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frailtypack: a computer program for the analysis of correlated failure time data using penalized likelihood estimation.

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(1)frailtypack: a computer program for the analysis of correlated failure time data using penalized likelihood estimation. Virginie Rondeau, Juan Gonzalez. To cite this version: Virginie Rondeau, Juan Gonzalez. frailtypack: a computer program for the analysis of correlated failure time data using penalized likelihood estimation.. Computer Methods and Programs in Biomedicine, Elsevier, 2005, 80 (2), pp.154-64. �10.1016/j.cmpb.2005.06.010�. �inserm-00138520�. HAL Id: inserm-00138520 https://www.hal.inserm.fr/inserm-00138520 Submitted on 27 Mar 2007. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés..

(2) HAL author manuscript Comput Methods Programs Biomed 11/2005; 80(2): 154-64. HAL author manuscript.     

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(7) HAL author manuscript inserm-00138520, version 1. ?BFqήJ CEA“JEOGäLÍ¡ÍDOLÐdý MPÍ¡CEH]JPCEA®MPäGýL?BÐ]MP^´MPA“H]MPÍiJEAiç~MpúÚ?Á^B?BH_Í,MPFGK 3ýLH]FÚήýLHµJEæLÍDH]ADÌpMpΓ?BJEFGÍ MPA“HÚFLJEFžå±?BFLKLH_äRH_FLKLH_F©Î]Wê"ýL?ÁÍ°úß?BCEýqÎXA“H_͓OL^Î çéADJEú ήýLHßç~MPÐ_ΠήýVMÎ°ÍDOLæDH]ÐTήͦ?ÁFήýGH Í®MPúßH3Ð]^BOGÍDήH_A4͓ýVMpA“H3͓?ÁúÚ?Á^ûMPA²FLJEFžå±JEæLÍDH]ADÌPH]KÚH]Fq̒?BA“JPFLúÚH_FqÎdMP^Lç~MPÐTήJEADÍ4JEA4CEH_FLH_Γ?BÐ"ç~MPÐTå ήJEAD1Í 3ýL?ÁÐdý-2M ›H_Ð_ÎÚήýLH_?BAß͓OLAb̞?ÌpMP^yW-ê"ýLHtA“MPFLKLJPú 3H ›H_Ð_ΓͷúÚJ’KLH_^B?BFGC ?ÁF ÍDOLAD̒?ÁÌpMP^ MPFVMP^ùžÍD?BÍ"Ð]MPFlæRH¾MP^Á͓J¦H]MP͓?Á^Áù—MPäLäL^Á?BH]KÚήJ¹KLHNMp4^ 3?ÁΓý A“H]äZHNMÎ®H]KÒúßHNMPÍDOLA“H_úÚH_F©Î“Í3JEFlM äRH_A“Í“JPFŽS,MPFGK+äLADJEäRH_A“^ù MPÐ]Ð_JEOLFqÎ çéJPAXKGH]äZH]FLKLH_FLÐ]&H 3?Î®ýL?ÁF ͓OLæ DH_Ð_ΓÍ]WlޥͰMÒADH]͓OG^ÁÎNS MPFVMP^ùž\_H];ήýVMÎ[ç~MP?B^0ΓJÒMPÐ]Ð_JEOLFqÎ çéJPA@ήýLHßÐ]JEADA“H_^ûMpΓ?BJEFº?ÁF ÍDOLAD̒?ÌPMp^,ή?BúßH]Í@MPA“H¹^B?ÁüPH_^Áù ήJ·OLFGKLH]ADH]ÍDΓ?BúÚMpήH ήýLHXÌPMpA“?