO UHDVRQV S  7KH SUHIHUHQFH IRU WKH VHOHFWLRQRIPDOHGRQRUVIRUVWHPFHOOWUDQVSODQWDWLRQZDVGLVFXVVHGEHIRUHLQUHODWLRQVKLS WRWUDQVSODQWUHODWHGPRUWDOLW\UHODSVHLQFLGHQFHDQG*UDIWYHUVXV+RVW'LVHDVH8-11_2QWKH EDVLVRIRXU¿QGLQJVDQGIDFWVDVGHVFULEHGLQWKHOLWHUDWXUHWKHWUDQVSODQWFHQWUHVSUHIHUPDOH WRIHPDOHGRQRUVLISRVVLEOH 7KHUHDVRQVIRUDPHGLFDOFDQFHOODWLRQDUHQRWDOZD\VVSHFL¿HGDOWKRXJKDGRQRUFHQWUH LVIUHHWRJLYHLQIRUPDWLRQWRWKHWUDQVSODQWFHQWUHLQWKLVSRLQW,QDQXPEHURIFDVHVWKH PHGLFDOUHDVRQZDVVSHFL¿HG2EHVLW\LVDPDMRUUHDVRQIRUGRQRUGHIHUUDODWGRQRUZRUNXS VWDJHDVDGRQRUZLWKVHULRXVREHVLW\VKRXOGEHGHIHUUHGDWOHDVWDWWKHWLPHRIFRQ¿UPDWRU\ +/$W\SLQJUHTXHVWEXWPRUHIDYRXUDEO\DWWKHWLPHRIUHFUXLWPHQWIRUWKHXQUHODWHGGRQRU UHJLVWU\'RQRUUHJLVWULHVVKRXOGJLYHPRUHDWWHQWLRQWRWKLVSRLQW 7KHUHZDVQRGLIIHUHQFHLQGRQRUJHQGHULQWKHQRQPHGLFDOUHDVRQV%HLQJXQDYDLODEOHDW WKHWLPHRIWKHZRUNXSUHTXHVWRUSHUVRQDOZLWKGUDZDOZHUHWKHPDLQUHDVRQV([WHQVLYH HGXFDWLRQDQGLQIRUPDWLRQRIWKHGRQRUPLJKWUHGXFHWKLVQXPEHURIFDQFHOODWLRQV,QWHUPV RIYROXQWHHUKLVWRU\LWZDVIRXQGWKDWVWHPFHOOGRQRUVZKRDUHDOVREORRGGRQRUVDUHOHVV OLNHO\WRGURSRXW3_{*HQHUDOO\WKHWUDQVSODQWFHQWUHLVQRWLQIRUPHGDERXWWKHEORRGGRQRU} VWDWXVRIXQUHODWHGVWHPFHOOGRQRUVWKHUHIRUHZHFRXOGQRWFRQ¿UPWKLV¿QGLQJ 7RGHWHUPLQHWKHEHQH¿WRILGHQWLI\LQJDEDFNXSGRQRULQWKHLQLWLDOVHDUFKWKHGHJUHHRI GHOD\LQDQRUPDOZRUNXSSURFHGXUHKDVEHHQHVWDEOLVKHG$GHOD\FDQEHEURXJKWDERXW E\HLWKHUGRQRUUHODWHGRUSDWLHQWUHODWHGUHDVRQV:HVKRZHGWKDWDGHOD\FDXVHGE\GRQRU GHIHUUDOFRXOGEHPLQLPLVHGE\LGHQWLI\LQJDEDFNXSGRQRU7KHEHQH¿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¶VFRQGLWLRQLQJUHJLPHQLVVWDUWHGDQGWKHWUDQVSODQWDWLRQLVGHIHUUHGGXHWRDGRQRU FDQFHOODWLRQDQGQREDFNXSGRQRULVDYDLODEOH

