of 139 /139
Simultaneous determination of specimen composition and thickness using the Transmission Electron Microscope Citation for published version (APA): Boon, G. (2000). Simultaneous determination of specimen composition and thickness using the Transmission Electron Microscope. Eindhoven: Technische Universiteit Eindhoven. https://doi.org/10.6100/IR529745 DOI: 10.6100/IR529745 Document status and date: Published: 01/01/2000 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 24. Jun. 2020

Simultaneous determination of specimen composition and ... · FRQWHQWV 915 Sureohpvdqgwkhluvroxwlrqv 11111111111111111111111 :5 91514 HGVwdnhr>dqjoh 1111111111111111111111111 :5 91515

  • Author

  • View

  • Download

Embed Size (px)

Text of Simultaneous determination of specimen composition and ... · FRQWHQWV 915...

  • Simultaneous determination of specimen composition andthickness using the Transmission Electron MicroscopeCitation for published version (APA):Boon, G. (2000). Simultaneous determination of specimen composition and thickness using the TransmissionElectron Microscope. Eindhoven: Technische Universiteit Eindhoven. https://doi.org/10.6100/IR529745


    Document status and date:Published: 01/01/2000

    Document Version:Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers)

    Please check the document version of this publication:

    • A submitted manuscript is the version of the article upon submission and before peer-review. There can beimportant differences between the submitted version and the official published version of record. Peopleinterested in the research are advised to contact the author for the final version of the publication, or visit theDOI to the publisher's website.• The final author version and the galley proof are versions of the publication after peer review.• The final published version features the final layout of the paper including the volume, issue and pagenumbers.Link to publication

    General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.

    • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal.

    If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, pleasefollow below link for the End User Agreement:www.tue.nl/taverne

    Take down policyIf you believe that this document breaches copyright please contact us at:[email protected] details and we will investigate your claim.

    Download date: 24. Jun. 2020


  • Vlpxowdqhrxv ghwhuplqdwlrq ri vshflphq

    frpsrvlwlrq dqg wklfnqhvv xvlqj wkh Wudqvplvvlrq

    Hohfwurq Plfurvfrsh


    whu yhunulmjlqj ydq gh juddg ydq grfwru ddq gh Whfkqlvfkh XqlyhuvlwhlwHlqgkryhq/ rs jh}dj ydq gh Uhfwru Pdjql?fxv/ suri1gu1 P1 Uhp/ yrruhhq frpplvvlh ddqjhzh}hq grru khw Froohjh yrru Surprwlhv lq khw

    rshqeddu wh yhughgljhq rsgrqghugdj 53 mdqxdul 5333 rp 49133 xxu


    Jhuehq Errq

    jheruhq wh Ur}hqexuj

  • Glw surhivfkuliw lv jrhgjhnhxug grru gh surprwruhq=

    suri1gu1 U1 Phwvhodduhqsuri1gu1 G1E1 Zlooldpv

    Frsurprwru=gu1lu1 J1I1 Edvwlq

    Guxn= Xqlyhuvlwhlwvguxnnhulm/ Whfkqlvfkh Xqlyhuvlwhlw HlqgkryhqNdiwrqwzhus= Jhuehq Errq


    Vlpxowdqhrxv ghwhuplqdwlrq ri vshflphq frpsrvlwlrq dqg wklfnqhvv xvlqj wkhwudqvplvvlrq hohfwurq plfurvfrsh 2 e| Jhuehq Errq1 0 Hlqgkryhq = WhfkqlvfkhXqlyhuvlwhlw Hlqgkryhq/ 53331Surhivfkuliw1 0 LVEQ

  • Lq d fdu |rx*uh dozd|v lq d frpsduwphqw/ dqg ehfdxvh |rx*uh xvhg wr lw|rx grq*w uhdol}h wkdw wkurxjk wkdw fdu zlqgrz hyhu|wklqj |rx vhh lv mxvw pruh WY1

    +U1P1 Sluvlj/ ]hq dqg wkh Duw ri Prwruf|foh Pdlqwhqdqfh1,

    ddq plmq rxghuv

  • ly

  • Frqwhqwv

    4 Lqwurgxfwlrq 4414 Surmhfw hqylurqphqw 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4415 Txdqwlwdwlyh hohfwurq plfurvfrs| 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4

    41514 Fkhplfdo dqdo|vlv zlwk dq hohfwurq plfurvfrsh 1 1 1 1 1 1 1 1 1 441515 Wudqvplvvlrq hohfwurq plfurvfrshv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 541516 Wzr gl>huhqw dssurdfkhv wr wklq dqdo|vlv 1 1 1 1 1 1 1 1 1 1 1 1 641517 Wkh ehvw ri erwk zruogv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8

    5 Txdqwlwdwlyh dqdo|vlv +wkhru|, <514 Lqwurgxfwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 <515 Dq ryhuylhz ri sk|vlfdo hyhqwv lq uhodwlrq wr txdqwlwdwlyh dqdo|vlv 1 1 1 43516 Hohfwurq vfdwwhulqj hyhqwv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 46

    51614 Hodvwlf vfdwwhulqj 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4651615 Lqhodvwlf vfdwwhulqj 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 46

    517 [0ud| jhqhudwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4751714 Wklq ?op 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4751715 Exon vshflphq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 47

    518 [0ud| hplvvlrq dqg ghwhfwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 48

    6 Pdwul{ fruuhfwlrq prghov= Exon 4<614 Lqwurgxfwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4<615 Exon prghov 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 53616 * +ã}, fxuyhv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 54

    61614 Sursrvhg prghov 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 5461615 Frpelqlqj wkh ] dqg D fruuhfwlrq idfwruv 1 1 1 1 1 1 1 1 1 1 1 1 56

    617 Jdxvvldq edvhg * +ã}, prghoolqj 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 57618 Grxeoh Jdxvvldq prgho 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 57

    61814 Gh?qlwlrq riU* +ã}, jhqhudwhg dqg hplwwhg1 1 1 1 1 1 1 1 1 1 1 59



    61815 Vxppdu| ri wkh grxeoh Jdxvvldq prgho 1 1 1 1 1 1 1 1 1 1 1 1 1 66

    7 Pdwul{ fruuhfwlrq prghov iru wkh xvh lq wklq ?opv 6<714 Lqwurgxfwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 6<715 * +ã}, prghoolqj xvhg iru wklq ?op dqdo|vlv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 73

    71514 Edvlf sulqflsohv= d wklq ?op ri nqrzq frpsrvlwlrq dqg wklfnqhvvrq d vxevwudwh ri nqrzq frpsrvlwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 73

    71515 Uhyhuvh fdvh= Xqnqrzq ?op wklfnqhvv zlwk nqrzq frpsrvl0wlrqv/ xvlqj phdvxuhg n0udwlrv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 77

    71516 Ilop ri xqnqrzq wklfnqhvv dqg frpsrvlwlrq/ xqvxssruwhg ru rqnqrzq vxevwudwh 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 78

    71517 Rwkhu/ pruh frpsoh{ fdvhv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 79

    8 Txdqwlwdwlyh dqdo|vlv lq WHP 7<814 Lqwurgxfwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 7<

    81414 Dqdo|vlv frqglwlrqv lq wkh WHP 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 83815 Prghov xvhg iru txdqwlwdwlyh dqdo|vlv lq wkh WHP 1 1 1 1 1 1 1 1 1 1 1 1 84

    81514 Fol>0Orulphu 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8481515 H{wudsrodwlrq Phwkrg 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8781516 G[D phwkrg 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8881517 Sdudphwhuohvv fruuhfwlrq phwkrg e| ydq Fdsshoohq 1 1 1 1 1 1 1 8981518 í0idfwru dssurdfk +í0G[D, 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 89

    816 Xvlqj d ixoo pdwul{ fruuhfwlrq surfhgxuh 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8:81614 Prqwh Fduor vlpxodwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8:81615 * +ã}, wklq ?op dqdo|vlv surfhgxuh/ dv sursrvhg lq wklv Wkhvlv 1 8:

    817 Qhhg iru vwdqgdugv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8;81714 Ehdp fxuuhqw phdvxuhphqw 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8<

    818 Phwkrgv iru vdpsoh wklfnqhvv ghwhuplqdwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8<819 Frpsdulvrq ri wkh dqdo|vlv phwkrgv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 94

    81914 Phwkrgv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 9481915 Dssur{lpdwlrqv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 9581916 Devruswlrq fruuhfwlrq1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 9581917 Sdudphwhuohvv phwkrgv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 9681918 Ixoo pdwul{ fruuhfwlrq phwkrgv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 9781919 Rxu * +ã}, phwkrg 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 97

    9 H{shulphqwdo surfhgxuhv 9<914 Lqwurgxfwlrq wr htxlsphqw dqg dqdo|wlfdo phdvxuhphqwv 1 1 1 1 1 1 1 1 :3

    91414 Lqlwldo vhwxs ri wkh WHP 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :3



    915 Sureohpv dqg wkhlu vroxwlrqv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :591514 HGV wdnhr> dqjoh 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :591515 Xvlqj exon vwdqgdugv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :591516 Ehdp fxuuhqw dqg vwdelolw| 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :691517 HGV vwdelolw| 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :7

    916 Qhz ehdp fxuuhqw phwhu 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :791614 SFG ghvljq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :791615 Fxuuhqw phwhu 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :9

    917 Fkrlfh ri v|vwhpv xvhg iru whvwlqj wkh * +ã}, wklq ?op prgho1 1 1 1 1 1 :991714 Exon vshflphq frpsrvlwlrqv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ::91715 Xvhg suhsdudwlrq whfkqltxhv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ::91716 Vwdqgdugv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :;

    918 Vriwzduh 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 :<919 Ilqdo vhwxs 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ;3

    : Uhvxowv ;8:14 Lqwurgxfwlrq 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ;8:15 Htxlsphqw whvw 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ;9

    :1514 Ehdp fxuuhqw phwhulqj 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ;9:1515 HGV olqhdulw| 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ;:

    :16 Exon dqdo|vlv whvwv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ;;:17 WHP wklq ?op dqdo|vlv whvwv 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1


    D Olvw ri v|perov dqg deeuhyldwlrqv 44<

    Vxppdu| 456

    Vdphqydwwlqj 458

    Qdzrrug 45:

    Fxuulfxoxp Ylwdh 45<


  • Fkdswhu 4


    414 Surmhfw hqylurqphqw

    Wkh uhvhdufk ghvfulehg lq wklv wkhvlv zdv fduulhg rxw zlwklq wkh Ghsduwphqw riVrolg0Vwdwh dqg Pdwhuldov Fkhplvwu| dw Hlqgkryhq Xqlyhuvlw| ri Whfkqrorj| lq WkhQhwkhuodqgv1 Wkh surmhfw zdv ?qdqfhg e| VRQ +Irxqgdwlrq iru Fkhplfdo Uhvhdufklq Wkh Qhwkhuodqgv,/ zklfk lv ?qdqfhg e| QZR +Wkh Qhwkhuodqgv Uhvhdufk Frxqflo,1

    Wkh Ghsduwphqw kdv vhyhudo hohfwurq plfurvfrshv wr shuirup fkhplfdo +frp0srvlwlrqdo, dqg vwuxfwxudo dqdo|vlv/ sulpdulo| xvhg lq wkh uhvhdufk rq vrolg vwdwhfkhplvwu| dqg pdwhuldov vflhqfh1 Lq wkh frxuvh ri wkhvh lqyhvwljdwlrqv d orw ri h{0shulhqfh zdv jdwkhuhg lq wkh ?hog ri dqdo|wlfdo hohfwurq plfurvfrs|1

    415 Txdqwlwdwlyh hohfwurq plfurvfrs|

    41514 Fkhplfdo dqdo|vlv zlwk dq hohfwurq plfurvfrsh

    Lq d Vfdqqlqj Hohfwurq Plfurvfrsh/ VHP/ wkh vshflphq lv erpedughg e| hohfwurqviurp d ?qho| irfxvhg hohfwurq ehdp1 E| vfdqqlqj wkh ehdp ryhu wkh vshflphq/ vxuidfhlpdjhv fdq eh rewdlqhg dw kljk pdjql?fdwlrqv +w|slfdoo| xs wr 4331333 {,1 Wkhhohfwurqv shqhwudwh wkh vshflphq dqg froolgh zlwk wkh dwrpv ri wkh vshflphq pdwhuldo1Lq wklv surfhvv/ zklfk zloo eh ghvfulehg lq pruh ghwdlohg lq wkh qh{w fkdswhu/ [0ud|v duh jhqhudwhg lq wkh vshflphq dqg fdq eh hplwwhg iurp lw1 E| dqdo|vlqj wkhhqhuj| glvwulexwlrq +wkh zdyhohqjwk, dqg wkh lqwhqvlw| ri wklv udgldwlrq/ zh fdq rewdlqlqirupdwlrq derxw wkh fkhplfdo frpsrvlwlrq ri wkh qhdu vxuidfh od|hu ri wkh vshflphq1Sorwwlqj wkh [0ud| lqwhqvlw| yhuvxv lwv hqhuj|/ dv vkrzq lq Iljxuh 414/ surylghv d


  • Fkdswhu 41 Lqwurgxfwlrq











    3 5 7 9 ; 43 45 47 49 4; 53(QHUJ\#+NH9,






    Iljxuh 4141 D w|slfdo HGV vshfwuxp ri d Do6]u7 vshflphq/ uhfrughg lq rxuWudqvplvvlrq Hohfwurq Plfurvfrsh +WHP, dw 453 nY1

    fkhplfdo ?qjhusulqw ri wkh dqdo|vhg pdwhuldo1Xqiruwxqdwho|/ wkh surfhvvhv ri jhqhudwlrq ri [0ud|v zlwklq wkh vshflphq dqg

    wkdw ri hplvvlrq iurp lw/ duh frpsoh{1 Zh fdq rqo| jdwkhu lqgluhfw lqirupdwlrquhjduglqj wkh vxemhfw e| phdvxulqj wkh hplwwhg [0ud| lqwhqvlwlhv1 D prgho kdv wr ehxvhg wr fdofxodwh wkh vshflphq frpsrvlwlrqv iurp wkh revhuyhg [0ud| hplvvlrqv= dvr0fdoohg *pdwul{0fruuhfwlrq* prgho1

    Hohfwurq plfurvfrshv/ vshfldoo| exlow iru wklv dqdo|vlv sxusrvh/ duh wkh HohfwurqSureh Plfur Dqdo|vhuv +HSPD*v,1 Dowkrxjk wkh odwhudo uhvroxwlrq lq wkhvh lqvwux0phqwv fdq eh lq wkh rughu ri vhyhudo qdqrphwhuv/ wkh vpdoohvw dqdo|vlv yroxph lv olplwhgwr d plqlpxp ri derxw 4 çp61 Wkh uhdvrq iru wklv lv/ wkdw wkh hohfwurqv vsuhdg rxw lqdoo gluhfwlrqv rqfh wkh| duh lq wkh pdwhuldo1 Iru wkhvh w|shv ri dqdo|wlfdo plfurvfrshv/pdwul{0fruuhfwlrq prghov ri yhu| kljk shuirupdqfh kdyh ehhq ghyhorshg1

    41515 Wudqvplvvlrq hohfwurq plfurvfrshv

    Wkh frqfhsw ri d Wudqvplvvlrq Hohfwurq Plfurvfrsh/ d WHP/ lv voljkwo| gl>huhqw iurpd VHP ru HSPD1 E| xvlqj d yhu| wklq vshflphq dqg d pxfk kljkhu dffhohudwlrq


  • Txdqwlwdwlyh hohfwurq plfurvfrs| 4151

    yrowdjh +w|slfdoo| 53 nY iru HSPD dqg 433 0 633nY iru WHP,/ wkh hohfwurqv fdqhdvlo| wudyho wkurxjk wkh vshflphq1 Wkh lpdjh lv rewdlqhg e| surmhfwlqj wkh hohfwurqvwkdw wudyhoohg wkurxjk wkh vshflphq rqwr d vfuhhq1 Wklv fdq hlwkhu eh grqh e| xvlqjd sdudooho ehdp +frpsdudeoh wr d volgh surmhfwru,/ ru e| vfdqqlqj wkh vshflphq zlwkwkh hohfwurq ehdp +Vfdqqlqj WHP/ VWHP,1

    Wkhvh plfurvfrshv doorz xv wr pdnh lpdjhv dw dq hyhq kljkhu pdjql?fdwlrq +xswr vhyhudo ploolrq wlphv,/ grzq wr dwrplf ohyhov1 Pruhryhu/ wkh dqdo|vlv yroxph lq dqHSPD +wkh yroxph zlwklq wkh vshflphq lq zklfk [0ud|v duh jhqhudwhg, lv d whdugursru erwwoh vkdshg zlwk d zlgwk ri derxw 4 çp/ zkloh lq wkh WHP/ zkhuh d wklq ?opvshflphq lv xvhg/ rqo| wkh qhfn ri wkh erwwoh lv lq wkh vshflphq/ dqg wkhuhiruh/ wkhzlgwk ri dqdo|vlv yroxph zloo rqo| eh voljkwo| odujhu wkdq wkh hohfwurq ehdp gldphwhu1Khqfh/ dqdo|vlv dw wkh qdqrphwhu ohyho lv srvvleoh1

    41516 Wzr gl>huhqw dssurdfkhv wr wklq dqdo|vlv

    Txdqwlwdwlyh dqdo|vlv xvlqj wkh WHP

    Li wkh WHP vshflphqv duh yhu| wklq +w|slfdoo| ? 83 qp,/ wkhuh lv dq doprvw olqhduuhodwlrq ehwzhhq wkh lqwhqvlw| ri wkh [0ud|v/ fkdudfwhulvwlf iru d fhuwdlq hohphqw/ dqglwv frqfhqwudwlrq1 Wkhuhiruh/ frpsoh{ pdwul{ fruuhfwlrq prghov duh qrw frpprqo|xvhg lq dqdo|wlfdo WHP1 Lqvwhdg/ wkh vr0fdoohg *wklq0?op dssur{lpdwlrq* lv xvhg/ lqzklfk lw lv dvvxphg wkdw wkh [0ud| jhqhudwlrq lv xqlirup wkurxjkrxw wkh ?op dqg wkdwdoo jhqhudwhg [0ud|v zloo dovr eh hplwwhg iurp wkh vshflphq1 Vrph pruh h{whqghgprghov duh dovr edvhg rq wklv wklq ?op dssur{lpdwlrq/ exw dsso| dq dgglwlrqdo fru0uhfwlrq iru devruswlrq ri wkh jhqhudwhg [0ud|v lq wkh vshflphq/ ghshqghqw rq lwvwklfnqhvv1 Lw vkrxog eh fohdu wkdw vxfk fruuhfwlrqv duh rqo| dssolfdeoh zlwklq fhuwdlqolplwv ^4`1