ûMpFLÐ]H_Í@JPç4ήýGH°äVMPA“MPúßH_ήH_A“Í_W[IµH_͓H]MPA“Ðdý JEFΓýLHnÍbÎdMpΓ?BÍDΓ?å ÐNMP^iMPFVMp^Áù’Í“?ÁÍ[JPç¤Ð_JEA“ADH]^ûMÎ®H]K ͓OGAD̒?ÁÌpMP^4KVMÎdMlýVMPÍXA“H]Ð_H]?ÌEH]K+Ð]JEFLÍD?BKLH_A®MPæG^BHßMpΓΓH]Fqή?ÁJEFŽS ͓ýVMPADH]KçéA“MP?B^ÎùºúÚJ’KLH_^BÍ MPA“HÚOL͓H_6 K 5 Ö S7՞S72È 7vW<Þ A“HT̞?ÁH JPç¤Î“ýLH—KG? RH]A“H_FqÎn͓Jpç‡ Î ¤MPADH äVMPÐdüMPCEH_Í7OLÍDH]K°çéJPA MPFVMP^ùž\_?BFLC3Ð_JEA“ADH]^ûMÎ®H]KX͓OGAD̒?ÁÌpMP^qKVMÎdM3ýVMPÍ æRH_H]F A“H]Ð_H]Fqή^8ù 3A“?Î“ήH_F æ©, ù 5 × 7yWiĞH_úÚ? åäVMpA®MPúßH_ΓA“?BÐ3?ÁFGçéH]ADH]FLÐ_H¥çéJEA¡çéA“MP?B^Îù¹úÚJ’KLH_^B9Í ÓMPͤ?ÁFqήA“J’KLOLÐ_H]K æq;ù :[^ÁH]?BF ˆT|Ó}P§ 5âí 7(MPFLKÒõ?BH]^Á͓H_F ˆT|Ó}P§ 5 Ø 7yW4ê"ýGH]?BA3MpäLäLA“JEMPÐdýLH]Í3OLÍDH]KÒMPFlÅiÆMP^BCEJPA“?ÁΓýLú MPäžå äL^B?ÁH]K¦Î®J[ήýGH¥ÜÓJNÔ¹äLMPADΓ?ûMP^ž^B?BüpH]^Á?BýLJ’JžK›=W <fMPÍDΓ?BH3MPFGKßê"?ÁæL͓ýG?BA®MpFL$? 5 Û 7VäLADJEäRJP͓H]KÚM[CEH]F’å H]A®Mp^0úßJžKLH_=^ 3?Î®ýΓ?BúßH ÌpMPADù’?ÁFLC·Ð]J’H >ßÐ_?BH]FqΓ;MPFLKºÍ“OGCECEH]ÍbήH_K H_ÍDΓ?BúÚMpή?ÁJEF<ΓýLA“JEOGCEý äRH_FVMP^B?Á\]H_KÒäLMPADΓ?ûMP^R^B?BüpH]^Á?BýLJ’JžK›W0ê"ýLH_A“FLH]MPOMpFLKtY[A®MpúnæL͓Ðd? ý 5èÈGSV2É 7(FGJPήH_KM¦^B?ÁFLüßæRH»å Î ÓH_H]F·Î®ýGHfCqMpúÚúÚM¥çéA®MP?Á^Á΁ù°úÚJ’KLH]^´MpFLK·M¾äRH_FVMP^Á?B\]H_KÚäLMPADΓ?ûMP^V^Á?BüPH_^B?ÁýLJžJ’K ë 3ýLH]ADHfήýGH äRH_FVMP^B?Á\NMpΓ?BJEF æZHNMpA“͵JEFtM¹A“H_CEA“H_͓͓?ÁJEFÐ_Jž3H >ßÐ]?BH_FqλìTW¡ê"ýLH]ÍDH¦MPäLäGA“JqMPÐdýGH]Í¥ýLM{ÌPH ÍDJEúßH CEH]FLH_A®MP^0KLA®@M 3æVMPÐdü©Í_W FºäVMpADή?ÁÐ]OL^BMPA]S´Î®ýGHnÐ]JEFqÌPH]A“CPH]FLÐ_HßÐ]MPFºæZHn͓^ÁJ 9MPFGK M—KL?BADH]ÐTÎ H]ÍDΓ?BúÚMpήHlJPçfήýLHlÌpMPA“?BMPFLÐ_HÒJpç¥Î®ýGHlçéA“MP?B^Îù+ΓH]A“ú ?Á͹FLJPÎßäLA“J{̒?BKGH]KŽW ÝVOLAbήýLH_A“úßJEA“H ήýLH_͓HßúÚHTήýLJ’KLÍ[ÐNMpFFLJpξæRH¹OLÍDH]KΓJlH]ÍDΓ?BúÚMpήH ήýLH¹ýVMP\]MPA“K çéOLFLÐTή?ÁJEFŽAS 3ýL?ÁÐdýýVMpÍ JPç‡Î®H_F<M úÚH]MPFL?BFGCPçéOL^Z?BFqήH_A“äLADH_ÎdMÎ®?BJPF·?BF H_äL?BKLH_úÚ?ÁJE^BJPCPùEW²Þ¥FÒMP^Î®H]ADFVMpΓ?ÁÌEHfúÚHTήýLJ’K ?BÍ Î®ýLH¹FLJEF’åäVMPA“MPúßH_ήAD?BÐ H]ÍDΓ?BúÚMpή?ÁJEFtJPçkΓýLH¹æVMP͓H_^B?ÁFLHnýVMP\]MPA“K çéOLFLÐTή?ÁJEFºOL͓?ÁFLCÒM·Ð]JEF’å ×.