60

Conclusion and recommendations

61

References

 2XGVKRRUQ0&RUQHOLVVHQ--)LEEH:(HWDO3UREOHPV DQG SRVVLEOH VROXWLRQV3UREOHPVDQGSRVVLEOHVROXWLRQV

LQ¿QGLQJDQXQUHODWHGERQHPDUURZGRQRU5HVXOWVRIFRQVHFXWLYHVHDUFKHVIRU'XWFK SDWLHQWV%RQH0DUURZ7UDQVSODQW20  6WURQFHN'5HVXOWVRIERQHPDUURZWUDQVSODQWVIURPXQUHODWHGGRQRUV7UDQVIXVLRQ 32  6ZLW]HU*('HZ0$6WXNDV$$*R\FRROHD-0+HJODQG-6LPPRQV5*)DFWRUVDV-VRFLDWHGZLWKDWWULWLRQIURPDQDWLRQDOERQHPDUURZUHJLVWU\%RQH0DUURZ7UDQVSODQW 24: 313-319

 .ROOPDQ&:HLV76ZLW]HU*(HWDO1RQ+/$ EDUULHUV WR XQUHODWHG GRQRU VWHP FHOO1RQ+/$EDUULHUVWRXQUHODWHGGRQRUVWHPFHOO WUDQVSODQWDWLRQ%RQH0DUURZ7UDQVSODQWDWLRQ27

 2XGVKRRUQ0)DONHQEXUJ-+)(EHOLQJ/-HWDO8QUHODWHG ERQH PDUURZ WUDQVSODQWD 8QUHODWHGERQHPDUURZWUDQVSODQWD-WLRQDVDUHVFXHSURFHGXUHIROORZLQJLQDGYHUWHQWORVVRIDQDXWRORJRXVERQHPDUURZJUDIW %RQH0DUURZ7UDQVSODQW 18

 +HHPVNHUN0%$9DQ:DOUDYHQ60&RUQHOLVVHQ--HWDO+RZ WR LPSURYH WKH VHDUFK IRU+RZWRLPSURYHWKHVHDUFKIRU DQXQUHODWHGKDHPDWRSRLHWLFVWHPFHOOGRQRU)DVWHULVEHWWHUWKDQPRUH6XEPLWWHGIRU SXEOLFDWLRQWR%RQH0DUURZ7UDQVSODQW  %RQH0DUURZ'RQRUV:RUOGZLGHZZZ%0':RUJ  *UDWZRKO5+HUPDQV-1LHGHUZLHVHU'YDQ%LH]HQ$YDQ+RXZHOLQJHQ+&$SSHUOH\ -)HPDOHGRQRUVLQÀXHQFHWUDQVSODQWUHODWHGPRUWDOLW\andUHODSVHLQFLGHQFHLQPDOHUH-FLSLHQWVRIVLEOLQJEORRGDQGPDUURZWUDQVSODQWV7KH+HPDWRO-2  .ROOPDQ&+RZH&:$QDVHWWL&HWDO'RQRUFKDUDFWHULVWLFVDVULVNIDFWRUVLQUHFLSL-HQWVDIWHUWUDQVSODQWDWLRQRIERQHPDUURZIURPXQUHODWHGGRQRUVWKHHIIHFWRIGRQRUDJH %ORRG2FW98  2WWLQJHU+'0XOOHU&5*ROGPDQQ5)HWDO6HFRQG*HUPDQFRQVHQVXVRQLPPXQR-JHQHWLFGRQRUVHDUFKIRUDOORWUDQVSODQWDWLRQRIKDHPDWRSRLHWLFVWHPFHOOV$QQ+HPDWRO.   +XUOH\&.)HUQDQGH]9LQD06HWWHUKROP00D[LPL]LQJRSWLPDOKDHPDWRSRLHWLFVWHP FHOOGRQRUVHOHFWLRQIURPUHJLVWULHVRIXQUHODWHGDGXOWYROXQWHHUV7LVV$QW