    Iljxuh 415 vkrzv dq h{dpsoh ri frpsrvlwlrq fdofxodwlrq xvlqj wkh wklq ?opdssur{lpdwlrq1 Gh ruljlqdo hplvvlrq gdwd iru wkh Do0N dqg Ql0N udgldwlrq hplwwhgiurp d DoQl vshflphq zdv edvhg rq vlpxodwlrq xvlqj Edvwlq*v qhzhvw WID surjudp^5`/ dv ghvfulehg lq vhfwlrq 7151 Lq wkh ?jxuh/ wkh vrolg olqh uhsuhvhqwv wkh frpsrvlwlrqydoxhv rewdlqhg iurp fdofxodwlrqv zlwk wkh edvlf Fol>0Orulphu phwkrg xvlqj wkh wklq?op dssur{lpdwlrq +^6`/ vhh vhfwlrq 81514,1 Wkh nDoQl ydoxh zdv rewdlqhg xvlqj wkh?uvw gdwd srlqw zlwk wkh vpdoohvw ?op wklfnqhvv1

    Wkh grwwhg olqh vkrzv wkh fdofxodwhg frpsrvlwlrq ydoxhv diwhu dsso|lqj de0vruswlrq fruuhfwlrq +vhh htxdwlrq 818 dqg 81; lq vhfwlrq 81514,1 Lq wklv fdvh wkhh{wudsrodwlrq phwkrg zdv xvhg wr rewdlq wkh nDoQl ydoxh iru }hur ?op wklfnqhvv+xvlqj gdwd srlqwv dw 433 dqg 533 qp/ vhh vhfwlrq 81515,1 Lw vkrxog eh qrwhg wkdw wkhfrpsrvlwlrq edvhg rq vwrlfklrphwu| zdv xvhg wr fdofxodwh wkh frpelqhg devruswlrq


  • Fkdswhu 41 Lqwurgxfwlrq











    3 833 4333 4833 53337KLFNQHVV#+QP,


    3435363738393:3;30Orulphu phwkrg/ zlwkrxw +vrolg olqh, dqg zlwk +grwwhg olqh, devruswlrq fruuhfwlrq1Wkh ruljlqdo [0ud| hplvvlrq gdwd iru Do0N udgldwlrq lq DoQl dw 493 nY dqg :3ï wdnhr>dqjoh zhuh rewdlqhg e| vlpxodwlrq zlwk wkh WID

  • Txdqwlwdwlyh hohfwurq plfurvfrs| 4151

    Txdqwlwdwlyh dqdo|vlv xvlqj wkh HSPD

    Rq wkh rwkhu kdqg/ wkhuh duh dovr wklq ?op surjudpv ghyhorshg iru xvh rq wkh HSPD1Lq wkh pdmrulw| ri fdvhv wkhvh surjudpv duh phdqw iru wkh dqdo|vlv ri wklq ?opv+frdwlqjv, ghsrvlwhg rqwr d vxevwudwh1 Wkh lqflghqw hohfwurqv pd| eh vfdwwhuhg d vpdoodprxqw e| wkh wklq ?op/ exw duh dovr vfdwwhuhg e| wkh vxevwudwh/ dqg fdq hyhq ehvfdwwhuhg edfn lqwr wkh wklq ?op rq wrs1 Wkhvh frpsoh{ v|vwhpv fdq rqo| eh kdqgohge| xvlqj pdwul{ fruuhfwlrq prghov wkdw xvh d ghswk ghshqghqw [0ud| glvwulexwlrqixqfwlrq/ d vr fdoohg * +ã}, fxuyh1

    Wzr gl>huhqw dssurdfkhv

    Khqfh/ wkhuh duh wzr dssurdfkhv iru wklq ?op dqdo|vlv= rqh ruljlqdwlqj iurp wkh WHPzruog/ edvhg rq wklq ?op dssur{lpdwlrqv dqg h{whqghg zlwk fruuhfwlrqv iru devrus0wlrq1 Wkh rwkhu dssurdfk/ ruljlqdwlqj iurp wkh HSPD zruog1 Wkhvh duh hvvhqwldoo|h{whqvlrqv ri exon pdwul{ fruuhfwlrq surjudpv/ zklfk kdyh ixuwkhu ehhq ghyhorshg iruwklq ?op dssolfdwlrqv1 Wkh *SUR]D* surjudp ghyhorshg lq rxu jurxs lv dq h{dpsoh riwklv= lw lv ixuwkhu ghyhorshg wr d wklq ?op dqdo|vlv surjudp +WID,/ dqg hyhq h{whqghgwr ghdo zlwk dqdo|vlv ri vxevwudwh0ohvv/ xqvxssruwhg wklq ?opv1

    41517 Wkh ehvw ri erwk zruogv

    Iru wklv wkhvlv/ zh wulhg wr dsso| wkh pdwul{ fruuhfwlrq prghov/ ruljlqdwlqj iurp wkhHSPD dqdo|vhv/ wr WHP wklq ?op dqdo|vlv/ wkxv frpelqlqj *wkh ehvw ri erwk zruogv*=wkh kljk odwhudo dqdo|wlfdo uhvroxwlrq ri wkh WHP dqg wkh delolw| ri wkh HSPD wrkdqgoh vshflphqv ri d odujh udqjh lq wklfnqhvv1 Wkh HSPD prghov pdnh xvh ri exonvwdqgdugv/ xvxdoo| sxuh hohphqwv/ zklfk duh hdv| wr suhsduh dqg kdqgoh1 Wklv lvlq frqwudvw wr wkh WHP prghov/ zkhuh pxowl0hohphqw wklq ?op vwdqgdugv ri h{dfwo|nqrzq frpsrvlwlrq duh uhtxluhg1

    Lq rxu jurxs/ pdq| |hduv ri uhvhdufk lqwr pdwul{ fruuhfwlrq prghov iru HSPDxvh kdg douhdg| ehhq shuiruphg1 Xqwlo qrz/ wkh HSPD pdwul{ fruuhfwlrq prghovfrxog rqo| eh whvwhg wr derxw 73 nY> wkh| zhuh qhyhu dssolhg lq wkh WHP1 Dw ?uvwvljkw/ wkhuh vhhpv wr eh dq dpd}lqj gl>huhqfh lq dffhohudwlrq yrowdjh ehwzhhq wkhvhdssolfdwlrqv= dq HSPD xvhv yrowdjhv xs wr 73 nY/ zkloh d WHP xvhv yrowdjhv iurp ;3wr 533 nY/ ru hyhq kljkhu +wkh pd{lpxp iru rxu WHP lv 533 nY,1 Krzhyhu/ d pdmrusdudphwhu lqvlgh d pdwul{ fruuhfwlrq prgho lv wkh *ryhuyrowdjh udwlr*/ X3 @ [email protected]/zkhuh H3 lv wkh dssolhg dffhohudwlrq yrowdjh/ dqg Hf lv wkh plqlpxp dffhohudwlrqyrowdjh qhhghg wr jhqhudwh wkh fkdudfwhulvwlf [0ud|v iru wkh hohphqw ri lqwhuhvw +fulwlfdoh{flwdwlrq yrowdjh,1 Uhjduglqj wklv ryhuyrowdjh/ wkh gl>huhqfh ehwzhhq HSPD xowud0oljkw hohphqw dqdo|vlv dqg WHP lv qrw vr odujh1 Diwhu doo/ zkhq dqdo|vlqj dq xowud0oljkw


  • Txdqwlwdwlyh hohfwurq plfurvfrs| 4151

    hohphqw olnh Erurq +zlwk Hf @ 3=4;8 nhY, lq dq HSPD dw 53 nY/ X3 zloo eh lq wkhrughu ri 433/ dqg X3 kdv doprvw wkh vdph ydoxh/ zkhq dqdo|vlqj d phglxp oljkwhohphqw olnh Do +zlwk Hf @ 4=7;: nhY, lq wkh WHP/ dw 493 nY1

    Ixuwkhupruh wkh fruuhfwlrq prghov/ ghyhorshg lq rxu jurxs/ fdq dovr eh xvhg irudqdo|vlv ri wklq ?opv rq ydulrxv vxevwudwhv ru hyhq xqvxssruwhg/ dqg wkxv dssurdfkwkh WHP frq?jxudwlrq1 Wkh| fdq ghwhuplqh erwk ?op frpsrvlwlrq dqg wklfnqhvvvlpxowdqhrxvo| iurp rqo| rqh phdvxuhphqw dw rqh sduwlfxodu dffhohudwlrq yrowdjh/dqg duh suryhq wr shuirup zhoo iru oljkw hohphqwv dv zhoo dv iru wklq ?op dqdo|vlv/ wkdwlv/ lq wkh HSPD/ ri frxuvh1

    Frqvlghulqj wkhvh idfwv/ zh zhuh ri wkh rslqlrq wkdw wkh prghov ghyhorshg lqrxu jurxs dqg lpsohphqwhg lqwr wzr surjudpv/ *SUR]D

  • Eleolrjudsk|

    ^4` ]hqml Krulwd1 Ryhuylhz= Txdqwlwdwlyh {0ud| plfurdqdo|vlv lq wkh dqdo|wlfdo hohfwurqplfurvfrs|1 Pdwhuldov Wudqvdfwlrqv/ MLP/ 6



  • Fkdswhu 5

    Txdqwlwdwlyh dqdo|vlv +wkhru|,

    514 Lqwurgxfwlrq

    Lq hohfwurq sureh plfurdqdo|vlv/ d vpdoo yroxph ri wkh vshflphq wr eh dqdo|vhg lvluudgldwhg zlwk dq hohfwurq ehdp lq rughu wr jhqhudwh fkdudfwhulvwlf [0ud|v1 Iurpwkh zdyhohqjwkv dqg lqwhqvlwlhv ri wkhvh [0ud|v/ wkh hohphqwv suhvhqw lq wkh vshflphqpd| eh lghqwl?hg dqg wkhlu frqfhqwudwlrqv fdofxodwhg1

    Lq vxfk d txdqwlwdwlyh dqdo|vlv/ wkh prvw lpsruwdqw wklqj wr uhdolvh lv wkhfrpsoh{ qdwxuh ri wkh surfhvv ri lqwhudfwlrq ehwzhhq wkh hohfwurq ehdp dqg wkhvshflphq1 Pdq| surfhvvhv fdq wdnh sodfh/ dqg deryh doo/ wkh surfhvvhv lq xhqfhhdfk rwkhu1 Wkh| fdq d>hfw wkh vshflphq dqg uhvxow lq surgxfwlrq ri gl>huhqw nlqgvri udgldwlrq ghshqglqj rq wkh hqhuj| ri lqflghqw hohfwurqv1

    Rqh phwkrg zklfk lv edvhg rq wkh yhu| sulqflsohv ri doo wkh vhsdudwh h>hfwv lvwkh Prqwh Fduor hohfwurq wudmhfwru| vlpxodwlrq1 Lq wkhvh vlpxodwlrqv wkh srvvleoh sdwkri hyhu| lqflghqw hohfwurq ri wkh hohfwurq ehdp lv suhglfwhg e| dsso|lqj wkh suredelolw|irupxodv ri hyhu| hyhqw wkdw fdq wdnh sodfh1 Vlpxodwlrq ri pdq| wkrxvdqgv ri hohfwurqsdwkv wkhuhiruh jlyhv xv dq xqghuvwdqglqj ri wkh surfhvvhv zklfk wdnh sodfh ehqhdwkwkh vshflphq vxuidfh/ dqg fdq eh xvhg dv d phwkrg iru txdqwlwdwlyh dqdo|vlv1

    Lw lv wkh sxusrvh ri wklv fkdswhu wr ghvfuleh wkhvh surfhvvhv dqg wkhlu sured0elolwlhv/ iroorzlqj wkh vljqdo sdwk iurp wkh yhu| ehjlqqlqj zkhuh wkh hohfwurq ehdphqwhuv wkh vshflphq/ wr wkh yhu| hqg zkhuh wkh [0ud|v duh frxqwhg e| wkh ghwhfwlrqv|vwhp dqg uhfrughg lq d vshfwuxp/ vr dv wr surylgh d edvlv iru wkh glvfxvvlrqv lq wkhvxevhtxhqw fkdswhuv1

    Lq wkh qh{w vhfwlrqv/ dq hohfwurq zloo eh iroorzhg dorqj lwv sdwk wr lqwurgxfhwkh whuplqrorj| dqg dv d jxlgholqh wr foduli| wkh fdofxodwlrqv pdgh lq wkh fruuhfwlrq

  • Fkdswhu 51 Txdqwlwdwlyh dqdo|vlv +wkhru|,

    prghov zh zloo xvh wr shuirup txdqwlwdwlyh dqdo|vlv1 Wkh prghov wkhpvhoyhv zloo ehglvfxvvhg odwhu lq wklv fkdswhu1

    515 Dq ryhuylhz ri sk|vlfdo hyhqwv lq uhodwlrq wrtxdqwlwdwlyh dqdo|vlv

    Wkh hohfwurqv shqhwudwlqj wkh vshflphq pd| froolgh zlwk wkh dwrpv ri wkh vshflphq1Wkh hqhuj| ri wkhvh hohfwurqv lv ghwhuplqhg e| wkh dffhohudwlrq yrowdjh xvhg lq wkhplfurvfrsh dqg uhihuuhg wr dv H31 Wkh lqwhudfwlrq ri wkh lqflghqw hohfwurqv zlwk wkhdwrpv ri wkh vshflphq fdxvhv wkh hohfwurqv wr vfdwwhu e| ydulrxv phfkdqlvpv lq zklfkwkh gluhfwlrqv dqg2ru hqhuj| ri wkh hohfwurqv fkdqjh1 Hyhu| lqflghqw hohfwurq zloo jrwkurxjk pdq| vfdwwhulqj hyhqwv/ dv orqj dv lw kdv nlqhwlf hqhuj| dqg lv vwloo zlwklqwkh vshflphq1 Wkh suredelolw| ri wkhvh vfdwwhulqj hyhqwv lv ghvfulehg e| furvv vhfwlrqirupxodv ru h{suhvvhg e| wkh phdq iuhh sdwk ri wkh hohfwurq1

    Lq jhqhudo wkhuh duh wzr w|shv ri vfdwwhulqj= Hodvwlf dqg lqhodvwlf1 Hodvwlfvfdwwhulqj hyhqwv d>hfw wkh gluhfwlrq ri wkh hohfwurq wudmhfwru|/ exw qr hqhuj| lvwudqvihuuhg wr wkh vshflphq1 Wkhuhiruh wkhvh hyhqwv gr qrw frqwulexwh wr wkh sur0gxfwlrq ri [0ud|v/ exw wkh| gr lq xhqfh wkh vsuhdglqj ri wkh hohfwurqv dqg wkhuhiruhwkh wrwdo h{flwdwlrq yroxph1 Gxh wr wklv w|sh ri vfdwwhulqj/ hohfwurqv fdq hyhq ehvfdwwhuhg rxw ri wkh vshflphq djdlq1 D sdudphwhu iru wkh dprxqw ri edfnvfdwwhuhghohfwurqv lv wkh vr fdoohg *edfnvfdwwhu idfwru*/ ì1 Wkhvh hohfwurqv fdq eh xvhg wr irup dqlpdjh/ surylglqj lqirupdwlrq derxw wkh vshflphq frpsrvlwlrq/ vlqfh wkh edfnvfdwwhuidfwru kljko| ghshqgv rq dwrplf qxpehu1

    Lqhodvwlf vfdwwhulqj hyhqwv d>hfw wkh hohfwurq yhorflw|1 Wkh hqhuj| orvw e| dqhohfwurq lq dq lqhodvwlf froolvlrq lv wudqvihuuhg wr wkh vshflphq dwrp dqg pd| ohdgwr surgxfwlrq ri vhfrqgdu| hohfwurqv> Dxjhu hohfwurqv> fkdudfwhulvwlf dqg frqwlqxxp[0ud| udgldwlrq +wkh odwwhu lv riwhq uhihuuhg wr dv *Euhpvvwudkoxqj*,> rwkhu hohfwurpdj0qhwlf udgldwlrq lq wkh lqiuduhg/ ylvleoh dqg xowudylrohw> odwwlfh yleudwlrqv> dqg hohfwurqrvfloodwlrqv1

    Vlqfh lw lv gl!fxow wr rewdlq furvv vhfwlrqv iru hyhu| vshfl?f hyhqw/ doo lqhodvwlfvfdwwhulqj hyhqwv duh xvxdoo| jurxshg dqg h{suhvvhg lq dq dyhudjh udwh ri hqhuj| orvv/gHgv / zkhuh v uhsuhvhqwv wkh glvwdqfh wudyhoohg lq wkh vshflphq1 Lq fdofxodwlrqv irutxdqwlwdwlyh dqdo|vlv wklv frqwlqxrxv hqhuj| orvv dssur{lpdwlrq lv riwhq h{suhvvhg dvwkh *vwrsslqj srzhu*=

    V @ ý4ã



    zkhuh ã ghqrwhv wkh pdvv ghqvlw|1


  • Dq ryhuylhz ri sk|vlfdo hyhqwv lq uhodwlrq wr txdqwlwdwlyh dqdo|vlv 5151

    Li wkh hqhuj| wudqvihuuhg gxh wr dq lqhodvwlf vfdwwhulqj hyhqw/ lv kljk hqrxjk/zklfk lv wkh fdvh li lw lv lq h{fhvv ri wkh fulwlfdo h{flwdwlrq hqhuj| ri d vshfl?f dwrplfvkhoo ri wkh lqyroyhg dwrp/ dq hohfwurq fdq eh nqrfnhg rxw ri rqh ri wkh lqqhu vkhoovri wkh dwrp1 Wkh kroh/ fuhdwhg e| wkh lrqlvdwlrq ri dq lqqhu vkhoo/ zloo eh ?oohglpphgldwho| e| dq hohfwurq gursslqj lq iurp d kljkhu vkhoo1 Wkh hqhuj| lqyroyhgzlwk wkdw wudqvlwlrq fdxvhv wkh surgxfwlrq ri dq [0ud| txdqwxp1 Wklv txdqwxp fdqeh hplwwhg iurp wkh dwrp1 Krzhyhu 0 dqg xqiruwxqdwho| iru txdqwlwdwlyh hohfwurqplfurvfrs| 0 lw lv pxfk pruh olnho| wr eh devruehg zlwklq wkh dwrp djdlq1 Wkhhqhuj| lv glvvlsdwhg lq zhdno| erxqg rxwhu hohfwurqv/ zklfk fdq eh hmhfwhg1 Wklv lvnqrzq dv wkh *Dxjhu h>hfw*1 Wkh suredelolw| ri d udgldwlyh wudqvlwlrq/ l1h1 wkh iudfwlrqri lrqlvdwlrqv ri d vshfl?f vkhoo wkdw uhvxow lq fkdudfwhulvwlf [0ud| hplvvlrq/ lv nqrzqdv wkh * xruhvfhqfh |lhog* ç$/ zkloh ç$ . d @ 4 +zkhuh d lv wkh Dxjhu |lhog,1