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(13) HAL author manuscript inserm-00138520, version 1. Â FLÐ_A“H]MP͓?ÁFLC—ήýGH°F©OLúnæZH]AfJPç4ü©FLJPΓͥKLJ’H]Í@FGJPÎ¥KGH_ήH_A“?ÁJEA®MpΓHXΓýLH¦ÆökFLٲŠà ήýL?ÁÍ¥?BÍ æRH_ÐNMPOLÍDH¥Î®ýGH¥KLH_CEA“H_H¥JPç(ÍDúÚJ’JPΓýL?BFLCX?BFßήýLHfäRH_FVMP^Á?B\]H_KÚ^Á?BüpH]^B?ÁýLJ’JžK¹úßH_ήýGJžKß?BÍkήOLFGH]K æ©ùήýLH—Í“úßJžJPΓýL?BFGCäVMPA“MPúßH_ήH_A î MPFLKFGJPΦæqùΓýLH·F©OLúnæZH]A°JPçµÍ“äL^Á?BFLH_Í] W ž@FLÐ_H M ͓O >ßÐ]?ÁH]FqÎ F©OLúnæZH]AßJPç[ü©FLJpήÍß?BÍßH]ÍDήMPæL^Á?B͓ýGH]KŽSÓΓýLH]ADH?ÁÍÚFLJ+MPKGÌpMPFqÎdMpCEH<?ÁF MpKLKL?BFGC úÚJEADHPW¡Æ<JEADH]J{ÌEH_A]SVήýGHXúßJEADH[ü’FGJPήÍ_S´Î“ýLH¾^BJEFGCEH]A¤Î“ýLH¾A“OLFLFG?BFLC¦Î®?ÁúڟH 3?B^B^›æRHpWÓĒJEúÚH A“OLFLFG?BFLC äLADJEæL^ÁH]úúÚMNùtMpA“?BÍDHPSŽäLMPADΓ?BÐ]OG^ûMPAD^ÁùlçéJEA[M·^BMPA“CEH°F’OGúnæRH_A@JPç¡ü©FLJPήÍ_W°ê"ýVMÎ ?BUÍ 3ýqùΓýLH·úÚMÔž?BúnOLúF©OLúnæZH]A¦Jpçfü©FLJpήͦ?BÍ ^B?ÁúÚ?Î®H]K ήJ ÕPǞS4MPFLKήýGH·úÚ?ÁFL?Bú°OLú F’OGúnæRH_AfJpç,ü©FLJPΓÍf?Á͵^Á?Búß?ÁΓH]K—ΓJ × W¤ÄžJß?Áε?BÍ"ADH]Ð]JPúÚúßH]FLKGH]K<ΓJÚÍbÎdMPAbËÎ 3?Áήý<M¹Í“úÚMP^B^ F’OGúnæRH_A—JPç¥ü©FLJPÎ®Í ë HpWâCLW ÍDH_ÌPH]F´ì—MpFLK ?ÁFLÐ]ADHNMPÍDH<ήýGH<F©OLúnæZH]AÚJPç@ü©FLJpή͗OGF©Î“?B^"ήýGH CEA®MPäGý<JPç²Î®ýGHXæLMP͓H_^B?BFGH[ýVMP\NMpA“KlçéOLFLÐ_Γ?BJEFlADH]úÚMP?BFLÍÓOLFLÐdýVMPFGCEH]KŽW ê²JÚJPæGÎdMP?ÁFÒMPäLäLADJ{Ԟ?Áú—MpΓH¾æVMNùEH]ÍD?ûMPF<äRJP?BFq Î 3?BÍDJH WE í

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(15) HAL author manuscript inserm-00138520, version 1. ?BFLCÚäVMPA®MpúÚHTήH]A î 5ÕW7yS´Î®ýLH JEOGΓäLOGÎ@Jpç,ήýLH äLA“JPCEA®MPú CP?ÁÌEH_ÍfΓýLH]ÍDH°Î ÓJ·ÌpMP^ÁOLH]Í_W3ê"ýLH úÚJ’KLH]^0KLH]CEADH]H_ÍXJpç¡çéADH]H]KGJEúKLH_Ð]ADHNMPÍDHÚ?ÁF î çéA“JEú Ú S(ήýLH¦F©OLú°æRH_AXJpç¡äLMPA®MPúßH_ΓH]ADÍ ë ?Áç î | ÇqìÓήJ—Õ ë ?ç î Ö ì 3ýL?ÁÐdý?BÍ"ΓýLH°F©OLúnæZH]AµJPç0KLH]CEADH]H_Í¥JPç7çéA“H]H_KLJEú JPç,M ÍDήA“MP?BCPý©Î3^Á?BFLHpgW <fJ ¡H_ÌEH_A]SZ?BFl͓JPúÚH¾ÐNMp͓H]Í_SVήýLH¾Í“H]MPA“ÐdýÒçéJEA¤Î®ýGHXÍDúÚJ’JPΓýL?BFLC¦äLMPA®MPúßHTå ήH]A[úÚMNùFGJPÎ[æZH¦A“H]^Á?