    Ilqdoo| wkh [0ud|v uhohdvhg lq dq lqhodvwlf vfdwwhulqj h>hfw kdyh wr wudyho wkurxjkwkh vshflphq pdwhuldo wr uhdfk wkh vxuidfh1 Rq wkhlu sdwk rxw wkh| fdq eh uhdevruehge| rwkhu dwrpv lq wkh pdwhuldo1 Wkh prvw lpsruwdqw sdudphwhuv lq wklv devruswlrqri h{flwhg [0ud|v duh wkh pdvv0devruswlrq frh!flhqwv1 Dq devruehg [0ud| fdq djdlqfdxvh qhz lrqlvdwlrqv lq wkh vdph zd| dv wkh lqflghqw hohfwurq/ uhohdvlqj qhz hohfwurqvdqg2ru [0ud|v zlwk orzhu hqhuj|1 Wkh wudqvlwlrq iurp [0ud|v wr [0ud|v zlwk orzhuhqhuj| lv fdoohg xruhvfhqfh1

    Wkh sdwk zklfk lv wr eh iroorzhg e| wkh [0ud|v wrzdugv wkh [0ud| ghwhfwru lvghwhuplqhg e| wkh srvlwlrq +wdnh0r> dqjoh, ri wkh ghwhfwru1 Rqo| d iudfwlrq ri wkh[0ud|v hphujlqj iurp wkh vshflphq*v vxuidfh lv froohfwhg e| wkh [0ud| ghwhfwru vlqfhwkh [0ud|v duh hplwwhg lq doo gluhfwlrqv dqg rqo| wkrvh wkdw duh zlwklq wkh froohfwlrqdqjoh ri wkh ghwhfwru duh uhfrughg1

    Rqh vkrxog nhhs lq plqg wkdw hdfk ehdp hohfwurq pd| vfdwwhu pdq| wlphv1Exw dovr/ vhfrqgdu| hohfwurqv/ rqfh jhqhudwhg/ fdq sduwlflsdwh djdlq lq d vfdwwhulqjhyhqw1 Hyhq wkh [0ud|v surgxfhg lq wkh vshflphq fdq fdxvh qhz lrqlvdwlrq hyhqwvuhohdvlqj qhz hohfwurqv dqg2ru gl>huhqw [0ud|v1

    Iljxuh 514 jlyhv d srvvleoh wudmhfwru| ri rqh vlqjoh hohfwurq hqwhulqj d exonvshflphq vlpxodwhg zlwk d Prqwh Fduor vlpxodwlrq surjudp1 Li zh fdofxodwh dqg sorwwkh sdwk ri pdq| hohfwurqv lq wkh vdph zd|/ d sorw olnh ?jxuh 515 lv rewdlqhg1 Lq wkhodwwhu sorw/ lw ehfrphv fohdu wkdw wkh h{flwdwlrq yroxph lv d *whdu0gurs* vkdshg yroxph1Iurp wklv zh fdq ghgxfh wkh odwhudo uhvroxwlrq ri wkh dqdo|vlv dv zhoo dv wkh ghswkglvwulexwlrq ri wkh vfdwwhulqj hyhqwv1 E| glylglqj wkh vshflphq lqwr od|huv ri wklfnqhvvü} +ru pdvv0wklfnqhvv ü+ã},,/ wkh qxpehu ri vfdwwhulqj hyhqwv dqg wkhlu uhodwhghqhuj| fdq eh ghwhuplqhg dqg wkhuhiruh wkh dprxqw ri jhqhudwhg [0ud|v lq hyhu|od|hu fdq eh fdofxodwhg1 Wklv uhvxowv lq d glvwulexwlrq ixqfwlrq ri [0ud| jhqhudwlrq+*, yhuvxv ghswk +ã},/ wkh ** +ã}, fxuyh*1 Pruh ghwdlov derxw wkhvh * +ã}, fxuyhv zlooeh jlyhq lq fkdswhu 61


  • Fkdswhu 51 Txdqwlwdwlyh dqdo|vlv +wkhru|,

    Iljxuh 5141 Prqwh Fduor vlpxodwlrq ri d vlqjoh hohfwurq wudmhfwru| lq Doxplqlxp/ dw53 nY dffhohudwlrq yrowdjh1

    Iljxuh 5151 Prqwh Fduor vlpxodwlrq ri pdq| hohfwurq wudmhfwrulhv1 Fohduo| wkh *whdu0gurs* vkdsh ri wkh h{flwdwlrq yroxph ehfrphv ylvleoh1


  • Hohfwurq vfdwwhulqj hyhqwv 5161

    516 Hohfwurq vfdwwhulqj hyhqwv

    Dowkrxjk pdq| irupxodv iru vfdwwhulqj hyhqwv duh nqrzq/ rqo| wkrvh wkdw duh hvvhqwldowr xqghuvwdqg wkh prghoolqj iru txdqwlwdwlyh dqdo|vlv zloo eh glvfxvvhg khuh1

    51614 Hodvwlf vfdwwhulqj

    Dv phqwlrqhg/ hodvwlf vfdwwhulqj fkdqjhv wkh gluhfwlrq ri wkh hohfwurqv/ exw wkh yhorflw|uhpdlqv dssur{lpdwho| frqvwdqw/ w|slfdoo| ohvv wkdq 4 hY ri hqhuj| lv wudqvihuuhg1Wkh hohfwurq lv vfdwwhuhg e| wkh Frxorpelf lqwhudfwlrq zlwk wkh fkdujh ri wkh dwrplfqxfohxv +Uxwkhuirug vfdwwhulqj,/ dv sduwldoo| vfuhhqhg e| wkh dwrplf ruelwdo hohfwurqv1Dv d uhvxow/ wkh hohfwurq ghyldwhv iurp lwv ruljlqdo lqflghqw sdwk e| dq dqjoh ëh+odvwlf,1Wkh dqjoh fdq eh dq|wklqj ehwzhhq 3ï dqg 4;3ï1 Wkh furvv vhfwlrq â iru wkh hodvwlfvfdwwhulqj hyhqwv wkdw h{fhhg d vfdwwhu dqjoh ë4 fdq eh ghvfulehg e| wkh vfuhhqhgUxwkhuirug h{suhvvlrq ^4`=

    â+ëh A ë4, @

    ] äë4

    gâ+ë, @ 4=95û 43ý53]5


    ë45, +515,

    zkhuh H lv wkh hohfwurq hqhuj| dqg ] wkh dwrplf qxpehu ri wkh lqyroyhg dwrp1Iurp wklv htxdwlrq lw ehfrphv fohdu wkdw wkh suredelolw| ri dq hodvwlf vfdwwhulqj

    hyhqw lqfuhdvhv zlwk wkh vtxduh ri wkh dwrplf qxpehu exw ghfuhdvhv zlwk wkh vtxduhri wkh hohfwurq hqhuj|1 Ixuwkhupruh/ vpdoo dqjoh vfdwwhulqj lv pxfk pruh olnho| wrrffxu wkdq odujh dqjoh vfdwwhulqj1

    51615 Lqhodvwlf vfdwwhulqj

    Furvv vhfwlrqv iru wkh lqglylgxdo surfhvvhv lqyroyhg lq lqhodvwlf vfdwwhulqj duh gl!fxowwr rewdlq1 Krzhyhu/ jurxslqj doo lqhodvwlf vfdwwhulqj hyhqwv wrjhwkhu jlyh xv dq dyhudjhhqhuj| orvv udwh/ gHgv 1 Ehwkh ^5` surylghv d xvhixo frqwlqxrxv hqhuj| orvv h{suhvvlrq/jlylqj dq dssur{lpdwlrq iru gHgv =


    @ ý5äh7Q3 ]ãDHp



    zkhuh h lv wkh hohfwurq fkdujh/ Q3 lv Dyrjdgur*v qxpehu/ ã wkh ghqvlw|/ D wkhdwrplf pdvv ri wkh hohphqw/ dqg Hp +nhY, wkh dyhudjh hqhuj| dorqj wkh sdwk vhjphqwv1

    Wkh phdq lrqlvdwlrq srwhqwldo/ M / fdq eh dssur{lpdwhg e| vhyhudo irupxodv/hdfk kdylqj lwv rzq dgydqwdjhv/ olplwdwlrqv dqg dssolfdwlrqv1 D jhqhudoo| xvhgghvfulswlrq lv jlyhq e| Vwhuqkhlphu +txrwhg lq Ehujhu dqg Vhow}hu +4

  • Fkdswhu 51 Txdqwlwdwlyh dqdo|vlv +wkhru|,

    517 [0ud| jhqhudwlrq

    Wkh lrqlvdwlrq furvv vhfwlrq jlyhv ulvh wr wkh dprxqw ri fkdudfwhulvwlf [0ud|v jhqhudwhglq d vfdwwhulqj hyhqw1 Qxphurxv h{suhvvlrqv fdq eh irxqg iru wkh lrqlvdwlrq furvvvhfwlrq1 D uhylhz lv jlyhq e| Srzhoo ^8`^9`^:`1 Wkh edvlf h{suhvvlrq ri wkh lrqlvdwlrqfurvv vhfwlrq lv wkh rqh ghulyhg e| Ehwkh ^;`=

    T @ 9=84 ü 43ý53 qvevXH5f

    orj +fvX, +518,

    zkhuh qv lv wkh qxpehu ri hohfwurqv lq wkh lqqhu vkhoo ri lqwhuhvw/ dqg ev dqg fvduh frqvwdqwv iru wkh vshfl?f vkhoo1 Hf lv wkh fulwlfdo lrqlvdwlrq hqhuj| ri wkh vkhoo dqgX lv wkh ryhuyrowdjh= wkh udwlr ehwzhhq wkh suhydlolqj ehdp hqhuj| dqg wkh fulwlfdolrqlvdwlrq hqhuj|



    51714 Wklq ?op

    Lq fdvh ri d yhu| wklq ?op vshflphq/ wkh hodvwlf phdq iuhh sdwk/ gh?qhg dv wkh phdqglvwdqfh dq hohfwurq kdv wr wudyho wkurxjk wkh vshflphq wr xqghujr dq dyhudjh rirqh hodvwlf vfdwwhulqj/ zloo eh vxevwdqwldoo| odujhu wkdq wkh vshflphq wklfnqhvv1 Wklvphdqv hohfwurqv fdq eh frqvlghuhg wr jr wkurxjk wkh vshflphq zlwkrxw vljql?fdqwgh hfwlrq1 Wkh hqhuj| orvv gxh wr lqhodvwlf vfdwwhulqj fdq dovr eh qhjohfwhg lq wkhfdvh ri d yhu| wklq vshflphq/ hvshfldoo| lq WHP zkhuh wkh lqflghqw hohfwurq hqhuj| lvpdq| wlphv wkh fulwlfdo hqhuj|1

    Xvlqj wkh lrqlvdwlrq furvv vhfwlrq h{suhvvlrq/ wkh qxpehu ri fkdudfwhulvwlf [0ud|v jhqhudwhg/ L/ fdq eh suhglfwhg e| wkh uhodwlrq=

    L @Q3ãFDDD

    TD$DdDQhw +519,

    zkhuh TD lv wkh lrqlvdwlrq furvv vhfwlrq iru wkh vkhoo ri lqwhuhvw/ dD lv wkhsuredelolw| ri hplvvlrq ri wkh [0ud| olqh ri lqwhuhvw uhodwlyh wr doo wkh olqhv wkdw fdqeh hplwwhg ehfdxvh ri lrqlvdwlrq ri wkh vdph vkhoo/ Qh wkh qxpehu ri hohfwurqv wkdwluudgldwhg wkh vshflphq +htxdov wkh hohfwurq ehdp fxuuhqw,1 DD lv wkh dwrplf pdvv riwkh hohphqw D/ FD wkh frqfhqwudwlrq +ru zhljkw iudfwlrq,/ $D wkh xruhvfhqfh |lhogdqg w lv wkh vshflphq wklfnqhvv1

    51715 Exon vshflphq

    Lq wklfn wdujhwv/ hodvwlf vfdwwhulqj dqg hqhuj| orvvhv duh qrw qhjoljleoh1 Wkhuhiruh Tvkrxog eh lqwhjudwhg ryhu wkh hqhuj| udqjh iurp wkh lqflghqw hohfwurq hqhuj| H3 wrHf1 Wkh wklfnqhvv vkrxog eh uhsodfhg e| d wklq volfh lq ghswk gluhfwlrq/ g} ru gã}1


  • [0ud| hplvvlrq dqg ghwhfwlrq 5181

    Krzhyhu/ vlqfh wkh hodvwlf vfdwwhulqj fkdqjhv wkh hohfwurq*v gluhfwlrq dorqj lwv hqhuj|orvv sdwk wkhuh lv qr gluhfw uhodwlrq ehwzhhq wkh ghswk dqg wkh hqhuj| glvwulexwlrq1Wkhuhiruh wkh hqhuj| orvv h{suhvvlrq lv lqwhjudwhg ryhu wkh hohfwurq*v sdwk/ gv/ lqvwhdgri olqhdu ghswk +},1 Wklv uhvxowv lq wkh iroorzlqj h{suhvvlrq=

    L @

    ] HfH3


    [email protected] +51:,

    Wkh fdofxodwlrq ri [email protected] lv frpsolfdwhg vlqfh d iudfwlrq ri wkh hohfwurqv zlooedfnvfdwwhu dqg ohdyh wkh vshflphq zlwk d fhuwdlq hqhuj| glvwulexwlrq1 Qhyhuwkhohvv/wklv htxdwlrq lv yhu| xvhixo iru fdofxodwlqj wkh wrwdo dprxqw ri [0ud|v surgxfhg zlwklqwkh vshflphq1 Pruh derxw wklv zloo eh h{sodlqhg lq wkh prghoolqj fkdswhu1

    518 [0ud| hplvvlrq dqg ghwhfwlrq

    Lq rughu wr ghwhfw wkh [0ud|v surgxfhg zlwklq wkh vshflphq/ wkh h{flwhg [0ud|v kdyhwr wudyho ?uvw iurp d fhuwdlq ghswk zlwklq wkh vshflphq wr wkh vxuidfh1 Dorqj wklvsdwk wr wkh vxuidfh wkh| pd| eh devruehg e| wkh pdwul{ pdwhuldo dqg pd| hyhqjhqhudwh qhz [0ud|v ri d orzhu hqhuj|1 Wr fdofxodwh wkh dprxqw ri devruswlrq/ dqg?qdoo| wkh wrwdo hplwwhg lqwhqvlw| ri d vshfl?f [0ud| olqh/ wkh ruljlq ri wkh jhqhudwlrqri wkh [0ud|v kdv wr eh nqrzq1 Wkhuhiruh wkh ghswk glvwulexwlrq ri wkh jhqhudwhg[0ud| udgldwlrq +iru hdfk fkdudfwhulvwlf [0ud| olqh lqyroyhg, kdv wr eh nqrzq wr pdnhdssursuldwh devruswlrq fruuhfwlrqv1

    Wkh ghswk glvwulexwlrq ri wkh jhqhudwhg [0ud| olqhv lv ghvfulehg e| wkh vr0fdoohg** +ã}, fxuyhv*/ lq zklfk * ghqrwhv wkh qxpehu ri jhqhudwhg [0ud|v dv ixqfwlrq ri wkhpdvv ghswk/ ã}1 Lw vkrxog eh qrwhg wkdw wkh * +ã}, ydoxh lv gh?qhg ^

  • [0ud| hplvvlrq dqg ghwhfwlrq 5181

    wkhvlv lv derxw WHP/ dqg lq WHP/ HGV lv doprvw h{foxvlyho| xvhg/ ixuwkhu dwwhqwlrqzloo eh frqfhqwudwhg h{foxvlyho| rq wklv w|sh ri ghwhfwru1

    Wkh dprxqw ri [0ud|v ri d vshfl?f olqh/ ghwhfwhg e| HGV lv/ xqiruwxqdwho|/qrw htxdo wr wkh dfwxdo dprxqw ri [0ud|v hqwhulqj wkh ghwhfwru/ exw lv lq xhqfhge| wkh ghwhfwru vhqvlwlylw|1 Wklv vhqvlwlylw| ghshqgv rq ghwhfwru sdudphwhuv vxfk dvwkh ghwhfwru zlqgrz w|sh dqg wklfnqhvv xvhg/ wklfnqhvv ri wkh jrog frqwdfw od|hudqg vlolfrq ghdg od|hu exw dovr rq wkh frxqwlqj hohfwurqlfv1 D yhu| frpsuhkhq0vlyh h{sodqdwlrq derxw [0ud| ghwhfwruv/ wkhlu ghvljq dqg rshudwlqj sulqflsohv/ wkhghwhfwlqj surfhvv dqg duwlidfwv dqg huuruv wkdw fdq dsshdu gxulqj ghwhfwlrq/ lv jlyhqe| Jrogvwhlq hw do1 ^43/ fkdswhu 8`1

    Dv lqsxw sdudphwhuv iru wkh pdwul{ fruuhfwlrq surjudpv/ lqwhqvlw| udwlrv duhphdvxuhg/ hlwkhu ehwzhhq wzr [0ud| olqhv ru ehwzhhq wkh vdph olqh phdvxuhg rqvshflphq dqg vwdqgdug1 Wklv lv grqh wr dyrlg wkh qhfhvvlw| wr fdofxodwh wkh h>hfw ridoo wkhvh/ riwhq xqnqrzq/ ghwhfwru sdudphwhuv1

    Prvw WHP phwkrgv xvh udwlrv ehwzhhq wzr [0ud| olqhv ri gl>huhqw hqhuj|+iurp gl>huhqw hohphqwv,1 Xvlqj wklv udwlr/ wkh ghwhfwru fkdudfwhulvwlfv dsshdulqj lqqxphudwru dqg ghqrplqdwru ehorqj wr gl>huhqw hohphqwv1 Wklv phdqv wkdw wkh| grqrw fdqfho rxw exw uhvxow lq d +frpsrvlwlrq lqghshqghqw, frqvwdqw1

    Li wkh udwlr ehwzhhq [0ud| lqwhqvlwlhv ri rqh vshfl?f olqh phdvxuhg rq wkhvshflphq lq sursruwlrq wr wkh vwdqgdug lv xvhg/ olnh lq exon pdwul{ fruuhfwlrq sur0judpv/ wklv udwlr lv uhihuuhg wr dv d n0udwlr +qrw wr eh frqixvhg zlwk n0idfwruv,1 Wkhdgydqwdjh ri wklv phwkrg lv wkdw wkh ghwhfwru fkdudfwhulvwlfv fdqfho rxw frpsohwho|+dv orqj dv wkh vdph dffhohudwlrq yrowdjh lv xvhg/ ri frxuvh,1


  • Eleolrjudsk|

    ^4` U1G1 Hydqv1 Wkh Dwrplf Qxfohxv1 PfJudz0Kloo/ Qhz \run/ +4



  • Fkdswhu 6

    Pdwul{ fruuhfwlrq prghov=Exon

    614 Lqwurgxfwlrq

    Pdwul{ fruuhfwlrq prghov duh qhfhvvdu| lq rughu wr frqyhuw wkh phdvxuhg lqwhqvlw|udwlrv lqwr frqfhqwudwlrq xqlwv1 Dv phqwlrqhg lq wkh suhylrxv fkdswhu/ wkh lqwhqvlw|udwlrv duh h{suhvvhg lq vr0fdoohg n0udwlrv/ wkh udwlr ehwzhhq wkh lqwhqvlw| ri wkh hplwwhgfkdudfwhulvwlf [0ud|v iurp wkh vshflphq lq uhvshfw wr wkh vdph [0ud| olqh iurp wkhvwdqgdug1

    Lq wkh hduo| vwdjhv ri wkh ghyhorsphqw ri pdwul{ fruuhfwlrqv prghov/ wkh prghovzhuh lq xhqfhg e| wkh lqlwldo dvvxpswlrq ri d olqhdu uhodwlrq ehwzhhq frpsrvlwlrqdqg jhqhudwhg lqwhqvlw| dqg edvhg rq wkh fdofxodwlrq ri wkuhh idfwruv ]/ D dqg I= Wkhdwrplf qxpehu fruuhfwlrq idfwru/ wkh devruswlrq fruuhfwlrq idfwru dqg wkh xruhvfhqfhidfwru/ uhvshfwlyho|1 Zlwk wkhvh wkuhh idfwruv wkh uhodwlrq ehwzhhq wkh phdvxuhglqwhqvlwlhv dqg wkh frqfhqwudwlrqv lv h{suhvvhg dv=


    @ ^]DI `l ü LlLl>vwg

    @ ^]DI `l ü nl +614,

    zkhuh Fl dqg Fl>vwg duh wkh frqfhqwudwlrqv ri hohphqw l lq wkh vshflphq dqgwkh vwdqgdug/ uhvshfwlyho|/ dqg Ll dqg Ll>vwg wkh lqwhqvlwlhv ri wkh fkdudfwhulvwlf [0ud|vphdvxuhg dw wkh vshflphq dqg vwdqgdug1 nl lv wkh n0udwlr ri hohphqw l1 Wklv lv wkhvr0fdoohg ]DI dssurdfk1

    Odwhu/ wkh prghov zhuh pruh dqg pruh edvhg xsrq wkh xvh ri * +ã}, fxuyhv/zklfk ghvfuleh wkh lqwhqvlw|/ */ ri wkh fkdudfwhulvwlf [0ud|v jhqhudwhg dw d fhuwdlq


  • Fkdswhu 61 Pdwul{ fruuhfwlrq prghov= Exon

    ghswk +ã},1 Wkh lghd zdv edvhg xsrq phdvxuhphqwv lq zklfk d wudfhu hplwwlqj wkhrevhuyhg udgldwlrq zdv exulhg lq d pdwul{ dw ydu|lqj ghswkv1 Xvlqj wkhvh wudfhuphdvxuhphqw dq h{shulphqwdo * +ã}, fxuyh frxog eh rewdlqhg1

    Gxulqj wkh |hduv/ d orw ri lghdv iru wkh irup ri wkh * +ã}, fxuyhv kdyh ehhqvxjjhvwhg= Iurp wkh ruljlqdo vlpsol?hg Sklolehuw +4

  • * +ã}, fxuyhv 6161

    jhqhudwhg lqwhqvlw| lw fdq eh h{suhvvhg dv=

    i +", @wrwdoo| hplwwhg lqwhqvlw|wrwdoo| jhqhudwhg lqwhqvlw|


    U43 * +ã}, h{s ^ý"ã}` g +ã},U4

    3 * +ã}, g +ã},+615,

    lq zklfk= " @ çã frvhf ë dqg ç@ã lv wkh pdvv devruswlrq frh!flhqw1

    î Ilqdoo|/ lw lv vrphwlphv qhfhvvdu| wr dffrxqw iru vhfrqgdu| xruhvfhqfh/ zklfkfdq wdnh sodfh zkhqhyhu rqh ri wkh sulpdu| jhqhudwhg udgldwlrqv lv ri vx!flhqwo|kljk hqhuj| wr h{flwh rwkhu [0ud| udgldwlrq zlwklq wkh vshflphq1 Wklv zlooohdg wr hplvvlrq ri dq dgglwlrqdo [0ud| olqh/ exw dovr uhgxfhv wkh hplvvlrq riwkh sulpdu| [0ud| udgldwlrq fdxvlqj wkh xruhvfhqfh1 Wkh fruuhfwlrq iru wklvskhqrphqrq lv frqwdlqhg lq wkh vr0fdoohg I ý idfwru1

    Qrwh wkdw wkh ]/ D dqg I idfwruv xvhg lq wkh ]DI dssurdfk/ vwdqg iru wkh udwlrehwzhhq wkh lqwhqvlw| jhqhudwhg lq wkh vshflphq dqg wkdw lq wkh vwdqgdug/ zkloh lqwkh * +ã}, dssurdfk wkh ]/ D dqg I duh fdofxodwhg vhsdudwho| iru wkh vshflphq dqgwkh vwdqgdug/ dqg ri frxuvh iru hdfk vshfl?f [0ud| olqh ri hdfk phdvxuhg hohphqw1Ixuwkhupruh wkh ]/ D/ dqg I idfwruv duh qrw xvhg e| wkh * +ã}, surfhgxuh/ exw duhrqo| fdofxodwhg wr ylvxdolvh wkh h>hfwv ri wkh dwrplf qxpehu/ wkh devruswlrq dqg wkh xruhvfhqfh fruuhfwlrqv1

    Ri doo wkuhh fruuhfwlrq idfwruv lqyroyhg/ wkh devruswlrq fruuhfwlrq kdv uljkwixoo|uhfhlyhg wkh prvw dwwhqwlrq/ vlqfh wklv xvxdoo| frqvwlwxwhv wkh pdmru fruuhfwlrq uhtxl0uhg1 Wkh shuirupdqfh ri wkh devruswlrq fruuhfwlrq lv frpsohwho| ghshqghqw rq wkh* +ã}, fxuyh xvhg1 Wkhuhiruh d orw ri h>ruw kdv ehhq grqh wr ?qg wkh prvw dssursuldwh* +ã}, e| xvlqj pdq| gl>huhqw prghov1

    616 ) E45ä fxuyhv

    61614 Sursrvhg prghov

    Sklolehuwv* prgho

    Lq 4

  • Fkdswhu 61 Pdwul{ fruuhfwlrq prghov= Exon

    htxdwlrqv/ wkh ghyhorshg * +ã}, irupxod ehfdph=

    * +ã}, @ 7 h{s +ýâã},ý +7ý *3, h{séýâ

    ë4 .





    Ixuwkhupruh wkh ydoxh ri * +3,/ wkh vxuidfh lrqlvdwlrq +ã} @ 3,/ zdv dvvxphgwr eh }hur lq devhqfh ri dydlodeoh gdwd/ uhvxowlqj lq=


    i +",@í4 .



    ìë4 .


    4 . k




    Sklolehuw dvvxphg k @ 4=5 ü[email protected]]5 dqg xvhg hpslulfdo ydoxhv iru â1Xvlqj dq h{srqhqwldo vkdshg ghswk glvwulexwlrq ixqfwlrq iru wkh [0ud| jhqhud0

    wlrq lv qrw yhu| uhdolvwlf/ vlqfh qr sursruwlrqdo uhodwlrq ehwzhhq oq* dqg ã} fdq ehrevhuyhg1 Ixuwkhupruh wkh dvvxpswlrq *3 @ 3 vljql?fdqwo| fkdqjhv wkh vkdsh ri wkh* +ã}, fxuyh qhdu wkh vxuidfh1 Li devruswlrq lv kljk wklv uhvxowv lq odujh huuruv/ vlqfh/lq vxfk fdvh/ prvw ri wkh revhuyhg [0ud|v ruljlqdwh iurp wkh vxuidfh duhd1

    Wkh lpsuryhg Sklolehuw prgho

    Pdq| lpsuryhphqwv wr wkh vlpsol?hg Sklolehuw prgho zhuh sursrvhg/ olnh lqwurgxflqjghshqghqfh rq wkh fulwlfdo h{flwdwlrq hqhuj|/ Hf/ e| Gxqfxpe dqg Vklhogv +4

  • * +ã}, fxuyhv 6161

    Sduderolf prgho

    Srxfkrx dqg Slfkrlu +4

  • Fkdswhu 61 Pdwul{ fruuhfwlrq prghov= Exon

    617 Jdxvvldq edvhg ) E45ä prghoolqj

    Xvlqj d * +ã}, dssurdfk iru frpelqhg dwrplf qxpehu dqg devruswlrq fruuhfwlrq/ wkhshuirupdqfh ri dq| pdwul{ fruuhfwlrq prgho ghshqgv frpsohwho| rq wkh fruuhfwqhvvri wkh * +ã}, fxuyh1 Wkhuhiruh/ uhdolvwlf * +ã}, fxuyhv kdg wr eh irxqg1 Sdfnzrrg dqgEurzq lqwurgxfhg lq 4xvh hohfwurq forxg>vhfrqgo|/ lw lqfrusrudwhv wkh idfw wkdw wkh jhqhudwlrq ri [0ud|v ehfrphv pruh h!flhqwzkhq wkh hohfwurqv vorz grzq lq wkh ?uvw sduw ri wkh * +ã}, fxuyh1

    Frpelqdwlrq ri htxdwlrq 618 dqg 619 jlyhv wkh ryhudoo * +ã}, fxuyh=

    * +ã}, @ ð

    é4ý ð ý *+3,

    ðh{s +ýñã},


    kýò5 +ã},5


    Xvlqj wklv * +ã}, fxuyh/ wkh prgho lv qrz fkdudfwhulvhg e| sdudphwhulvdwlrqri wkh irxu lqsxw sdudphwhuv ò/ ñ/ ð/ dqg * +3,1 D ghwdlohg glvfxvvlrq rq wkhsdudphwhulvdwlrq ri wkh odwwhu sdudphwhuv lv jlyhq e| Edvwlq +4

  • Grxeoh Jdxvvldq prgho 6181









    3 533 733 933 ;33 4333 4533





    / 5

    Iljxuh 6141 Vfkhpdwlf uhsuhvhqwdwlrq ri wkh grxeoh Jdxvvldq * +ã}, prgho1 Wkh ohiw0kdqg eudqfk/ zlwk Jdxvvldq lqfuhdvh udwh ñ/ lv frqqhfwhg dw wkh wrs +zlwk frruglqdwhvã}p/ *p, wr wkh uljkw0kdqg eudqfk zlwk Jdxvvldq ghfd| udwh ò1

    zklfk duh vprrwko| frqqhfwhg dw wkh pd{lpxp *p dw +ã},p +?j 614,1 Wkh dqdo|wlfdoghvfulswlrq ri wkh wzr Jdxvvldq eudqfkhv *o+hiw, dqg *u+ljkw, fdq eh jlyhq dv iroorzv=

    *o +ã}, @ *p h{skýñ5 +ã} ý ã}p,5

    liru 3 é ã} é ã}p

    *u +ã}, @ *p h{skýò5 +ã} ý ã}p,5

    liru ã}p é ã} é4 +61;,

    zhuh *p @ * +3, h{síñ5 +ã}p,

    5ìdqg ñ kdv d frpsohwho| gl>huhqw phdqlqj wkdq lq

    wkh vxuidfh fhqwuhg Jdxvvldq prgho1Lq wklv prgho * +3,/ ã}p dqg ò duh frqvlghuhg wr eh lqghshqghqw txdqwlwlhv1

    Wkh irxuwk lqghshqghqw sdudphwhu lv IL/ qrw ñ1 IL lv wkh lqwhjudo ri * +ã},/ ehlqjwkh wrwdo jhqhudwhg lqwhqvlw|/ ñ lv ghwhuplqhg e| xvlqj * +3,/ ã}p/ ò dqg IL1 Wkhirxu lqsxw sdudphwhuv duh fdofxodwhg wkurxjk lqghshqghqw h{suhvvlrqv/ doorzlqj xv wrfkdqjh wkh h{suhvvlrqv xvhg iru hyhu| sdudphwhu/ dqg pdlqwdlq frpsohwh h{lelolw|dqg prgxodu vwuxfwxuh ri wkh prgho1


  • Fkdswhu 61 Pdwul{ fruuhfwlrq prghov= Exon

    61814 Gh?qlwlrq riU) E45ä jhqhudwhg dqg hplwwhg1

    Jhqhudwhg lqwhqvlw|

    Wkh wrwdo jhqhudwhg lqwhqvlw| zlwklq wkh vshflphq IL/ lv wkh lqwhjudo ri * +ã}, ehwzhhq}hur dqg lq?qlw|=

    IL @

    ] 43

    * +ã}, @

    ] ã}p3

    *p h{skýñ5 +ã} ý ã}p,5

    lg +ã},


    ] 4ã}p

    *p h{skýò5 +ã} ý ã}p,5

    lg +ã}, +61

  • Grxeoh Jdxvvldq prgho 6181

    Lqwhjudwlrq ri wkhvh ixqfwlrqv zlwklq wkhlu olplwv |lhogv=

    ILH>o @*psä



    ê5ý "ã}p


    ëñã}p ý "

    ê. hui


    êèILH>u @



    éí "5ò

    ì5ý "ã}p

    èük4ý hui

    í "5ò


    Wkh wrwdo hplwwhg lqwhqvlw| ILH lv wkh jlyhq e| ILH @ ILH>o . ILH>u1

    Fdofxodwlrq ri ñ

    Dv zlwk wkh roghu Jdxvvldq prgho/ wkh prgho lv edvhg dv pxfk dv srvvleoh rq uhfrj0ql}deoh dqg phdvxudeoh sdudphwhuv zlwk d fohdu sk|vlfdo edfnjurxqg1 Wkh irxu lqsxwsdudphwhuv duh/ dv phqwlrqhg ehiruh/ edvhg rq lqghshqghqw h{suhvvlrqv1 Rqo| ñ lv dghshqghqw sdudphwhu dqg fdq eh ghulyhg iurp wkh rwkhu irxu sdudphwhuv e| uhzulwlqjhtxdwlrq 6143 wr=

    h{síñ5 +ã}p,


    íñ5 +ã}p,

    5ìý S8

    ñý 5IL* +3,

    sä@ 3 +6149,

    Iurp wklv lw lv fohdu wkhuh lv qr dojheudlf vroxwlrq iru ñ +qrwh wkdw dovr S8 lvd ixqfwlrq ri ñã}p,1 Khqfh d qxphulfdo surfhgxuh kdv wr eh xvhg wr ghwhuplqh wkhydoxh ri ñ1

    Iru wklv wkh ixqfwlrq IFQ /

    IFQ @h{s

    íñ5 +ã}p,


    íñ5 +ã}p,

    5ìý S8

    ñý 5IL* +3,


    lv plqlplvhg iru d ?{hg vhw ri * +3,/ ã}p/ ò dqg IL sdudphwhuv e| ydu|lqj ñ1 VlqfhIL lv d prqrwrqlfdoo| lqfuhdvlqj ixqfwlrq/ wkh ghvluhg ñ ydoxh fdq eh ghwhuplqhg e|?qglqj wkh srlqw ri lqwhuvhfwlrq/ zhuh IFQ @ 3/ xvlqj dq lwhudwlyh surfhgxuh edvhgxsrq d vlpsoh vwudljkw olqh dssurdfk +?j1 615,1

    Wkh irxu lqghshqghqw lqsxw sdudphwhuv

    Lq wklv zd| wkh prgho ri wkh * +ã}, fxuyh lv frpsohwho| hvwdeolvkhg e| 7 lqghshqghqwsdudphwhuv ò/ *3/ ã}p dqg IL1 Wkh sdudphwhuv ñ dqg *p duh ghshqghqw1 Wkh 7lqghshqghqw sdudphwhuv duh ghvfulehg e| sdudphwhulvdwlrqv zlwk dv pxfk uhodwlrq dvsrvvleoh wr sk|vlfdo txdqwlwlhv1 Hdfk sdudphwhulvdwlrq fdq eh fkdqjhg +dqg lqwhu0fkdqjhg zlwk rwkhu h{suhvvlrqv, zlwkrxw d>hfwlqj wkh rwkhuv dqg zlwkrxw glvuxswlqjwkh pdwkhpdwlfdo lqwhjulw| ri wkh prgho1


  • Fkdswhu 61 Pdwul{ fruuhfwlrq prghov= Exon










    3 4333 5333 6333 7333 8333 9333 :333



    Ã 418Â

    Ã Â

    Iljxuh 6151 Yduldwlrq lq IFQ +Htxdwlrq 614: dv d ixqfwlrq ri ñ iru ?{hg ydoxhv riò/ ã}p/ dqg IL1 Wkh duurzv vkrz wkh lqlwldo hvwlpdwhv iru ñ zlwk zklfk wkh lwhudwlrqsurfhgxuh/ dlphg dw plqlpl}lqj IFQ/ lv vwduwhg1

    î Ghfd| Udwh ò=

    E| h{wudfwlqj wkh ò ydoxhv iurp qxphurxv ?wv ri * +ã}, fxuyhv zlwk wkh PF8Prqwh Fduor surjudp/ Edvwlq hw do1 ^45` revhuyhg wkdw oq +ò@T, lv sursruwlrqdowr oq +H3,1 Wklv olqhdu uhodwlrq fdq eh h{suhvvhg dv=