ûMPæG^BHXæRH_ÐNMPOLÍDH¹JPçi^BJ’ÐNMP^²HTԒήADH]úÚMGWXê"ý’OG;ΓýLH¦H]Íbή?Áú—MpΓHnJPçkήýGH ͓úßJžJPΓýL?BFGC äVMpA®MPúßH_ΓH]AÓ?ÁÍ¡FGJPÎÓJPäGή?Áú—MP^vW7ê"ýG?BÍÓÐ]MPF·æZH¥H»ÔLMpúÚ?ÁFLH]K·æqù¹ÎdMpü’?ÁFLC°KG? RH]Abå H]FqÎ¥ÍbÎdMPAbή?ÁFLC¹äRJE?ÁFqήÍ]W¡Æ<JPA“H]J{ÌPH]A]S´?Î3͓H]H_úÚÍ3ήýLMpÎ3ήýLH¾Ð]ADJE͓͌å±ÌpMP^Á?BKVMpΓ?BJEF—Í“Ð]JPA“H¾Î®H]FGKLÍ Î®J¦OLFLKGH]A“ÍDúÚJ’JPΓýLHPSLH_͓äZH]Ð_?ûMP^Á^Áù¹çéJEAÓÍDú—Mp^B^ZÍ®MPúßäL^BH_Í]SžÍ“J¹?BF—ΓýL?BÍÓÐNMPÍDH@ήýLH@ÍDúÚJ’JPΓýL?BFLC äVMPA®MpúÚHTήH]A"úÚMNù æZšH žÔGH_KM¹äLAD?BJEAD?›?BF ΓýLH¾äLA“JECPA®MPúÒW. . . . RKPéSâH?P8-u. IML&-ËIMS=P. $. ' P /' P8SS.(1#. )$. -Ë(/+,#;%.@#. )KP8H. G. "!. . ( %RKPiP *%P8#,Sâ. (/#. (*)KP8L. %(. *. H,' (*-uP8SâS. 0(/'gG. 'gPa-Ÿ+,'g' P8#&%. +,LIJ% .(1#. ( %RKPTE. &%. ('. P /P8#&%S. +. IU#,). ­(/'Ì% .@G. #! (. .3% R. -, P. .%. P8#,)KP8#&%T-Ë( ­IM'g. I­%P8S. Ž¢ ‰D}Pw‡á|B»¿G}’d¸ ÐNMpFMP^Á͓J¦æZH[OL͓H_K<ΓJßKGHNMP4^ 3?Î®ýlA“H_Ð]OLADA“H_F©ÎfH_ÌPH]FqήÍ_WÓI3H]Ð_OLA“ADH]FqÎfH_ÌEH_FqÎ®Í ?BÍ 3ýLH_A“HºçéJEA·?ÁFLÍDήMPFLÐ_HήýLHºÍDOLæDH_Ð_ÎÒHTԞäZH]A“?ÁH]FLÐ_H]ÍlA“H_äRH]MpήH_K J’Ð]Ð_OLA“ADH]FLÐ_H]ÍlJPç¾Î®ýGH Í®MPúßHX΁ù’äZH Jpç,H_ÌPH]FqÎNS›MPÍ3A“H_äRH]MpήH_KºMPÍDΓýLúÚMßMÎ“ÎdMpÐdü’Í_SRÐ]MPFLÐ_H]AµA“H]^BMPäLÍDH]Í]SZA“H_ýLJEÍDäL?ÁήMP^å ?B\NMÎ®?BJPFlMpç‡Î®H_A¤Í“OLADCEH]AbùEWiê"ýLH¾H_ÌPH]FqήÍ3çéA“JEú ήýLH[͓MPúßH[͓OLæ DH_Ð_ΓÍfúÚMNù·æZH[äRJPΓH]Fqή?BMP^B^ù Ð]JEADA“H]^BMpήH_KŽ0W /@? RH]ADH]FqÎÓΓ?BúßH]ÍDÐNMP^ÁH]ÍÓÐ]MPF æZH@OL͓H_K 5 Ö í 7yW4ê"ýGH@ή?BúßH]ÍDÐNMP^ÁHµÎ“ýVMpÎ"?ÁÍÓúßJEÍDÎ JPç‡Î®H_F OG͓H]K ?ÁͥήýLH¦CEMPäºÎ®?BúßH à Mpç‡Î“H]A¾MPFºHTÌEH_F©Î]S(ήýLH¦ÍDOLæ DH]ÐTÎXÍDÎdMpADή;MpCqMP?BFtMpÎ[ή?ÁúÚH ǺMPFLKήýLH·Î“?BúßHÚΓJtήýLH·FGHTԒÎßH_ÌEH_FqÎÚÐ_JEA“ADH]ÍDäRJEFGKLÍnήJtΓýLH F©OLúnæZH]A¦JPçµKVMNù’ÍnήýVMÎ ÖÇ.