    ê@ L ý W oqH3 +614;,

    zkhuh L lv lqwhufhsw/ W lv wkh wdqjhqw/ dqg xvlqj

    T @

    v]D oq


    üH53 ý H5f


  • Grxeoh Jdxvvldq prgho 6181

    L dqg W zhuh ?wwhg dqg wkh iroorzlqj uhodwlrqv zhuh irxqg=

    oq L @ 45=

  • Fkdswhu 61 Pdwul{ fruuhfwlrq prghov= Exon

    dowkrxjk rwkhu h{suhvvlrqv zhuh wulhg wrr1 d/ e dqg f zhuh sdudphwhulvhg e|?wwlqj dqg irxqg wr eh=

    d @ 5=43737;6 . 3=377

  • Grxeoh Jdxvvldq prgho 6181

    î IL/ wkh lqwhjudo ri * +ã},Wkh ydoxh iru wkh lqwhjudo ri wkh * +ã}, fxuyh/ IL/ lv ghwhuplqhg e| fdofxodwlrqri wkh sulpdu| lqwhqvlw|/ SL iurp wkh edfnvfdwwhulqj idfwru U dqg wkh vwrsslqjsrzhu 4V =

    SL 2 T +X3,IL @ T +X3,] 43

    * +ã},gã} +6167,

    zkhuh X3 @ [email protected]/ dqg

    SL @U


    Iroorzlqj wkh dwrplf qxpehu fruuhfwlrq ri Srxfkrx dqg Slfkrlu +^55`/ dovr flwhglq ^56/ s1 651`, wkh ghfhohudwlrq ri hohfwurqv lv ghvfulehg e|=


    [email protected]

    ] HfH3

    T +H,gHgãv

    gH +6169,

    Wkh lrqlvdwlrq furvv vhfwlrq T +X,/ zkhuh X @ [email protected] / lv edvhg rq wkdw ghulyhge| Ehwkh +4huhqw ydoxhv iru wkh p frh!flhqw/ wr lpsuryhshuirupdqfh rq wkh oljkw hohphqwv=

    N olqhv p @ 3=< h{fhsw iru F Nò +p @ 3=;;;, / Q Nò +p @ 3=;9, dqgR Nò +p @ 3=;

  • Fkdswhu 61 Pdwul{ fruuhfwlrq prghov= Exon

    U lv fdofxodwhg xvlqj wkh h{suhvvlrq=

    U @ 4ý çì çZ ^4ýJ +X3,` +6173,

    zkhuh wkh phdq edfnvfdwwhu frh!flhqw çì lv jlyhq e|=

    çì @ 4=:8 ü 43ý6 ç]f . 3=6:û4ý h{s ý3=348 ü ç]4=6f üú +6174,

    dqg ç]f lv gh?qhg e| wkh iroorzlqj dyhudjlqj uxoh=

    ç]f @í[



    Wkh phdq uhgxfhg hqhuj| ri wkh edfnvfdwwhuhg hohfwurq/ çZ / lv fdofxodwhg dviroorzv +xqghu qrupdo shushqglfxodu ehdp lqflghqfh,=

    çZ @çH

    [email protected] 3=8huhqw dffhohudwlrq yrowdjhv duh frpsduhg wr hdfk rwkhu1

    î Vxuidfh lrqlvdwlrq ydoxh * +3,Edvwlq wulhg d qxpehu ri h{suhvvlrqv iru * +3, lq wkh grxeoh Jdxvvldq prgho1Iluvwo| wkh ruljlqdo h{suhvvlrq e| Srxfkrx dqg Slfkrlu ^55`/ zklfk zdv xvhg lqwkh suhylrxv vxuidfh fhqwuhg prgho wrr=

    * +3, @ 4 . 6=6

    ë4ý 4


    êì4=5 +6179,


  • Grxeoh Jdxvvldq prgho 6181

    zlwk ð @ 5ý 5=6ì1Iru wkh grxeoh Jdxvvldq prgho/ Edvwlq ?wwhg d qhz h{suhvvlrq rq d odujhdprxqw ri h{shulphqwdo gdwd froohfwhg iurp wkh wklq ?op phdvxuhphqwv rqvxssruwhg dqg xqvxssruwhg Do dqg Sg ?opv rq pdq| gl>huhqw vxevwudwhv ^59`1Wkh h{suhvvlrqv duh edvhg xsrq Uhkedfk dqg Ndugxfn*v ^5:` h{suhvvlrqv/ re0wdlqhg iurp Prqwh Fduor vlpxodwlrq/ xvlqj X3 ghshqghqf|=

    * +3, @ 4 . e üë4ý 4s



    zlwk/ dffruglqj wr Uhkedfk dqg Ndugxfn=

    d @

    ë4 . 3=338



    êë3=9; .





    e @

    ë4 .



    êýý3=34 . 3=37;38] ý 3=848

  • Grxeoh Jdxvvldq prgho 6181

    Hdfk sdudphwhu lv ghvfulehg e| d sdudphwhulvdwlrq ghulyhg e| edvlf sk|vlfvdqg2ru h{shulphqwdo ?wwlqj dqg duh edvhg xsrq sk|vlfdo txdqwlwlhv dqg frqvwdqwv1Wkh iroorzlqj olvw vkrzv wkhlu ghshqghqfh rq wkh sk|vlfdo sdudphwhuv=

    ò @ i +H3> Hf> ]>D> M,

    ã}p @ i +H3> Hf> ]>D> M,

    IL @ i +H3> Hf> ]>D> M,

    * +3, @ i +H3> Hf> ], +6185,

    zkhuh ] dqg D ghqrwh wkh dwrplf qxpehuv dqg pdvv ri doo hohphqwv/ wkh udgldwlqjhohphqw lq txhvwlrq dv zhoo dv wkh pdwul{ hohphqwv1

    Wkh edvlf surfhgxuh lv wr ghwhuplqh wkh wrwdo jhqhudwhg [0ud| lqwhqvlw| ILxvlqj wkh dwrplf qxpehu fruuhfwlrq ri Srxfkrx dqg Slfkrlu ^55`1 Vxevhtxhqwo| ò/ã}p/ dqg * +3, duh fdofxodwhg dqg ñ lv fdofxodwhg xvlqj wkh rwkhu sdudphwhuv dqg dqqxphulf lwhudwlyh dssur{lpdwlrq phwkrg1 Ilqdoo| *p lv fdofxodwhg1

    Zlwk wkh rewdlqhg * +ã}, fxuyh ghvfulelqj wkh ghswk glvwulexwlrq ri wkh [0ud|surgxfwlrq/ wkh wrwdo hplwwhg [0ud| lqwhqvlw| lv fdofxodwhg/ fruuhfwlqj wkh jhqhudwhglqwhqvlw| iurp hyhu| vshfl?f ghswk iru devruswlrq rq wkh sdwk wr wkh [0ud| ghwhfwru1Qrwh/ wkdw * khuh vwloo ghqrwhv wkh lqwhqvlw| ri [0ud|v surgxfhg lq d wklq od|hu exulhgehqhdwk wkh vxuidfh lq uhodwlrq wr wkh vdph od|hu iuhh dqg xqvxssruwhg/ dqg wkdw wkh* +ã}, fxuyhv iru hdfk hohphqw lq erwk vshflphq dqg vwdqgdug kdyh wr eh ghwhuplqhgdqg lqwhjudwhg wr jhw wr wkh n0udwlrv ri hdfk hohphqw1


  • Eleolrjudsk|

    ^4` M1 Sklolehuw1 D phwkrg iru fdofxodwlqj wkh devruswlrq fruuhfwlrq lq hohfwurq surehplfurdqdo|vlv1 Lq= Surfhhglqjv ri wkh 6ug Lqwhuqdwlrqdo Frqjuhvv rq [0Ud| Rswlfvdqg Plfurdqdo|vlv +LF[RP,/ ss1 6:


    ^43` J1I1 Edvwlq/ I1M1M1 ydq Orr/ dqg K1M1P1 Khlmoljhuv1 Hydoxdwlrq ri wkhxvh ri jdxvvldq fxuyhv lq txdqwlwdwlyh hohfwurq sureh plfurdqdo|vlv= D qhzrswlpl}dwlrq1 [0ud| Vshfwurp1/ 46+5,=


    ^55` M1 O1 Srxfkrx dqg I1 Slfkrlu1 Edvlf h{suhvvlrq ri %SDS% frpsxwdwlrq iru txdq0wlwdwlyh HSPD1 Lq= M1 G1 Eurzq dqg U1 K1 Sdfnzrrg/ hglwruv/ Surfhhglqjv riwkh 44wk Lqwhuqdwlrqdo Frqjuhvv rq [0Ud| Rswlfv dqg Plfurdqdo|vlv +LF[RP,/ss1 57



  • Fkdswhu 7

    Pdwul{ fruuhfwlrq prghov iruwkh xvh lq wklq ?opv

    714 Lqwurgxfwlrq

    Zkhq wkh vdpsoh lv d wklq ?op/ vxssruwhg rq d vxevwudwh ri d gl>huhqw pdwhuldo ruhyhq iuhh dqg xqvxssruwhg/ wkh hohfwurqv iurp wkh lqflghqw ehdp zloo shqhwudwh wkhwklq od|hu dqg duh olnho| wr wudyho wkurxjk wkh od|hu dqg hvfdsh iurp lw dw wkh rwkhuvlgh/ hqwhulqj wkh qh{w od|hu +zklfk fdq eh wkh vxevwudwh,/ ru hvfdslqj lqwr wkh ydfxxplq fdvh ri wkh xqvxssruwhg wklq ?op1 Ri frxuvh/ wkh sk|vlfv ri wkh vfdwwhulqj hyhqwvlv vwloo wkh vdph/ dqg wkhuhiruh zh vkrxog eh deoh wr dsso| wkh vdph prghov1 Lq idfwzh frxog vhh wkh exon fdvh dv d ghjhqhudwhg yhuvlrq ri wkh wklq ?op dqdo|vlv sureohp/zlwk wkh ?op wklfnqhvv dssurdfklqj lq?qlwh ydoxhv1

    Krzhyhu/ wkh vsuhdglqj ri wkh hohfwurqv gxh wr vfdwwhulqj/ wkh edfnvfdwwhulqj rihohfwurqv dqg wkh surgxfwlrq ri [0ud|v zloo eh gl>huhqw lq hdfk od|hu dqg/ pruhryhu/wkh vfdwwhulqj lq rqh od|hu lq xhqfhv wkh sdwk dqg hqhuj| ri wkh hohfwurqv lq hdfkrwkhu od|hu erwk deryh dqg ehorz wkh fxuuhqw od|hu1 Lq fdvh ri dq xqvxssruwhg ?opiru h{dpsoh/ wkhuh zloo eh qr edfnvfdwwhulqj rqfh wkh hohfwurqv kdyh wudyhoohg wkurxjkwkh ?op/ zkhuhdv lq wkh exon fdvh wkhuh zrxog eh dq dprxqw ri hohfwurqv uhhqwhulqj wkh?op e| vfdwwhulqj edfn iurp wkh vxevwudwh/ frqwulexwlqj wr dq hqkdqfhg surgxfwlrqri [0ud|v lq wkh ?op1

    Lw lv reylrxv wkdw wkh rqo| zd| wr jhw dq dssursuldwh dqdo|vlv lq fdvh wkhh{flwdwlrq yroxph lv qrw d krprjhqhrxv pdwhuldo exw exlow xs ri gl>huhqw od|huv/ lve| kdylqj d ghswk0uhodwhg ghvfulswlrq ri [0ud| surgxfwlrq1 Vlqfh wklv lv h{dfwo| zkdwwkh * +ã}, fxuyh grhv/ * +ã}, prghoolqj lv lghdo iru wklq ?op dqdo|vlv1 Rq wkh rwkhu


  • Fkdswhu 71 Pdwul{ fruuhfwlrq prghov iru wkh xvh lq wklq ?opv

    kdqg/ lw dovr ehfrphv hyhq pruh lpsruwdqw wr ?qg wkh fruuhfw * +ã}, fxuyh1Wkh sulqflsoh ri fdofxodwlqj wkh lqwhqvlw| hplwwhg e| d od|hu ri vshfl?f frp0

    srxqg orrnv yhu| vwudljkwiruzdug= Wkh fdofxodwlrq lv shuiruphg e| sduwldo lqwhjudwlrqri wkh * +ã}, fxuyh ri wkh vshfl?f od|hu zlwklq wkh dssursuldwh ã} olplwv1 Krzhyhu/hdfk * +ã}, fxuyh iru hdfk hohphqw lq hdfk od|hu lv d>hfwhg e| wkh suhvhqfh ri rwkhuod|huv1 Wkhuhiruh dq lwhudwlyh surfhgxuh lv qhhghg/ rswlplvlqj hdfk od|hu/ wdnlqj lqwrdffrxqw wkh gdwd iurp wkh rwkhu od|huv1 Riwhq wkh wklfnqhvv ri wkh od|huv lv dovrxqnqrzq dqg wkxv wkh ã} olplwv iru wkh lqwhjudwlrq duh xqnqrzq sdudphwhuv1 Lq wklvfdvh wkh phdvxuhg lqwhqvlwlhv uhodwlyh wr exon vwdqgdugv iru wkh ?op fdq eh xvhg lq dqlwhudwlyh surfhgxuh wr ?qg wkh od|hu wklfnqhvv1

    715 ) E45ä prghoolqj xvhg iru wklq ?op dqdo|vlv

    Edvwlq dqg Khlmoljhuv vwduwhg lq 4

  • * +ã}, prghoolqj xvhg iru wklq ?op dqdo|vlv 7151

    wr fdofxodwh wkh hplwwhg lqwhqvlwlhv iurp ?op dqg vxevwudwh1 Sduwldo lqwhjudwlrq riwkh Do0Nò * +ã}, fxuyh ehwzhhq wkh ã} olplwv 3 dqg W zloo |lhog wkh wrwdo jhqhudwhgDo0Nò udgldwlrq lqwhqvlw|/ zkloh lqwhjudwlrq ri wkh Vl0Nò fxuyh ehwzhhq W dqg4 zloo|lhog wkh jhqhudwhg Vl0Nò lqwhqvlw|1 Ri frxuvh/ erwk lqwhqvlwlhv kdyh wr eh fruuhfwhgiru vhoi devruswlrq/ dqg dgglwlrqdoo| wkh hplwwhg Vl0Nò udgldwlrq +vxevwudwh, kdv wr ehfruuhfwhg iru devruswlrq gxh wr sdvvlqj wkurxjk wkh ryhuod|lqj Do od|hu1 Li wkh od|huwklfnqhvv lv xqnqrzq/ wkh phdvxuhg lqwhqvlw| udwlrv uhodwlyh wr wkh exon vwdqgdugv iru?op dqg vxevwudwh hohphqwv fdq eh xvhg lq dq lwhudwlyh surfhgxuh wr fdofxodwh lw1

    Wklv ?uvw dssur{lpdwlrq zrunv ?qh dv orqj dv wkh gl>huhqfh lq dwrplf qxpehuehwzhhq wkh vxevwudwh dqg ?op hohphqwv lv vpdoo/ vd| 6 wr 7 xqlwv1 Zkhq krzhyhu/wkh dwrplf qxpehu ri hohphqwv lq wkh vxevwudwh lv vxevwdqwldoo| kljkhu ru orzhu wkdqwkh dwrplf qxpehu ri wkh hohphqw lq ?op/ d fruuhfwlrq kdv wr eh dssolhg lq rughuwr ghdo zlwk wkhvh gl>huhqfhv1 Wklv sureohp lv vroyhg e| xvlqj wkh iroorzlqj edvlfdvvxpswlrqv=

    î Wkh ã} vfdoh lq hdfk sduwlfxodu * +ã}, fxuyh lv frqwlqxrxv dfurvv wkh lqwhuidfhv/dqg iru hdfk hohphqw lq wkh ?op ru vxevwudwh/ rqo| rqh frqwlqxrxv * +ã}, fxuyhlv fdofxodwhg1

    î Rqo| wkh * +ã}, fxuyhv iru wkh hohphqwv lq wkh ?op duh d>hfwhg e| wkh qdwxuh dqgwklfnqhvv ri wkh rwkhu ?opv dqg wkh vxevwudwh/ zkhuhdv wkh vxevwudwh hohphqwfxuyhv uhpdlq xqd>hfwhg1

    î Wkh vkdsh sdudphwhuv ò/ ã}p/ *3/ dqg IL/ dv ghvfulehg lq vhfwlrq 618/ iru wkh* +ã}, fxuyhv ri hdfk hohphqw lq wkh ?op ydu| ehwzhhq wzr h{wuhphv/ w|slfdo rihlwkhu h{wuhpho| wklq ?opv ru h{wuhpho| wklfn ?opv1 Lq wkh odwwhu fdvh/ lw zloo ehfohdu wkdw wkh exon sdudphwhuv iru wkh ?op hohphqw zloo eh dssurdfkhg/ zkhuhdvlq wkh iruphu fdvh/ wkh sdudphwhuv fdq eh dssur{lpdwhg dv li wkh hohphqwzdv glvvroyhg lq wkh vxevwudwh1 Lq doo lqwhuphgldwh fdvhv/ wkh sdudphwhuv duhfrpsrvhg wkurxjk zhljkwlqj surfhgxuhv/ lq zklfk wkh Jdxvvldq sdudphwhuv iruhdfk sduwlfxodu hohphqw lq hdfk ri wkh od|huv dqg lq wkh vxevwudwh duh dvvljqhgvshfl?f zhljkw idfwruv ghshqglqj rq wkh glvwdqfh wr wkh od|hu h{dplqhg1

    Fdofxodwlrqv lqyroyhg zlwk wklq ?op dssurdfk1

    Lq wkh iroorzlqj glvfxvvlrq rq wkh wklq ?op dssurdfk/ wkh vxevfulswv e/ i / dqg v zlooeh xvhg wr lqglfdwh wkdw zh duh ghdolqj zlwk exon/ ?op ru vxevwudwh txdqwlwlhv1

    D vwhs e| vwhs glvfxvvlrq ri wkh wklq ?op surfhgxuh=

    41 Iluvwo| wkh exon vwdqgdug lqwhqvlwlhv iru doo hohphqwv lq ?op dqg vxevwudwh duhfdofxodwhg1 Iru wkdw/ wkh ò/ ã}p/ *3/ dqg IL ydoxhv iru hdfk hohphqw l duh ehlqj