(16) HAL author manuscript inserm-00138520, version 1. Á? Î@ήMPüPH_;ΓJ HTԞäZH]A“?ÁH]FLÐ_H¦Î®ýLH¦FLH»Ô’Î HTÌEH_F©Î]WnÞ¥^Î®H_A“FVMpΓ?ÁÌPH°Î®?ÁúÚH_͓ÐNMp^BH°?ÁÍ@ήýLH¦Ð]MP^BH_FLKVMPA ή?BúßHPS0MP^BÍDJÐ]MP^B^ÁH]K+Ð_JEOLFqή?ÁFLCtäLADJžÐ_H]ÍDͦMPäLäLADJqMPÐdý65 Ö{Ø 7e 3ýL?ÁÐdýüPH]H_äLÍnήA“MPÐdü JPç"ή?ÁúÚH ͓?BFGÐ]H A®MpFLKLJEúß?B\]Mpή?ÁJEFŽWºê"ýLHlKLOLA“Mpή?ÁJEFJPç3ΓýLH·Î®?ÁúÚH MÎ¦A“?Á͓ü çéJEA¦MPF H_ÌPH]FqÎßÐ]JEADA“H»å ͓äZJEFLKLÍiήJ ΓýLH¥KGOLA®MpΓ?BJEFßJPçŽÎ“ýLH3ή?BúßHµMpΡA“?BÍDü¦?BF¹Î®ýLHfCqMPä¹Î®?ÁúÚH3A“H_äLA“H_͓H_F©Î®Mpή?ÁJEF·æLOžÎ ήýLHnÍbÎdMPAbÎ@JPç0ήýLH¦MÎDåAD?BÍDü äRH_A“?BJ’K?ÁÍ¥FLJpÎ@A“H_͓HTÎ@ήJ—ÇGW¥Þ9͓OLæ DH_Ð_ξ?ÁÍfFLJpÎ@Ð]JPFL͓?ÁKLH]ADH]K ήJlæRHßMpξAD?BÍDü<çéJEA@ΓýLH¹ü©Î“ý H_ÌEH_FqÎnOLFqή?Á^4Mpç‡Î“H]A@ήýGH ë üEå Ö ìÎ®ý H_ÌPH]FqÎNW H 3?Á^B^7KLH_ήMP?B^ ήýL?ÁÍiÐ]MP^BH_FLKVMPAkή?ÁúÚH¤çéJPA“únOL^BMpή?ÁJEFŽSpæRH_ÐNMPOLÍDHfΓýLHfúßH_ΓýLJ’KÚJPç›H]Íbή?BúÚMpΓ?BJEF¦?ÁÍiKG? RH]A“H_FqÎ çéA“JEú ήýLMpΰäGA“H_̒?ÁJEOL͓^ù ͓H]H_FŽWÒê"ýLH·ýVMP\]MPA“KçéOLFLÐ_Γ?BJEF çéJEA¾Î®ýLHßçéA®MP?Á^Á΁ùºúßJžKGH] ^ 3?ÁΓý ÐNMP^ÁH]FLKVMpAiΓ?BúßHf?ÁÍkΓýLH¥Í“MPúßH@MPÍkήýLHfJEFLHfJPçŽÎ®ýGH¥HTԞäLADH]ÍD͓?BJPF Ö S’æLOGÎÓΓýLHfçéA“MP?B^ÎùnήH_A“ú æ DH]ÐTΤMpFLKßΓ?BúßH¤KLH_äRH_FLKLH]FqΡÐ]J{ÌpMPA“?BMpήH_ÍkMPA“HµMP^Á^BJ ¡H]K à ¤ ƒ 3?B^Á^GæZH"͓äZH]Ð_? VÐ3ήJ¾HNMpÐdýÚÍDOL   ƒX‰ ¢ë ¡£Š¤ ƒ Ë ì | ¤ ƒ  ¥ «ë ¡ ìGHTԞä Bë ¦ § © ƒŠ‰ «ë ¡ ì“ìTW¾Þ1äLMPADΓ?BÐ]OG^ûMPAf͓OLæ DH_Ð_ÎXýVMPÍ¥KL? RH]ADH]FqξäRH_A“?ÁJžKLÍ MpÎ[A“?Á͓üÒKLOLAD?BFLC—ΓýLH°Î“JPÎdMP^7JEæLÍDH]ADÌpMpΓ?BJEF<ή?BúßHPW¥Â±çiΓýLH]ADH¦MPADH  ƒ MÎDåAD?BÍDüÒäZH]AD?BJ’KLÍ¥çéJEA äVMpή?ÁH]FquÎ “SLΓýLH]FlήýLH¾Ð_JEúÚäG^BH_ΓH[?BFGçéJPA“úÚMpή?ÁJEFÚçéJEA"äLMpή?ÁH]FquÎ 4ÐNMPFÒæRH¾ADH]äLADH]͓H_FqήH]Kæ©ù  ƒ ήAD?BäL^ÁH_Î®Í ë Œ ƒ ~ Œ ƒ ~  ƒ ì ~@€€~ ë Œ ƒ Ò ’ ~ Œ ƒ Ò ’ ~  ƒ Ò ’ a QQ Q~` Q Q ` ì 3ýGH]A“HpS²çéJPA@ήýL­H xEήý ήAD?BäL^ÁH_ÎN$S Œ ƒX‰ Q ?B͡ΓýLH@ÍbÎdMPAbΤJPçŽÎ“ýLH xEήý·MpÎDå±A“?BÍDü¦äRH_A“?ÁJžKŽ–S Œ ƒX‰ ` ?B͡ΓýLH@H_FLK·JPç(ΓýLH xEήý MÎDåAD?BÍDü¦äRH_A“?BJ’KŽS  ƒX‰ ?ÁͤήýLH¾Ð]H_FL͓JPA“?BFGCß?ÁFLKL?ÁÐNMpΓJEA"MPFL K Œ ƒ QQ | ÇGW ê"ýLH°HTԞäLA“H_͓ÍD?BJEF JPç4ήýGH°çéOL^B^²^BJPCpå^Á?BüPH_^B?ÁýLJžJ’K ?BÍfKL? RH]ADH]FqÎ@çéADJEúΓýVMpÎ¥JPçkήýLHnH»Ô©å. ÖPÖ.