  • Fkdswhu 71 Pdwul{ fruuhfwlrq prghov iru wkh xvh lq wklq ?opv

    fdofxodwhg dffruglqj wr wkh exon surjudp1

    51 Wkh ò ydoxhv iru hohphqw l0udgldwlrq lq doo rwkhu hohphqwv m duh fdofxodwhg1Vxevhtxhqwo| wkh ò ydoxhv iru wkh ?op hohphqwv duh frpsrvhg rq wkh edvlv riwkh exon frpsrvlwlrqv ri ?op dqg vxevwudwh wr |lhog òle>i dqg ò

    le>v uhvshfwlyho|1

    Wkhvh ò ydoxhv zloo eh xvhg odwhu lq d zhljkwlqj surfhgxuh wr hvwdeolvk wkh ?qdoòl0ydoxh w|slfdo iru wkh frpsohwh ?op2vxevwudwh frpelqdwlrq1

    61 Lq d vlplodu zd| wkh frpsrvhg ydoxhv ri ã}p/ *3/ dqg IL iru wkh exon frpsr0vlwlrqv ri ?op dqg vxevwudwh duh ehlqj fdofxodwhg iru hdfk hohphqw l0udgldwlrq1Li dq hohphqw rffxuv lq pruh wkdq rqh od|hu ru lq erwk ?op dqg vxevwudwh/ hdfkhohphqw0od|hu frpelqdwlrq lv odehoohg dqg fdofxodwhg vhsdudwho|/ dqg odwhu rq/dgghg wr |lhog wkh wrwdo hplwwhg lqwhqvlw| iru wkdw vshfl?f hohphqw1

    71 Wkh qh{w dqg fuxfldo vwhs lv wr hvwdeolvk wkh ghswk ri shqhwudwlrq U{ iruhdfk hohphqw l0udgldwlrq1 Vlqfh wkhuh lv qr ?{hg hqg wr wkh Jdxvvldq fxuyhd frqyhqlhqw phdvxuh kdg wr eh fkrvhq dw zklfk wkh Jdxvvldq kdv gursshgehorz d fhuwdlq ohyho1 Edvhg xsrq wkh roghu/ vxuidfh fhqwuhg/ Jdxvvldq prgho/Edvwlq ghvfulehg wklv srlqw e| ã} @ ã}lp . [email protected]ò

    l1 Vxevwlwxwlqj wklv srlqw lqwkh htxdwlrq ri uljkw kdqg sduw ri wkh grxeoh Jdxvvldq fxuyh iru wkh jhqhudwhglqwhqvlw| 61; uhvxowv lq=

    *ýã}lp . [email protected]ò

    lü@ *p h{s

    íý ýòlü5 ýã}lp . [email protected]òl ý ã}lpü5ì

    @ 3=334i dqg ò

    le>v/ xvlqj zhljkwlqj idfwruv wr zhljk wkhlu frqwulexwlrqv

    ryhu wkh uhohydqw pdvv ghswk uhjlrq grzq wr U{1 Vlqfh U{zdv wkh xqnqrzq wreh fdofxodwhg wklv sureohp kdg wr eh vroyhg e| xvlqj dq lwhudwlyh surfhgxuh1+Qrwh wkdw *p lv dovr xqnqrzq,1

    Lq wkh zhljkwlqj surfhgxuh +vlplodu wr wkh rqh xvhg e| Srxfkrx dqg Slfkrlu^:`^;`,/ wkh zhljkwlqj idfwruv s iru hdfk sdudphwhu duh ghvfulehg dv ixqfwlrq riwkh pdvv ghswk e| d irxuwk ghjuhh sro|qrpldo=

    s +ã}, @ Q +ã} ý O,5 ü +ã} ýU,5 +715,

    lq zklfk O dqg U duh ixqfwlrqv ri U{ rswlplvhg iru wkh vshfl?f sdudphwhu1 Odqg U duh wkh grxeoh urrwv rq wkh ohiw dqg uljkw kdqg vlgh ri wkh sro|qrpldo


  • * +ã}, prghoolqj xvhg iru wklq ?op dqdo|vlv 7151

    dqg Q lv d qrupdolvdwlrq idfwru wkdw hqvxuhv wkh qrupdolvdwlrq xqghu wkh s +ã},fxuyh1 Iru wkh ghwhuplqdwlrq ri wkh dssursuldwh U{ ydoxh/ lq rughu wr ghwhuplqhwkh ?fwlwlrxv *hqg* ri wkh * +ã}, fxuyh iru hohphqw l/ wkh rswlplvhg urrwv xvhgduh O @ ý3=7U{ dqg U @ U{1Wr vwduw wkh lwhudwlyh surfhgxuh/ wkh dyhudjh ri wkh

    ýã}lp . [email protected]ò

    lüydoxhv iru

    wkh exon ri wkh ?op dqg wkh vxevwudwh lv wdnhq dv dq lqlwldo urxjk hvwlpdwlrqri U{1 Zlwk wklv lqlwldo U{ ydoxh dqg wkh urrwv phqwlrqhg deryh/ d qhz U{lv fdofxodwhg e| lqwhjudwlrq ri wkh s ixqfwlrq1 Wkh qhzo| rewdlqhg U{ ydoxh lvfrpsduhg wr wkh suhylrxv rqh dqg wkh lwhudwlyh surfhgxuh lv vwrsshg zkhq wkhuhodwlyh ghyldwlrq lv vpdoohu wkdq 314 (1 Li qrw/ wkh qhz U{ ydoxh lv djdlq xvhgwr fdofxodwh qhz U dqg O ydoxhv dqg wkh surfhgxuh lv uhshdwhg1

    81 Rqfh wkh ?qdo U{ ydoxh kdv ehhq rewdlqhg/ wkh irxu sdudphwhuv wr ghvfulehwkh * +ã}, fxuyh iru hdfk hohphqw lq wkh ?op2vxevwudwh frpelqdwlrq fdq ehghwhuplqhg e| fdofxodwlqj wkh zhljkw idfwruv xvlqj wkh dffrpsdq|lqj U dqgO ixqfwlrqv iru hdfk sdudphwhu1 Edvwlq rswlplvhg wkhvh urrwv e| xvlqj wklq?op gdwd iurp olwhudwxuh dqg ?qh0wxqlqj wkhq e| xvlqj wkh wklq ?op gdwdedvh riphdvxuhphqwv shuiruphg lq rxu rzq jurxs/ dqg irxqg wkh iroorzlqj h{suhvvlrqv=

    O U

    ò ý3=6U{ U{ã}p ý3=hfwhg e| wkhsuhvhqfh ri wkh ?op> wklv dvvxpswlrq vhhpv wr eh mxvwl?hg li wkh ?op fdq eh frqvlghuhgwklq uhodwlyh wr wkh wrwdo shqhwudwlrq ri wkh * +ã}, fxuyh1

    Diwhu pdnlqj wkh dssursuldwh devruswlrq fruuhfwlrqv/ wdnlqj wkh udwlr wr wkhhplwwhg lqwhqvlwlhv fdofxodwhg iru wkh exon vwdqgdugv zloo |lhog wkh vr0fdoohg n0udwlrv1


  • Fkdswhu 71 Pdwul{ fruuhfwlrq prghov iru wkh xvh lq wklq ?opv

    71515 Uhyhuvh fdvh= Xqnqrzq ?op wklfnqhvv zlwk nqrzq frp0srvlwlrqv/ xvlqj phdvxuhg &0udwlrv

    Qrupdoo|/ zkhq shuiruplqj phdvxuhphqwv rq wklq ?opv/ rqh zrxog olnh wr shuirup wkhsurfhgxuh phqwlrqhg lq wkh suhylrxv sdudjudsk wkh rwkhu zd| durxqg/ l1h/ vwduwlqjzlwk phdvxuhg n0udwlrv dqg fdofxodwlqj wkh xqnqrzq ?op wklfnqhvv1 Vxssrvhg wkh?op dqg vxevwudwh frpsrvlwlrq duh nqrzq/ dqg rqh zrxog olnh wr fdofxodwh wkh ?opwklfnqhvv/ rqh vlqjoh n0udwlr iurp hlwkhu ?op ru vxevwudwh douhdg| lv vx!flhqw iru wklv1Pruh n0udwlrv/ dqg lghdoo| doo n0udwlrv iurp doo hohphqwv lq erwk ?op dqg vxevwudwhzloo wkhuhiruh surylgh xv zlwk lqirupdwlrq derxw wkh frqvlvwhqf| ri wkh v|vwhp dqgrxu phdvxuhphqwv1 Jurvv ghyldwlrqv pd|/ iru h{dpsoh/ srlqw wr wkh suhvhqfh rixqdqwlflsdwhg od|huv ru hohphqwv1

    Wr fdofxodwh wkh xqnqrzq wklfnqhvv xvlqj wkh wklq ?op dssurdfk dv phqwlrqhglq wkh suhylrxv sdudjudsk/ djdlq dq lwhudwlyh surfhgxuh kdv wr eh xvhg1 Vwduwlqj zlwkvrph lqlwldo hvwlpdwh ri wkh ?op wklfnqhvv/ wkh n0udwlrv iru vxevwudwh dqg ?op/ ne>vdqg ne>i uhvshfwlyho|/ fdq eh fdofxodwhg1 Vxevhtxhqwo| d qhz dssur{lpdwlrq iru wkh?op wklfnqhvv fdq eh pdgh e| frpsdulqj wkhvh fdofxodwhg n0udwlrv zlwk wkh phdvxuhgrqhv1 Xvlqj wkh qhz hvwlpdwhv/ wkh surfhgxuh lv uhshdwhg/ dqg wklv f|foh lv uhshdwhgxqwlo wkh ghyldwlrq lq ghulyhg ?op wklfnqhvv lv vljql?fdqwo| orz1

    Iru d ?uvw hvwlpdwlrq ri wkh ?op wklfnqhvv/ wkh surfhgxuh vwduwv zlwk wkhfdofxodwlrq ri d jhqhudo udqjh ri shqhwudwlrq U41 Iru wklv sxusrvh wkh htxdwlrqU4 @ 6H

    53 lv dgrswhg +U4 lq ç[email protected]

    5,1 Wkh ?op wklfnqhvv W / iru hdfk hohphqw llq wkh ?op/ lv qrz hvwlpdwhg dffruglqj wr=

    W li @ 3=68 üU4 ünlpnle>i


    zkhuh nlp lv wkh phdvxuhg n0udwlr iru hohphqw l1 Qrwh wkdw wklv n0udwlr fdq kdyhfrqwulexwlrqv iurp erwk ?op dqg vxevwudwh1

    Iru wkh vxevwudwh hohphqwv wkh ?uvw hvwlpdwlrqv duh pdgh dffruglqj wr=

    W lv @ 3=68 üU4 ü#4ý n




    Doo hvwlpdwhv iru wkh ?op dqg iru wkh vxevwudwh duh wkhq dyhudjhg wr |lhog dqlqlwldo Wi dqg Wv uhvshfwlyho|/ zkhuh Wv uhsuhvhqw wkh ?op wklfnqhvv edvhg xsrq wkhvxevwudwh hohphqw phdvxuhphqw1 Lq fdvh wkh vdph hohphqw rffxuv lq erwk ?op dqgvxevwudwh/ iru h{dpsoh dq r{lgh od|hu/ Do5R6/ rq Do/ wkh +frpelqhg, n0udwlr iru wklvryhuodsslqj hohphqw lv xvhg lq wkh ?uvw hvwlpdwh iru wkh ?op wklfnqhvv lq wkh ?op


  • * +ã}, prghoolqj xvhg iru wklq ?op dqdo|vlv 7151

    hohphqw f|foh dffruglqj wr=

    W li @ 3=8 üU4 ünle>v ý nlpnle>v ý nle>i


    Wkh qh{w vwhs lv wr fdofxodwh wkh frpelqhg n0udwlrv/ nlf/ zlwk wkh wklq ?opsurfhgxuh dv lq wkh suhylrxv sdudjudsk xvlqj wkh ?uvw hvwlpdwlrqv ri wkh ?op wklfnqhvv1Wklv lv grqh iru hdfk lqyroyhg hohphqw1 Wkh frpelqhg n0udwlrv uhsuhvhqw wkh frpelqhgfrqwulexwlrqv iru wkh hohphqw l iurp wkh ?op dqg wkh vxevwudwh1

    Vxevhtxhqwo| qhz hvwlpdwlrqv iru Wi dqg Wv kdyh wr eh pdgh e| frpsdulvrqri wkh fdofxodwhg n0udwlrv/ nlf/ wr wkh phdvxuhg n0udwlrv/ n

    lp1 Iru wklv wkh iroorzlqj

    htxdwlrqv duh xvhg=

    W li>qhz @ Wi>rog ünlpnlf


    Li ryhuods ri dq hohphqw rffxuv/ ehfdxvh lw rffxuv lq erwk ?op dqg vxevwudwh/ wkh qhzhvwlpdwlrq edvhg rq wkdw hohphqw lv jlyhq e|=

    W li>qhz @ Wi>rog ünle>v ý nlpnle>v ý nlf


    Wkh qhz ?op wklfnqhvv/ edvhg rq hvwlpdwhv ri wkh vxevwudwh gdwd/ lv fdofxodwhg e|=

    W lv>qhz @ Wv>rog ünle>v ý nlpnle>v ý nlf

    +71hu ohvv wkdq 314 (iurp wkh suhylrxv rqhv/ ru zkhqhyhu qr frqyhujhqfh lv dfklhyhg zlwklq d uhdvrqdeohqxpehu ri f|fohv1 Xvxdoo| vxfk fdvhv lqglfdwh lqdghtxdwh phdvxulqj frqglwlrqv zkhuh/iru h{dpsoh/ d wrr orz dffhohudwlrq yrowdjh lv xvhg dqg wkh * +ã}, fxuyh grhv qrw uhdfkvx!flhqwo| lqwr wkh vxevwudwh1

    71516 Ilop ri xqnqrzq wklfnqhvv dqg frpsrvlwlrq/ xqvxssru0whg ru rq nqrzq vxevwudwh

    Lq uhdolw|/ riwhq erwk wkh wklfnqhvv dqg wkh frpsrvlwlrq ri d ?op duh xqnqrzq1 Lw lvreylrxv wkdw iru vxfk fdvhv d grxeoh lwhudwlyh surfhgxuh kdv wr eh xvhg1 Iru uhdvrqvri fodulw| zh zloo olplw wkh glvfxvvlrq wr wkh vlwxdwlrq zkhuh wkhuh lv qr ryhuods rihohphqwv lq ?op dqg vxevwudwh1


  • * +ã}, prghoolqj xvhg iru wklq ?op dqdo|vlv 7151

    Dw wkh vwduw ri wkh grxeoh lwhudwlyh surfhgxuh/ wkh phdvxuhg n0udwlrv duh xvhgdv gluhfw lqsxw iru wkh ?uvw hvwlpdwlrqv ri wkh zhljkw iudfwlrqv/ {l/ ri wkh hohphqwvsuhvhqw1 Wkh zhljkw iudfwlrqv duh qrupdolvhg wr |lhog d wrwdo ri 433 (1 Qrz/ iru wklvvwduwlqj frpsrvlwlrq doo fdofxodwlrqv ghvfulehg lq wkh suhylrxv vhfwlrq duh shuiruphg=Wkh wklfnqhvv hvwlpdwlrqv duh pdgh dqg wkh hplwwhg lqwhqvlwlhv iru doo hohphqwv duhfdofxodwhg1 Wkh uhvxowlqj fdofxodwhg n0udwlrv duh frpsduhg wr wkh phdvxuhg rqhv dqgqhz hvwlpdwlrqv duh pdgh dffruglqj wr htxdwlrqv 71: dqg 71;1 Dw wklv srlqw dovrqhz hvwlpdwlrqv iru wkh zhljkw iudfwlrqv duh pdgh vlpxowdqhrxvo|/ xvlqj wkh iroorzlqjh{suhvvlrq=

    {lqhz @ {lrog ü



    Diwhu hdfk f|foh lw lv fkhfnhg zkhwkhu frqyhujhqfh kdv ehhq rewdlqhg iru erwk ?opwklfnqhvv dqg wkh zhljkw iudfwlrqv1 Wkh hqg ri wkh surfhgxuh lv qrz gh?qhg e| wzrfulwhuld/ rqh iru wkh wklfnqhvv/ zklfk vkrxog ydu| ohvv wkdq 314 ( dqg d vhfrqg rqh iruwkh zhljkw iudfwlrqv zkhuh wkh ghyldwlrq vkrxog eh zlwklq d fhuwdlq olplw/ vd| 313336devroxwh1 Qrwh wkdw erwk fulwhuld vkrxog eh pdwfkhg dqg wkdw wkh olplwv iru wkhvhfulwhuld fdq eh vhw dw fkrlfh1 Wkh ydoxhv xvhg khuh duh wdnhq iurp Edvwlq ^7`1

    71517 Rwkhu/ pruh frpsoh{ fdvhv

    Lw lv dovr srvvleoh wr vroyh pruh frpsoh{ vlwxdwlrqv zlwk wkh wklq ?op surjudp1 Hyhqdq h{whqvlrq wr pxowlsoh od|huv dqg lq0ghswk sur?olqj kdv ehhq pdgh e| Edvwlq1 Lqsulqflsoh/ lq0ghswk sur?olqj fdq eh grqh e| ydu|lqj wkh dffhohudwlrq yrowdjh/ dqg wkxvwkh shqhwudwlrq ghswk1 Pruh lqirupdwlrq derxw pxowlod|hu surfhvvlqj fdq eh irxqglq ^7` dqg ^9`1

    Li dq hohphqw lv suhvhqw lv erwk ?op dqg vxevwudwh/ hlwkhu wkh ?op wklfnqhvvkdv wr eh vxssolhg/ ru/ rqh fdq xvh lqirupdwlrq rq wkh vwrlfklrphwu|1 Wkh odwwhufdvh lv riwhq xvhg iru fdofxodwlrq ri r{lghv/ zkhuh vwrlfklrphwu| lv zhoo0nqrzq1 Lw lvdovr srvvleoh wr fdofxodwh wkh frpsrvlwlrq ri dq xqnqrzq vxevwudwh exulhg ehorz dwklq od|hu ri nqrzq frpsrvlwlrq/ exw xqnqrzq wklfnqhvv1 Wklv lv yhu| xvhixo lq exonphdvxuhphqwv zkhuh gholehudwho| d wklq ?op +xvxdoo| fduerq, kdv ehhq ghsrvlwhg rqwkh vshflphq/ dqg fdq dovr eh xvhg wr wdnh lqwr dffrxqw vxuidfh od|huv olnh qdwlyhr{lgh vnlqv1

    Pruh lpsruw wr wklv wkhvlv/ krzhyhu/ lv wkh xvh ri wkh wklq ?op surfhgxuhlq fdvh ri dq xqvxssruwhg wklq ?op1 Lq vxfk fdvh wkh dssur{lpdwlrq lv edvhg rqwkh dvvxpswlrq wkdw wkh vxevwudwh frxog eh uhjdughg wr kdyh dq dwrplf qxpehudssurdfklqj }hur1 Wklv lv lqghhg wkh olqh ri uhdvrqlqj iroorzhg lq wklv wkhvlv1 Pruhderxw wklv phwkrg zloo eh ghvfulehg lq wkh qh{w fkdswhu1


  • Eleolrjudsk|

    ^4` J1 I1 Edvwlq dqg K1 M1 P1 Khlmoljhuv1 Txdqwlwdwlyh hohfwurq sureh plfurdqdo|vlv/d qhz dssolfdwlrq= Wklq ?op dqdo|vlv1 Dwe Phwdooxujlh/ 6=:58:;/ +4



  • Fkdswhu 8

    Txdqwlwdwlyh dqdo|vlv lq WHP

    814 Lqwurgxfwlrq

    Doo wkhru| ghvfulehg lq wkh suhylrxv fkdswhuv/ kdv ehhq lqwurgxfhg rq edvlv ri hohfwurqsureh plfur dqdo|vhu +HSPD, dqg vfdqqlqj hohfwurq plfurvfrsh +VHP, xvh1 Prvwri wklv lv xvhg iru dqdo|vlv ri exon vdpsohv zlwk vrph h{whqvlrqv wr wklq ?op phd0vxuhphqwv ghyhorshg iru wkh HSPD1 Wklv phdqv lpsolflwo|/ wkdw wkh prghov zhuhghyhorshg iru HSPD dqg VHP frqglwlrqv= dffhohudwlrq yrowdjhv udqjlqj iurp dv orzdv ÷ 5 nY xs wr d pd{lpxp ri 73 nY/ zlwk dq rffdvlrqdo phdvxuhphqw dw 83 nY1

    Vlpxowdqhrxv zlwk wkh ghyhorsphqw ri wkhvh pdwul{ fruuhfwlrq surfhgxuhv iruHSPD dqg VHP xvh/ dqdo|wlfdo wudqvplvvlrq hohfwurq plfurvfrs| zdv ghyhorshg1Krzhyhu/ wkhuh zdv olwwoh ru qr olqn ehwzhhq wkhvh wzr ?hogv ri hohfwurq plfurvfrs|1Dqdo|wlfdo WHP kdv riwhq ehhq/ dqg suredeo| vwloo lv/ phuho| dq h{wud lqirupdwlrqvrxufh wr WHP lpdjhv dqg wr vwuxfwxudo lqirupdwlrq rewdlqhg wkurxjk vhyhudo gl>udf0wlrq whfkqltxhv1 Lw lv xvhg dv d txdolwdwlyh phwkrg/ qrw dv d txdqwlwdwlyh whfkqltxhrq lwv rzq1

    Iru txdqwlwdwlyh dqdo|wlfdo WHP/ wkh WHP prghov zhuh edvhg rq wkh xowud wklq?op dssur{lpdwlrq= Xvlqj wklq ?op uhihuhqfhv dqg dvvxplqj qr devruswlrq fruuhfwlrqvkdg wr eh pdgh dv orqj dv wkh WHP vdpsohv zhuh wklq hqrxjk1 Lq vxfk fdvh rqh fdqgluhfwo| ghulyh wkh uhodwlyh frpsrvlwlrqv iurp wkh shdn lqwhqvlw| udwlrv zlwk rqo| dsursruwlrqdolw| frqvwdqw/ wr ghdo zlwk htxlsphqw vshfl?f sdudphwhuv1 Edvhg rq wklvyhu| vwudljkwiruzdug prgho/ h{whqvlrqv iru ehdp vfdwwhulqj dqg devruswlrq fruuhfwlrqvzhuh lqwurgxfhg1

    Wkh dqdo|wlfdo WHP phwkrg sursrvhg lq wklv wkhvlv frpelqhv wkh frpsuhkhq0vlyh ixoo pdwul{ fruuhfwlrq phwkrgv ghyhorshg iru HSPD xvh zlwk dqdo|wlfdo WHP


  • Fkdswhu 81 Txdqwlwdwlyh dqdo|vlv lq WHP

    phdvxuhphqwv1 Lw lv/ lq idfw/ dq h{wudsrodwlrq ri wkh * +ã}, dssurdfk iurp HSPD wrWHP frqglwlrqv1 Wkh iroorzlqj vhfwlrqv zloo jlyh dq ryhuylhz ri txdqwlwdwlyh WHPdqdo|vlv prghov dqg zloo glvfxvv wkhlu dgydqwdjhv dqg vkruwfrplqjv1

    81414 Dqdo|vlv frqglwlrqv lq wkh WHP

    Lw lv reylrxv wkdw wkhuh duh wzr pdlq gl>huhqfhv ehwzhhq WHP dqg HSPD dqdo|vlvphdvxuhphqwv1 Iluvwo|/ lq WHP/ wkh vshflphqv duh xvxdoo| yhu| wklq/ w|slfdoo| lq wkhrughu ri 433 qp1 Vhfrqgo|/ wkh phdvxulqj frqglwlrqv lq wkh WHP duh txlwh gl>huhqwfrpsduhg wr HSPD phdvxuhphqwv1 Lqvwhdg ri wkh 5073 nY dffhohudwlrq yrowdjh xvhglq wkh HSPD/ lq WHP dffhohudwlrq yrowdjhv frpprqo| udqjh iurp ;3 wr 633 nY1 Wkhfrpelqdwlrq ri wkhvh wzr frqglwlrqv/ d wklq vshflphq dqg d kljk dffhohudwlrq yrowdjh/uhvxowv lq d orz ehdp vfdwwhulqj zlwklq wkh vdpsoh1

    Vlqfh wkh furvv vhfwlrq iru hodvwlf vfdwwhulqj hyhqwv lv lqyhuvho| sursruwlrqdo wrwkh vtxduh ri wkh hqhuj|/ T å [email protected]/ wkh dyhudjh vfdwwhulqj dqjoh zloo eh orz zkhqwkh dffhohudwlrq yrowdjh lv kljk1 Vr/ wkh hohfwurq sdwk lq d w|slfdo WHP phdvxuhphqwzloo eh vwudljkwhu gxh wr wkh kljkhu ehdp hqhuj| dqg wkxv wkh ehdp vsuhdglqj zloo ehorz1 Ixuwkhupruh/ dffruglqj wr Ehwkh/ wkh udwh ri hqhuj| orvv zlwk glvwdqfh wudyhoohglv lqyhuvho| sursruwlrqdo wr wkh hqhuj|= [email protected] å [email protected] Wkhuhiruh/ dv wkh hqhuj| riwkh lqflghqw hohfwurqv lqfuhdvhv/ wkh hohfwurqv zloo qrw rqo| hqwhu wkh vshflphq zlwkd kljkhu hqhuj|/ exw dovr orvh wkh hqhuj| dw d orzhu udwh/ djdlq uhvxowlqj lq d orzhuehdp vsuhdglqj lq d wklq vshflphq +ru d odujhu shqhwudwlrq ghswk lq fdvh ri d exonvdpsoh,1 Dv dq h{dpsoh/ d Prqwh Fduor vlpxodwlrq ri wkh sdwkv ri hohfwurqv/ zlwk dqlqflghqw hqhuj| ri 533 nY/ lq dq Doxplqlxp ?op lv fdofxodwhg dqg vkrzq lq ?jxuh8141

    Li zh orrn dw wkh h{flwdwlrq yroxph/ d kljk hqhuj| hohfwurq ehdp zrxog uhvxowlq d yhu| odujh shdu vkdshg yroxph/ lq fdvh ri d exon vshflphq/ zkhuhdv lq d wklqWHP vshflphq/ rqo| wkh qduurz erwwoh0qhfn vkdshg duhd ri wklv h{flwdwlrq yroxphzloo eh *zlwklq* wkh vshflphq1 Lq whupv ri wkh * +ã}, fxuyh/ xvlqj d kljk dffhohudwlrqyrowdjh zloo uhvxow lq vwuhwfklqj wkh fxuyh rxw lqwr odujh ghswkv lq wkh vdpsoh/ zkhuhdvlq wkh WHP vshflphq/ zklfk fdq eh frqvlghuhg dv dq xqvxssruwhg wklq ?op fdvh/ rqo|wkh yhu| ehjlqqlqj ri wkh fxuyh zloo eh *zlwklq* wkh vdpsoh1 Wklv lpsolhv wkdw prvwdwwhqwlrq vkrxog jr rxw wr wkh vxuidfh sdudphwhuv olnh *31

    Wkh orz ehdp vsuhdglqj lv dovr rqh ri wkh eljjhvw dgydqwdjhv ri dqdo|vlv xvlqjd WHP= Gxh wr orz ehdp vsuhdglqj d yhu| kljk vsdwldo dqdo|vlv uhvroxwlrq fdq ehrewdlqhg/ zlwk uhvroxwlrqv lq wkh rughu ri ehdp gldphwhu1 Ghshqglqj rq wkh WHPxvhg wklv fdq eh lq wkh rughu ri 43 qp grzq wr dv orz dv 4 qp1 Wklv lv lq frqwudvwwr HSPD exon phdvxuhphqwv zkhuh wkh ehdp vsuhdglqj uhvxowv lq d shdu vkdshgh{flwdwlrq yroxph/ olplwlqj wkh vsdwldo uhvroxwlrq wr w|slfdoo| derxw 4 çp1


  • Prghov xvhg iru txdqwlwdwlyh dqdo|vlv lq wkh WHP 8151

    Iljxuh 8141 D Prqwh Fduor vlpxodwlrq ri 5333 hohfwurq wudmhfwrulhv wkurxjk d 533 qpwklfn Doxplqlxp ?op dw 533 nY1

    Wklv h{wuhpho| vpdoo h{flwdwlrq yroxph rewdlqhg lq d WHP dqdo|vlv/ rq wkhrwkhu kdqg/ dovr lv wkh eljjhvw glvdgydqwdjh= Gxh wr wkh yhu| vpdoo h{flwdwlrq yroxph/wkh orz qxpehu ri vfdwwhulqj hyhqwv dqg wkh orz hqhuj| orvv/ wkh dprxqw ri [0ud|vsurgxfhg zloo eh yhu| orz/ uhvxowlqj lq orz frxqw udwhv1 Wklv ri frxuvh fdq eh frp0shqvdwhg e| xvlqj d odujh ehdp fxuuhqw1 Wklv/ krzhyhu zloo uhvxow lq d kljk hqhuj|ghqvlw| zlwk wkh fkdqfh ri vshflphq gdpdjh1 Ixuwkhupruh wklv odujh ehdp fxuuhqw lvriwhq gl!fxow wr dfklhyh dqg wr pdlqwdlq vwdeoh lq d WHP dqg lq jhqhudo eulqjv rq dodujhu ehdp vl}h1

    815 Prghov xvhg iru txdqwlwdwlyh dqdo|vlv lq wkh WHP

    81514 Fol>0Orulphu

    Dowkrxjk hduolhu uhsruwv rq frpelqhg xvh ri [0ud| plfurdqdo|vlv zlwk wudqvplvvlrqhohfwurq plfurvfrs| duh nqrzq ^4`/ Fol> dqg Orulphu zhuh wkh ?uvw wr lqwurgxfh dnlqg ri prghoolqj iru txdqwlwdwlyh dqdo|wlfdo WHP phdvxuhphqwv1 Wkh| uhodwhg wkhlqwhqvlwlhv/ phdvxuhg xvlqj dq HG[ ghwhfwru/ ri wkh fkdudfwhulvwlf [0ud|v +LD> LE> ==,wr wkh frpsrvlwlrqv lq zhljkw iudfwlrq +zw( = FD> FE> ==, wkurxjk wkh Fol>0Orulphuhtxdwlrq ^5`=


    @ nDELDLE



  • Fkdswhu 81 Txdqwlwdwlyh dqdo|vlv lq WHP

    zkhuh nDE lv d sursruwlrqdolw| frqvwdqw lqfrusrudwlqj vshflphq fkdudfwhulvwlfv dv zhoodv htxlsphqw sdudphwhuv1 Ghvslwh lwv olplwdwlrqv wklv vlpsoh htxdwlrq vwloo uhpdlqvwkh edvlv iru txdqwlwdwlyh dqdo|vlv diwhu pruh wkdq 58 |hduv1 Wkh n0idfwruv 0 qrw wreh frqixvhg zlwk wkh n0udwlrv xvhg lq * +ã}, prghoolqj 0 duh wkh fuxfldo sdudphwhuv1Wkh| fdq eh fdofxodwhg/ ghwhuplqhg h{shulphqwdoo| ru ghulyhg iurp hduolhu uhfrughgn0idfwruv1

    H{shulphqwdo ghwhuplqdwlrq ri n0idfwruv uhtxluhv d odujh udqjh ri wklq ?opvwdqgdugv1 Hdfk vwdqgdug vkrxog frqwdlq dw ohdvw wzr hohphqwv/ dovr suhvhqw lqwkh xqnqrzq vshflphq/ wr ghwhuplqh wkh dffrpsdq|lqj nDE idfwru1 Wkh uhtxluhgwklq ?op vwdqgdugv vkrxog kdyh d zhoo gh?qhg vwrlfklrphwulf frpsrvlwlrq/ vkrxog ehvwdeoh lq wkh hohfwurq ehdp dqg xqfkdqjhg e| vshflphq suhsdudwlrq1 Dowkrxjk vxfkvwdqgdugv surylgh dffxudwh n0idfwruv/ wklv phwkrg lv riwhq qrw sudfwlfdeoh ehfdxvh lwlv riwhq lpsrvvleoh wr suhsduh wkh dssursuldwh wklq ?op vwdqgdugv dqg hyhq li lw zrxogeh srvvleoh wr rewdlq d wklq ?op vwdqgdug lw vwloo wdnhv d vljql?fdqw dprxqw ri wlphwr ideulfdwh wkhp dqg wkh| pd| ghwhulrudwh idvw gxh wr r{lgdwlrq1 Dq dowhuqdwlyh lvwr xvh duhdv ri wkh vshflphq lwvhoi dv d vwdqgdug1 Wklv lv rqo| xvhixo li wkh vshflphqsurylghv duhdv ri zhoo nqrzq frpsrvlwlrq1

    Dq dowhuqdwlyh wr phdvxulqj doo n0idfwruv/ lv wr ghulyh wkhp iurp wdeohv risuhylrxvo| ghwhuplqhg n0idfwru gdwd ^6/ s1 93;`1 Krzhyhu/ vlqfh wkh n0idfwru gdwd lvdovr htxlsphqw ghshqghqw/ wkh| vkrxog eh fruuhfwhg zlwk htxlsphqw vshfl?f fruuhf0wlrq idfwruv/ pdnlqj wkhp ohvv uholdeoh1 Dv d uhvxow wkh| duh xvhixo iru frpsdulvrqsxusrvhv/ udwkhu wkdq iru gluhfw txdqwl?fdwlrq1

    Dq rwkhu/ uhfhqwo| lqwurgxfhg zd| wr ghwhuplqh wkh n0idfwruv lv e| xvlqj dwklq ?op vwdqgdug vxssolhg e| wkh Qdwlrqdo Lqvwlwxwh ri Vwdqgdugv dqg Whfkqrorj|+QLVW= VUP 5396, ^7`1 Wklv vwdqgdug lv dq dpruskrxv plqhudo jodvv ?op1 Wklfnqhvvdqg frpsrvlwlrq duh zhoo gh?qhg dqg duh vshfl?hg e| wkh pdqxidfwxuhu1 Lw frqwdlqvdffxudwho| nqrzq dprxqwv ri Pj/ Vl/ Fd/ Ih dqg R shuplwwlqj ghwhuplqdwlrq ri n0idfwruv ri frpelqdwlrqv ri wkhvh hohphqwv1 Xvlqj wkhvh ydoxhv dqg wkh jlyhq wklfnqhvvrqh fdq fdofxodwh d udqjh ri n0idfwruv +h1j1 Pj wr ]q,

    n0idfwruv fdq dovr eh fdofxodwhg iurp ?uvw sulqflsohv1 Wklv fdq r>hu dffxudwhn0idfwruv/ krzhyhu/ lw lv gl!fxow wr wdnh htxlsphqw sdudphwhuv lqwr dffrxqw1 Wklvriwhq uhvxowv lq huuruv xs wr 48 wr 53(/ zklfk lv xqdffhswdeoh lq prvw fdvhv1

    Fdofxodwlrq ri n0idfwruv iurp ?uvw sulqflsohv

    Iru d wklq vshflphq/ ixoo| wudqvsduhqw wr lqflghqw hohfwurqv dqg zkhuh [0ud| de0vruswlrq lv dvvxphg wr eh qhjoljleoh/ wkh iroorzlqj uhodwlrqvkls krogv +vhh wklq ?op


  • Prghov xvhg iru txdqwlwdwlyh dqdo|vlv lq wkh WHP 8151

    dssur{lpdwlrq/ Ht1 519,=

    L @Q3ãF

    DT$dlw +815,

    zkhuh L lv wkh jhqhudwhg lqwhqvlw| ri wkh fkdudfwhulvwlf [0ud| olqh/ Q3 lv Dyrjdgur*vqxpehu/ ã lv wkh ghqvlw|/ F lv wkh frqfhqwudwlrq +zhljkw iudfwlrq,/ D lv wkh dwrplfpdvv/ T lv wkh lrqlvdwlrq furvv vhfwlrq/ $ lv wkh xruhvfhqfh |lhog/ d lv wkh uhodwlyhwudqvlwlrq suredelolw| +wkh udwlr ri wkh lqwhqvlwlhv ri Nò@ +Nò .Nñ, ,/ l lv wkh wrwdoehdp fxuuhqw dqg ?qdoo| w lv wkh wklfnqhvv ri wkh vshflphq1 Dvvxplqj doo jhqhudwhg[0ud| udgldwlrq lv dovr hplwwhg iurp wkh vshflphq/ wkh dfwxdoo| phdvxuhg lqwhqvlw| rid fkdudfwhulvwlf [0ud| olqh ri d fhuwdlq hohphqw D/ fdq eh jlyhq e|=

    LD>p @ LD ü îD +816,zkhuh wkh fruuhfwlrq whup îD lv vshfl?f iru wkh phdvxuhg [0ud| olqh ri hohphqw D exwdovr iru wkh vshfl?f HGV xvhg1