(17) äLA“H_͓͓?ÁJEFÕßMPFGKÒæZH]Ð_JEúßH]Í à ë ëì. Pì. Í  k¥  ~ ¦ ~ ¯ | HAL author manuscript. Ï Î ƒ{Ð Ø. Ñ. Q. ë ÖÙ ¯. Ï. Ò ’. Q. ‰˜Ð. ë ` ì Ö Á^ F ë  k¥ ë Œ ƒX‰ ` Dì ìo×. ë× ì.  ƒX‰Ô ¦ § © ƒX‰ Œ ƒX‰. Ö}Ú&ƒ. ìG^ÁF Ü 9Ö Ö. áâ’ Ö Žá=’Ð ã ¥\— Ï å. 5. ¯ Ï. Ò ’ ‰¼Ð. ^BF ë Ö9Ö ¯ ë Ú&ƒ. Q. ë ¥ ë Œ ƒŠ‰ ` ì Ý. Ø}æ. ìDìÄ7˜ç. ë Q ì“ìGH»Ôžä ëB¦¨§ © ƒX‰ ë Œ ƒX‰ ` ì“ì Þ. ¥ Œ ƒX‰ Ø Ý. inserm-00138520, version 1. Q Þ¥Í3æRHTçéJEA“HXM¦äZH]FVMP^Á?B\_H]K çéOL^B^›^BJECpå±^B?ÁüPH]^Á?BýLJ’J’KÚ?ÁÍ"OL͓H_KÒΓJÚH_ÍDή?Áú—MÎ®H¥Î“ýLH¾äVMPA®MpúÚHTήH]ADÍ]W. 1. EF(/G. Ð. H,+%IJ%. (/#KIMLùH,'g(*-ËP8),+,' P. "ê ýLH<H]Íbή?BúÚMpΓH]K äLMPA®MPúßH_ΓH]ADÍ/ ¡H]ADHtJEæGήMP?BFLH_K æqù ήýLH<A“JEæGOLÍDÎ ÆMPA˜©OVMpA“KGηMP^å CEJEA“?Î®ýLú 5 Ö Û7 3ýL?ÁÐdý ?BÍ[M Ð]JPúnæL?BFLMpή?ÁJEFæZH_Î ¡H]H_FMlÃfH3 "ήJEFžåIfMpäLýL͓JPFMp^BCEJEAD?ÁΓýLú MPFLK·M¾ÍDΓH]H_äRH_ÍDΤKGH]͓Ð_H]FqÎ"Mp^BCEJEAD?ÁΓýLú<W ê"ýL?ÁÍÓMp^BCEJEAD?ÁΓýLú9ýLMPÍiΓýLHfMPKGÌpMPFqÎdMPCPHµJpçŽæZH]?BFGC úÚJEADHlÍDÎdMpæL^BH·Î“ýVMPF ήýLH<Ãf3H "ήJEFžåIfMpäLýL͓JPF MP^ÁCEJEAD?ÁήýGú 3ýL?Á^BH äLADH]ÍDH]AD̒?ÁFLC+?Î®Ínç~MPÍbÎ Ð]JEFqÌEH_A“CEH_FLÐ]H—äLA“JEäZH]Ab΁ù FLHNMPA[ΓýLHÚúÚMÔž?Bú°OLú<MW HßÍDήJPäLäRH_KΓýLHÚ?Î®H_A®MpΓ?BJEFLaÍ 3ýGH]F ήýLHnKG? RH]A“H_FLÐ]H¦æZH_ Î ¡H]H_Fº Î ÓJ Ð_JEFL͓H_Ð]OGΓ?ÁÌPHß^ÁJECpå±^B?BüpH]^Á?BýLJ’JžKGÍ ¤MpÍ@͓úÚMP^B^vSVήýLHnÐ_Jž3H >¦å Ð]?BH_FqήŸÍ ¡H]ADHnÍDήMPæL^ÁH°MPFGK<ήýGH°CEA“MPKL?BH_FquÎ ÓMPÍf͓úÚMP^B^(H_FLJEOLCEý›Wµê²J—æZH°ÍDOLA“H JPç,ýLM{̒?ÁFLC M¹äZJEÍD?Áή?ÌEH@çéOLFGÐ_ή?ÁJEFlMpεMP^Á^›ÍbÎdMPCEH_Í3JPç7ΓýLH¾MP^ÁCEJEA“?Î®ýLúÒ®S ÓHXA“H_ÍDΓA“?BÐTήH_K<Mp^B^RΓýLH¾Í“äL^Á?BFLH Ð]J’H >ßÐ]?ÁH]FqÎ®Í ‰ ήJ<æRHßäZJE͓?Î®?ÁÌPH¦çéJEAXMP^B¨^ xVW Hß?BúßäRJEÍDH]KMÒÐ_JEFLÍbήA®Mp?BFqΰJpç¤äZJE͓?Î®?ÁÌqå ?Á΁ù+çéJPAnήýLH ÌpMPA“?BMPFLÐ_H·äVMPA“MPúÚHTήH_A“Í]9S ¯ ô ÇGSkÍDJ ¡HlKL?BKFLJpÎÚÐ_JEFLÍD?BKLH_A¹M FGH]CqMpΓ?ÁÌPH KLH]äZH]FLKGH]FLÐ_H°?BF ΓýLH¾úÚJ’KLH]^v–S 3ýL?ÁÐdý<KG?BKlFLJPεýVMNÌEH MnçéA®MP?Á^Á΁ùÚ?BFqήH_A“äLADH_ήMpή?ÁJEFŽW -ýLH_F·çéA®MP?Á^Á΁ù¦äLMPA®MPúßH_ΓH]A¡?BÍÓÍDú—Mp^B^ySqF©OLúßH]AD?BÐ]MP^RäGA“JEæL^ÁH]úßÍ¡úÚMNùÚMPA“?Á͓HPW4ê²JnÍDJE^ÁÌPH ÖÕ.