    E| xvlqj wkh udwlr ehwzhhq lqwhqvlwlhv ri wzr gl>huhqw [0ud| olqhv +ri hohphqwv/D dqg E,/ d frqfhqwudwlrq lqghshqghqw n0idfwru fdq eh ghulyhg e| vxevwlwxwlrq riHtxdwlrq 815 lq wkh Fol>0Orulphu Htxdwlrq 814/ uhvxowlqj lq=

    nDE @+T$d,D DEîD+T$d,E DDîE


    Wkh î whup lv qrw fdqfhoohg rxw/ vlqfh î lv gl>huhqw iru hdfk vshfl?f [0ud| olqh1Fdofxodwlrq ri î uhtxluhv nqrzohgjh ri wkh devruelqj od|huv +zlqgrz/ frqwdplqdwlrq/jrog frqwdfw dqg ghdg0od|hu, lq wkh HGV xvhg dqg lwv vhqvlwlylw| wr wkh vshfl?fhohphqwv1

    Wkh n0idfwruv fdofxodwhg lq wklv zd| dsso| lq wkh fdvh ri qr devruswlrq1 Lidevruswlrq fruuhfwlrq lv wdnhq lqwr dffrxqw dqg li wkh surgxfwlrq ri [0ud|v lv dvvxphgwr eh frqvwdqw wkurxjkrxw wkh ?op/ wkh Fol>0Orulphu Htxdwlrq 814 fkdqjhv wr ^8`=


    @ nDE






    ;?=4ý h{s


    ìEãw frvhf ë

    ì4ý h{s


    ìDãw frvhf ë

    ì +818,




    ìEduh wkh pdvv devruswlrq frh!flhqwv iru wkh fkdudfwhulvwlf [0

    ud| olqhv ri hohphqw D dqg E lq wkh vshflphq1 ã dqg w duh wkh ghqvlw| dqg vshflphqwklfnqhvv +dw srlqw ri phdvxuhphqw, uhvshfwlyho|1 Wr dsso| wklv h{suhvvlrq ã dqg wkdyh wr eh ghwhuplqhg dw hdfk phdvxulqj srlqw1

    nDE lq wkh htxdwlrqv deryh lv wkh devruswlrq iuhh n0idfwru +nDE,31 Wkh phd0vxuhg n0idfwru +nDE,p fdq eh gh?qhg dv=

    +nDE,phdvxuhg @+nDE,3FI



  • Fkdswhu 81 Txdqwlwdwlyh dqdo|vlv lq WHP

    zkhuh FI lv d fruuhfwlrq idfwru iru wkh suhvhqfh ri devruswlrq +xvlqj Ht1 818,=

    FI @





    ;?=4ý h{síýíçã

    ìEãw frvhf ë

    ì4ý h{s


    ìDãw frvhf ë

    ì +81:,

    Li wkh jhqhudwlrq ri [0ud|v lv dvvxphg wr rffxu dw rqh0kdoi wkh wklfnqhvv ri wkhwklq ?op wkh devruswlrq fruuhfwlrq idfwru fdq eh vlpsol?hg wr=

    FIi @ h{s








    âü ãw5frvhf ë


    Li zh h{suhvv Htxdwlrq 819 lq orjdulwkplf irup dqg vxevwlwxwh Htxdwlrq 81; iru FI /

    oq +nDE,p @ oq +nDE,3 ý w üéýãë







    âü ã5frvhf ë

    è+81 wklv krzhyhu fdxvhv qhz sureohpv= Lw fdq eh gl!fxow wr ?qgvx!flhqwo| wklq duhdv/ dqg wr eh vxuh wkdw wkh wklfnqhvv lv ehorz wkh fulwlfdo ydoxhiru wkh dvvxpswlrqv pdgh1 Ixuwkhupruh/ orz [0ud| frxqw udwhv/ fdxvhg e| wkh yhu|vpdoo yroxph h{flwhg lq wkh wklq vshflphq/ uhtxluh orqj dftxlvlwlrq wlphv dqg wklv fdqfdxvh frqwdplqdwlrq exlog xs1 Dovr wkh h>hfw ri vxuidfh od|huv vxfk dv r{lgh od|huvdqg od|huv glvwxuehg e| wkh ?op suhsdudwlrq lqfuhdvhv zlwk wklqqhu ?opv1

    Lq rughu wr xvh wklfnhu duhdv iru n0idfwru ghwhuplqdwlrq/ wkh h{wudsrodwlrqphwkrg lv xvhg1 Wkh phwkrg frqvlvwv ri phdvxulqj pxowlsoh srlqwv rq wkh wklq ?opvwdqgdug vshflphq dw yduldeoh ?op wklfnqhvvhv1 Sorwwlqj wkh n0idfwruv ghwhuplqhg iurpwkhvh phdvxuhphqwv rq d orjdulwkplf vfdoh djdlqvw wkh vshflphq wklfnqhvv uhvxowv lqd olqh ^9`^:`/ zklfk fdq eh h{wudsrodwhg wr wklfnqhvv }hur +w @ 3, lq rughu wr ?qgwkh devruswlrq iuhh n0idfwruv/ +nDE,31 Iru wklv/ wkh wklfnqhvv lq hdfk phdvxuhg srlqwvkrxog eh nqrzq1 Krzhyhu/ iru d vr fdoohg *kdug [0ud| olqh*/ iru zklfk devruswlrqlv qhjoljleoh/ wkhuh lv/ dffruglqj wr Htxdwlrq 815/ d olqhdu uhodwlrq ehwzhhq wkh ?opwklfnqhvv w/ dqg wkh lqwhqvlw| L/ dvvxplqj wkh wklq ?op vfdwwhulqj dssur{lpdwlrq vwlookrogv1 Khqfh/ lw lv srvvleoh wr sorw wkh n0idfwruv djdlqvw wkh lqwhqvlw| ri wklv *kdug[0ud|* olqh lqvwhdg ri djdlqvw wklfnqhvv1 Rqfh wkh n0idfwru ri wkh devruswlrq iuhh olqhkdv ehhq irxqg/ wkh wklfnqhvv fdq eh hvwlpdwhg dqg xvhg lq wkh ghwhuplqdwlrq ri wkhrwkhu n0idfwruv1


  • Prghov xvhg iru txdqwlwdwlyh dqdo|vlv lq wkh WHP 8151

    Diwhu ghwhuplqdwlrq ri wkh devruswlrq iuhh n0idfwruv/ wkh vdph h{wudsrodwlrqphwkrg fdq eh xvhg wr ghwhuplqh wkh devruswlrq iuhh lqwhqvlw| udwlr [email protected],3 e|sorwwlqj wkh udwlr djdlqvw wkh lqwhqvlw| ri d kdug/ qrq0devruehg/ [0ud| olqh1 Wklvphdqv krzhyhu/ wkdw vhyhudo phdvxuhphqwv rq rqh vshfl?f frpsrvlwlrq duhd ri wkhvshflphq zlwk yduldeoh wklfnqhvv kdyh wr pdgh1 Wkhuhiruh wklv phwkrg lv qrw vxlwhgiru olqhvfdqv/ vpdoo duhd dqdo|vlv dqg frqfhqwudwlrq judglhqwv1

    81516 G[D phwkrg

    Wkh G[D/ gl>huhqwldo [0ud| dqdo|vlv/ zdv lqwurgxfhg e| Pruulv hw do1 +4huhqfh lq devruswlrq ehwzhhq gl>huhqw [0ud| olqhv+xvxdoo| N dqg O olqh, ri wkh vdph hohphqw lq wkh vdpsoh1

    Wkh lqwhqvlw| udwlr ehwzhhq wzr gl>huhqw [0ud| olqhv ri wkh vdph hohphqw fdqeh h{suhvvhg dv iroorzv/ xvlqj Htxdwlrq 818=










    ;AA?AA=4ý h{s


    ìD>lãw frvhf ë

    ê4ý h{s


    ìD>mãw frvhf ë

    ê +8143,

    Vlqfh ëLD>lLD>m


    @FDFD=nDl>Dm +8144,í


    ì3lv lqghshqghqw ri frqfhqwudwlrq1





    duh krzhyhu frpsrvhg

    iurp wkh devruswlrq frh!flhqwv ri wkh frpsohwh pdwul{/ dqg wkhuhiruh ghshqghqw rqwkh frqfhqwudwlrq ri doo rwkhu hohphqwv1 Devruswlrq iuhh n0idfwru ghwhuplqdwlrq lq wklvphwkrg lv htxlydohqw wr gluhfw fdofxodwlrq ri dq devruswlrq idfwru xvlqj d phdvxuhgwklfnqhvv dqg Htxdwlrqv 819 dqg 81:1 Dv dq dowhuqdwlyh wkh h{wudsrodwlrq phwkrg fdqeh xvhg wr ghwhuplqh n0idfwruv1

    Lq fdvh wkh frpsrvlwlrq lv nqrzq/ ãw fdq eh hdvlo| ghwhuplqhg e| fdofxodwlrqri wkh pdvv devruswlrq frh!flhqwv ri hdfk hohphqw lq wkh pdwul{ dqg vxevwlwxwlrq riwkhvh devruswlrq frh!flhqwv lqwr Htxdwlrq 81431 Lq fdvh ri dq xqnqrzq frpsrvlwlrq/wkh frpsrvlwlrq lv fdofxodwhg xvlqj=


    @ nME




    zkhuh M lv rqh ri wkh hohphqwv +D>F>G> = = = , rwkhu wkdq E ri wkh pdwul{1 Wkh

    fdofxodwlrq riíLMLE

    ì3uhtxluhv nqrzohgjh ri ãw/ fdxvlqj d sureohp/ zklfk fdq eh vroyhg

    e| xvlqj dq lwhudwlyh vroxwlrq phwkrg/ vwduwlqj zlwk d lqlwldo ydoxh iru wkh frpsrvlwlrq=FD @ 4> FE>F>=== @ 3 +iru ghwdlohg ghvfulswlrq ri wkh surfhgxuh vhh ^

  • Fkdswhu 81 Txdqwlwdwlyh dqdo|vlv lq WHP

    81517 Sdudphwhuohvv fruuhfwlrq phwkrg e| ydq Fdsshoohq

    Ydq Fdsshoohq +40Orulphu htxdwlrq dqg lqwurgxflqj devruswlrq fruuhfwlrq |lhogv +vlploduwr Ht1 815,=


    @ nMmDl






    ;AA?AA=4ý h{s


    ìDlãw frvhf ë

    ê4ý h{s


    ìMmãw frvhf ë

    ê +8148,

    zkhuh M lv dq hohphqw ri wkh pdwul{ rwkhu wkdq D [email protected] E>F> = = = ,1Li Dl uhsuhvhqwv d kdug [0ud| olqh zlwk qhjoljleoh devruswlrqv/ dqg íDl wkh

    fruuhvsrqglqj }hwd0idfwru rewdlqhg iurp phdvxuhphqwv ri Dl udgldwlrq/ Htxdwlrq 8147fdq eh xvhg iru vxevwlwxwlrq ri ãw lq 8148/ jlylqj=


    @ nMmDl






    ;AA?AA=4ý h{s



    LDlFDfrvhf ë

    ê4ý h{s



    LDlFDfrvhf ë

    ê +8149,


  • Xvlqj d ixoo pdwul{ fruuhfwlrq surfhgxuh 8161

    D plqlpxp ri wzr +suhihudeo| pruh, phdvxuhphqwv ri d kdug [0ud| olqh/ zlwkqhjoljleoh devruswlrq lq frpelqdwlrq zlwk d orz hqhuj| [0ud| olqh/ zlwk khdy| de0vruswlrq/ lv qhhghg wr ghwhuplqh wkh í0idfwr-u1 Jlyhq wkh frqfhqwudwlrqv FD dqg FMdqg wkh pdvv devruswlrq frh!flhqwv/ Htxdwlrq 8149 lv vroyhg iru nMlDl dqg íDl e|d qrq0olqhdu ohdvw0vtxduhv ?wwlqj surfhgxuh ^46`1 +Lq idfw wklv lv vlplodu wr xvlqj wkhh{wudsrodwlrq phwkrg zlwk d qrq0olqhdu ?wwlqj1,

    Rqfh wkh í0idfwru dqg wkh ?uvw n0idfwru/ nEmDl lv ghwhuplqhg/ wkh uhpdlqlqj +q05, n0idfwruv fdq eh ghwhuplqhg iurp phdvxuhphqwv rq vwdqgdug vshflphqv frqwdlqlqjd nqrzq frpsrvlwlrq ri hohphqw D dqg rqh ru pruh rwkhu frpsrqhqwv M [email protected] F>G> = = = ,xvlqj Htxdwlrq 81491

    Frpsrvlwlrq ghwhuplqdwlrq lq wkh xqnqrzq vshflphq lv shuiruphg e| vroylqjHtxdwlrq 8149 iru rqh phdvxuhphqw xvlqj wkh suhghwhuplqhg íDl dqg nMmDl idfwruv lqdq lwhudwlyh surfhgxuh dqdorjrxv wr wkh G[D phwkrg1 Qr wklfnqhvv phdvxuhphqw lvqhfhvvdu| dqg wkh pdvv wklfnqhvv fdq eh fdofxodwhg xvlqj Htxdwlrq 81471

    816 Xvlqj d ixoo pdwul{ fruuhfwlrq surfhgxuh

    81614 Prqwh Fduor vlpxodwlrq

    Prqwh Fduor vlpxodwlrq zdv wkh ?uvw phwkrg lqwurgxfhg lq WHP dqdo|vlv wr r>huvlpxowdqhrxv ghwhuplqdwlrq ri wklfnqhvv dqg frpsrvlwlrq xvlqj ixoo vfdwwhulqj fdo0fxodwlrqv dqg devruswlrq fruuhfwlrq1 Dupljoldwr dqg Urvd +4huhqw dssurdfk wr WHPtxdqwlwdwlyh dqdo|vlv= Zkhuh doo suhylrxvo| ghvfulehg phwkrgv duh h{whqvlrqv ri wkhwklq ?op phwkrg lqwurgxfhg e| Fol>0Orulphu/ rxu phwkrg lv qrw dq h{whqvlrq ri wkhFol>0Orulphu dssurdfk dqg lw grhv qrw pdnh dq| wklq ?op dssur{lpdwlrqv1

    Wkh phwkrg xvhv ixoo pdwul{ fruuhfwlrq edvhg xsrq d * +ã}, fxuyh dssurdfk/ dvghvfulehg lq wkh suhylrxv fkdswhu +Vhfwlrq 715,1 Glmnvwud +4

  • Fkdswhu 81 Txdqwlwdwlyh dqdo|vlv lq WHP

    vshflphq kdg wr eh wlowhg wr dftxluh HGV vshfwud, dqg wkh odfn ri dq dssursuldwhehdp fxuuhqw phwhu1

    Wkh wklq ?op fdofxodwlrqv duh fduulhg rxw e| shuiruplqj wkh fdofxodwlrqv iru dwklq ?op rq vxevwudwh vlwxdwlrq zkhuh wkh dwrplf qxpehu ri wkh vxevwudwh hohphqwdssurdfkhv }hur1 Lq wkdw fdvh wkhuh lv qr edfnvfdwwhulqj frqwulexwlrq ri wkh vxevwudwh1Wklv dssurdfk kdv ehhq suryhq vxffhvvixo dqg zdv whvwhg rq odujh vhulhv ri HSPDwklq ?op phdvxuhphqwv zlwk Do dqg Sg ?opv rq ydu|lqj vxevwudwhv udqjlqj ehwzhhqehu|oolxp dqg elvpxwk ^49`1

    Dsduw iurp vrph vriwzduh fkdqjhv pdnlqj wkh surjudp vxlwdeoh iru WHPdqdo|vlv fdofxodwlrqv/ qr fkdqjhv wr wkh ruljlqdo HSPD wklq ?op prgho zhuh pdgh1Wkhuhiruh wkh surfhgxuh lv h{dfwo| dv ghvfulehg lq wkh suhylrxv fkdswhu/ iru wkh fdvh ridq xqvxssruwhg ?op ri xqnqrzq wklfnqhvv dqg frpsrvlwlrq1 Dv ghvfulehg/ d grxeohlwhudwlyh surfhgxuh lv xvhg wr ghwhuplqh frpsrvlwlrq iru hdfk hohphqw lq wkh ?op dqgwkh ?op wklfnqhvv1 Sxuh hohphqw exon vshflphqv +ru nqrzq frpsrxqgv, duh xvhg dvvwdqgdugv1

    817 Qhhg iru vwdqgdugv

    Wkh qhfhvvlw| wr xvh vwdqgdugv lv vkrzq e| Krulwd +4

  • Phwkrgv iru vdpsoh wklfnqhvv ghwhuplqdwlrq 8181

    suhyhqw fkhplfdo frpsrvlwlrq fkdqjhv1 Wkh sursrvhg * +ã}, wklq ?op phwkrg xvhvsxuh hohphqw exon vwdqgdugv/ zklfk duh uhodwlyho| hdv| wr suhsduh dqg gr qrw vx>hupxfk iurp vxuidfh h>hfwv/ vlqfh wkh [0ud|v ruljlqdwh iurp d odujh yroxph lq wkh exon1

    81714 Ehdp fxuuhqw phdvxuhphqw

    Prvw WHP wklq ?op phwkrgv uhtxluh d frqvwdqw ehdp fxuuhqw gxulqj phdvxuhphqwri erwk vwdqgdugv dqg xqnqrzq vshflphq1 Phdvxulqj erwk vwdqgdugv dqg xqnqrzqvshflphq pd| yhu| zhoo uhtxluh d vshflphq fkdqjh/ riwhq dorqj zlwk fkdqjh lq WHPvhwxs dqg lw pd| hyhq eh qhfhvvdu| wr whpsrudulo| wxuq r> ?odphqw khdwlqj1 Ixu0wkhupruh/ wkh phdvxuhphqwv ri vhyhudo vwdqgdugv dqg iru h{dpsoh d olqhvfdq rq wkhxqnqrzq vshflphq pd| doo wrjhwkhu wdnh d frxsoh ri krxuv1 Nhhslqj wkh ehdp fxuuhqwvwdeoh gxulqj doo wkhvh rshudwlrqv lv yhu| xqolnho| li qrw lpsrvvleoh1

    Wkh * +ã}, phwkrg sursrvhg khuh/ xvhv exon vwdqgdugv1 Wkh gl>huhqfhv lq [0ud| lqwhqvlw| rewdlqhg iu