(18) HAL author manuscript. ήýL?Á͵äGA“JEæL^ÁH]úÒSLMPF<MP^Î®H]ADFVMpΓ?ÁÌEHfçéJEA“únOG^ûMnJPç²Î®ýLH¾äZH]FVMp^B?B\_H]Kl^B?ÁüPH_^B?BýGJžJ’K—?ÁÍ"OL͓H_K 5XW27yW ê"ýLŸH VA“ÍbÎ"KLH]AD?ÁÌpMpΓ?ÁÌEH ë ΓýLH¥ÍDÐ]JEADH{ìÓMPFGK·Î®ýLH@ÍDH]Ð_JEFLK KLH_A“?ÁÌpMpΓ?ÁÌPH ë ΓýLH@ýLH_͓ÍD?ûMPF´ìiJPç ήýLH¹^BJPCpå^Á?BüPH_^B?ÁýLJžJ’KlήýLH_úÚÍDH]^ÁÌPH]ÍXKLJÒFLJPξýVMNÌEHÚM ͓?ÁúÚäL^ÁH¹MPFVMP^ù©Î®?BÐ]MP^7çéJPA“úÒS(͓J ήýVMÎ. ÓHXÐ]JEúßäLOGΓH]KÒF©OLúÚH_A“?ÁÐNMP^Á^Áù¹Î®ýLH_͓­ H ©OVMPFqή?Î®?BH_Í3OL͓?ÁFLC VFL?ÁΓH[KL? RH]ADH]FLÐ_H]Í_W. 2. inserm-00138520, version 1. 3. Z\[. EF(/G. 4. $. H,+%P8'. H,'g( /' IMG. 5. `vÆa`$jkdgq/l8`$h ¨jp\þŸrp\t9Æ. Þ Úú MDJEA4äLADJEæL^ÁH]ú/?ÁFßΓýLH3äVMPA“MPúÚHTήH_AiH_ÍDΓ?BúÚMpή?ÁJEF¦?BÍ4ήýGHµ^Á?BüpH]^B?ÁýLJ’JžKnúÚMÔž?Búß?B\]Mpή?ÁJEF äLA“J’Ð]H_KLOLA“HpW3ê"ýL?BÍ3äLADJžÐ_H]KLOLADH°?ÁÍfCEH_FLH]A“MP^B^ù—ÌPH]ADùÒή?ÁúÚH[Ð_JEFLÍDOLúÚ?ÁFLCLS´úÚMPü©?BFLC¹FLH_Ð]H]͌å Í®MPAbùnήýLH3OLÍDH3JPç›Ð_JEúßäL?B^ÁH]KnäLADJECEA“MPúÚúß?BFGC¥^ûMpFLCEOVMPCPH]Í4͓OGÐdý—MPÍiÝVJEAbήA®MpFŽS©Ü¥S’Ü ÖšÖ SÁWWÁW ê"ýLHÚÐ_JEúnæL?ÁFVMpΓ?BJEFtJpçÓýL?ÁCEýºÍ“äZH]H_K+Ð_JEúÚäG?B^BH_Kº^ûMPFGCEOVMPCEH_Í[MPFLK ήýGH¹ÌPH]ADÍ®MpΓ?B^B?ÎùJp9ç  ë 6 H»ÔG?ÁæL^BHpSžýG?BCEýžå±^BHTÌEH]^VÍbÎdMpΓ?BÍbή?BÐ]MP^V^ûMpFLCEOVMPCPH{ì,äLA“J{̒?BKGHfOLeÍ 3?ÁΓýßΓýLH¥?ÁKLHNMP^LçéA“MPúßH ¡JEA“ü ήJßKLHNMP¨^ 3?Î®ýlήýLH_͓H°äGA“JEæL^ÁH]úßÍ]WÓÝ´JP^B^BJ 3?ÁFLC°Î®ýG?BÍ3äLýL?Á^BJEÍDJEäLýqùES ³»‰D}Pw‡á| d¿G}’d¸ ýLMPÍ3æRH_H]F ?BúßäL^BH_úÚH_F©Î“H]KÚMPͤMXKGù’FVMPúß?Bе^B?ÁFLün^B?ÁæLA®MpADù ë KL^B^ûì4?ÁF—ÝVJEAbήA“MPF ÛEے

(19) S 3ýG?BÐdý·?ÁÍ¡Ð]MP^B^ÁH]Kßæ©ù h çéOLFLÐTή?BJPFLJÍ 5 Ö É 7yW ±ΦÐ_JEúßäL?B^ÁH]ÍnMpFLKA“OLFGͦJEF  M 3?BKLHÚÌPMpA“?BHT΁ù+Jpç¥ÊfÃf8 7äL^BMpΓçéJPA“úßÍ°MPFGK͓?Búß?B^BMPA ÍDù’ÍDΓH]úßÍ ë ?BFGÐ]^BOGKL?BFLCfÝVA“H_HNÑ"5Ä / MpFLK¹Ù(?BF©OžÔLìTS -?BFLKLJ 3Í4MpFLKßÆMP@Ð žXÄZWpê"ýL?ÁÍ,äVMPÐdüMPCPH KLH]äZH]FLKGÍ¥JEFlJPΓýLH]A  äVMpÐdüpMpCEH]Í_SV͓OLÐdýMPÍ zT”ž‰»†{w‡†}P MPFLK z¿Záw‡„›ˆdz W ê"ýLH3ÍbήA“OGÐ_ήOGA“H3JPçZήýLH"KVMÎdaM V^BH"?ÁÍ4Þ[ÄLÜÓÂDÂ7çéADH]H¤çéJEADú—MpÎ]W7ê"ýGHµKG? RH]A“H_FqΡÐ_JE^BOGúÚFLÍ JPç3ήýLH KVMÎd2M V^ÁH 3?B^Á^¡Ð_JEFqÎdMP?ÁF ë ?ÁF MPFqùJEADKLH]A®ìTS4ήýGH·H]FqήAbùή?ÁúÚH ë 3ýL?ÁÐdý?BÍnKG? RH]Abå H]FqΰçéADJEú=\]H_A“JÒçéJEA¾^BH_ç‡Î¾Î“A“OLFLÐ]MpήH_K+KVMÎdMqì»S²Î“ýLHÚJPOGήÐ_JEúÚH¹ÌpMPA“?BMPæL^ÁHPSŽÎ®ýGHÚÐ_H]FLÍDJEA“?ÁFLC ÍDÎdMÎ®OLÍ_S´Î“ýLH¾CEA“JPOLäl?BKLH_F©Î“? VÐ]Mpή?ÁJEFlF©OLúnæZH]A]SLΓýLH¾HTԞäL^BMPFVMpΓJEADùÚÌPMpA“?ûMpæL^BH_Í]W4ê"ýLH¾Þ¥ä’å ÖÈ.

(20) HAL author manuscript. Rä H_FLKL?Ô Ö KLH_͓Ð_A“?BæZH]ÍnMPFHTԒΓA®MPÐTιJPç3MKVMÎdM2V^ÁH—ÍbήA“OGÐ_ήOGA“HPSkÐ_JEA“ADH]͓äZJEFLKG?BFLCΓJήýGH VA“ÍbÎ¥MpäLäL^B?ÁÐNMpΓ?BJEF ë ͓H_H ÍDH]ÐTή?BJPF ë Ø W Ö ì“ìTW ÝVJEOLA¹çéOLFLÐTή?ÁJEFLÍßÐNMPF æZHOG͓H]K OGFLKLH]AßήýLH<^B?ÁæLA®MPAbù ³»‰D}Pw‡á|d¿G}’d¸à·³»‰D}Pw‡á|{­3ˆT„Z}PË‚ W Hº?BFLKG?BÐNMÎ®H<ΓýLHº?BúßäZJE͓H_K ¿Z‰Tw‡„V|‡‚¹zT”ž¯¦¯ß}Po‰ {‚¾¿ZBx| 3?ÁΓý-MPKVMPäžÎ®H]KMPADCEOLúßH]FqήÍ_ì MPA“CEOGúÚH_F©Î“­Í 3?Î®ý æRJP^BK ÐdýVMPA®MpÐ_ήH_A“Í_S0?BF ?ÁήMP^B?ÁЦMPADHßΓýLHÚFLMPúÚH_;JPçÓΓýLHßÌpMPAD?ûMPæG^BH];JEA ήýLH@ÌpMP^ÁOLH]Í"JPç ΓýLH[äVMPA“MPúÚHTήH_A“ÍÓΓýVMpÎ"Ð]MPFlæRH[ÐdýVMpFLCEH]K›W¡ÃµJPήH@ΓýVMpΤΓýLH[ÐNMpäL?ÁήMP^B?Á\]H]K ÐdýVMPA®MpÐ_ήH_A“ÍfMPA“H¾KL€? ›H_A“H_F©Î3çéADJEú ÍDú—MP^Á^›^ÁH_ΓΓH]AD͵?ÁFÒIXW. inserm-00138520, version 1. 9;: õ =<?> »ñA@@ðCB =>EDFAG õIHJD |~w‡¯—ˆd‚ ˆT†PˆT„V|5KML¬†}P‰ ˜"N †}P‰»– N O>?G7÷ {ð©õ5D P‰dx”{¿=K"P zT|v‰D}P|y}Lsvz{ˆD•_€ Sö RQS BˆT„Z}P¯—ˆ SU(T õ =<?> »ñQWV h߃ŽgYX B0Z\[]B²ô ÷^Q ˜ o SU[ `_a_ Ab5Q ˜ mqmqm{‚´¸P}T¿q¿G}P–5c ˜Od mqm{‚Z¯ß}N•Ew‡|efc o d m{‚R‰®ˆdT”ž‰»‰®ˆT„V|B£ ¨ c V h߃(gk‚(T‰®x{zdz]§B†}Páw~‘q}P|~wyx„fc V h߃(g K . ¢. $. . v @. . ¢. 3. k. . v. ê"ýL?BÍXçéOLFLÐTή?BJPFMP^Á^BJ 3Í°MpA“æL?Î®A®MpADùºäVMÎ“ήH_A“FLÍ JPç"ή?ÁúÚH»åKLH_äRH_FLKLH_F©Î Ð]J{ÌpMPAD?ûMpΓH]Í]W ±Î0ýLMPFLKL^ÁH]ͲFLJPβJEFL^ù@ήýLHiÐ]^ÁOLÍDΓH]ADH]K°ç~MP?Á^BOLADH,ή?ÁúÚH4KVMÎdM3æLOGÎ0MP^BÍDJµÎ“ýLH¡ADH]Ð_OLA“ADH]FqÎ H_ÌPH]FqήÍkKVMpήMGW,ÝVOLAbήýLH_A“úßJEA“H¤M¥Í“OL

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