DK2772553T3 - Fremgangsmåder til genetisk analyse - Google Patents
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- DK2772553T3 DK2772553T3 DK14170551.7T DK14170551T DK2772553T3 DK 2772553 T3 DK2772553 T3 DK 2772553T3 DK 14170551 T DK14170551 T DK 14170551T DK 2772553 T3 DK2772553 T3 DK 2772553T3
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Claims (16)
1. Fremgangsmåde til bestemmelse af et individs risiko for at udvikle eller udvise en multifaktoriel medicinsk tilstand omfattende: a) bestemmelse af en score for individet baseret på genotypisk information, som er opnået ud fra en prøve fra individet, hvor den genotypiske information er tilstedeværelse eller fravær af alleler, som er associeret med den medicinske tilstand ved en flerhed af polymorfe loci, hvor én associeret allel tildeles en anden værdi for bestemmelse af scoren end andre associerede alleler, og hvor størrelsen af allelernes effekt på risikoen anvendes ved bestemmelse af scoren, og hvor bestemmelse af scoren for individet desuden er baseret på ikke-genetisk information; og b) sammenligning af scoren med mindst én tærskelværdi, hvor resultatet af denne sammenligning er en indikation af individets risiko for at udvikle eller udvise den multifaktorielle medicinske tilstand.
2. Fremgangsmåde ifølge krav 1, hvor den genotypiske information omfatter genotyper for individet ved en flerhed af biallele polymorfe loci, hvor hver af flerheden har en associeret allel og en ikke-associeret allel, og desuden hvor hver af genotyperne er valgt fra gruppen bestående af homozygot med hensyn til den associerede allel, heterozygot og homozygot med hensyn til den ikke-associerede allel.
3. Fremgangsmåde ifølge krav 2, der yderligere omfatter identificering af de associerede alleler og de ikke-associerede allelerfor nævnte flerhed af biallele polymorfe loci ved at udføre en associeringsundersøgelse med en casegruppe af individer og en kontrolgruppe af individer, hvorved der bestemmes et sæt alleler af de polymorfe loci, der er signifikant mere talrige i casegruppen end kontrolgruppen, hvor sættet af alleler eller en delmængde deraf er de associerede alleler.
4. Fremgangsmåde ifølge krav 3, hvor udførelse af en associeringsundersøgelse desuden omfatter a) genotypebestemmelse af casegruppen og kontrolgruppen ved et sæt polymorfe loci, der omfatter nævnte flerhed af biallele polymorfe loci; b) beregning af en relativ allelfrekvens for hvert af sættene af polymorfe loci for hver af casegruppen og kontrolgruppen; c) for hvert af sættene af polymorfe loci, sammenligning af den relative allelfrekvens, som er beregnet for casegruppen, med den relative allelfrekvens, som er beregnet for kontrolgruppen, hvorved der identificeres en delmængde af sættet af polymorfe loci, hvor hver af delmængderne har en relativ allelfrekvens, der er signifikant forskellig for casegruppen end for kontrolgruppen; og d) bestemmelse af en allel for hver af delmængden, som er mere talrig i casegruppen end kontrolgruppen, hvor allelen er én af de associerede alleler.
5. Fremgangsmåde ifølge krav 3, der yderligere omfatter validering af de associerede alleler ved at udføre en anden associeringsundersøgelse med en anden casegruppe og en anden kontrolgruppe, hvorved der bestemmes, hvilken af de associerede alleler der er signifikant mere talrig i den anden casegruppe end den anden kontrolgruppe, hvor de af de associerede alleler, som er signifikant mere talrige i den anden casegruppe end den anden kontrolgruppe, er de validerede associerede alleler.
6. Fremgangsmåde ifølge krav 3, der yderligere omfatter bestemmelse af én af den mindst ene tærskelværdi ved en fremgangsmåde, som omfatter a) beregning af en score for hvert medlem af casegruppen og kontrolgruppen; b) udvælgelse af en serie af risiko-cutoff-værdier; c) udregning af et sæt værdier for hver af serien af risiko-cutoff-værdier, hvor sættet af værdier omfatter mindst én af en sensitivitet, en specificitet, en PPV, en NPV, en nøjagtighed, en relativ risiko, en LR+, en LR- og klinisk information; d) udvælgelse af én af serien af risiko-cutoff-værdier som den ene af den mindst ene tærskelværdi, baseret på sættet af værdier, hvorved man bestemmer den ene af den mindst ene tærskelværdi.
7. Fremgangsmåde ifølge krav 6, hvor beregning af en score for hvert medlem af casegruppen og kontrolgruppen omfatter a) bestemmelse af en genotype for hvert medlem ved flerheden af biallele polymorfe loci, hvor genotypen er valgt fra gruppen bestående af homozygot med hensyn til en associeret allel, heterozygot og homozygot med hensyn til en ikke-associeret allel; b) tildeling af en første værdi til hvert af de polymorfe loci, der har en genotype, som er homozygot med hensyn til en allel, som ikke er den associerede allel; c) tildeling af en anden værdi til hvert af de polymorfe loci, der har en genotype, som er heterozygot; d) tildeling af en tredje værdi til hvert af de polymorfe loci, der har en genotype, som er homozygot med hensyn til den associerede allel; e) opsummering af de værdier, der er bestemt i trin b) til d) for alle de polymorfe loci, hvorved der beregnes en score for hvert medlem af casegruppen og kontrolgruppen.
8. Fremgangsmåde ifølge krav 6, hvor udvælgelsen af en serie af risiko-cutoff-værdier omfatter identificering af en højeste score ud fra de beregnede scorer for hvert medlem af casegruppen og kontrolgruppen; bestemmelse af et risiko-cutoff-område, hvor området er fra 1 til den højeste score; udvælgelse af en serie af værdier fra hele risiko-cutoff-området, hvorved serien af risiko-cutoff-værdier udvælges.
9. Fremgangsmåde ifølge krav 8, hvor udvælgelsen af serien af værdier fra hele risiko-cutoff-området omfatter en fremgangsmåde, som er valgt fra gruppen bestående af udvælgelse af enhver værdi inden for risiko-cutoff-området; udvælgelse af hver n’te værdi inden for risiko-cutoff-området; opdeling af risiko-cutoff-området i procentdele og udvælgelse af en værdi ved hver n’te procent af risiko-cutoff-området; udvælgelse af et større antal værdier fra en midterportion af risiko-cutoff-området end fra en top- eller bundportion af risiko-cutoff-området; og udvælgelse af et større antal værdier fra en top- eller bundportion af risiko-cutoff-området end fra en midterportion af risiko-cutoff-området.
10. Fremgangsmåde ifølge krav 5, hvor bestemmelsen af den ene af den mindst ene tærskelværdi desuden omfatter anvendelse af en ROC-kurve baseret på den under c) udregnede sensitivitet og specificitet, hvor en grafisk repræsentation af ROC-kurven betegnes som et diagram.
11. Fremgangsmåde ifølge krav 10, som desuden omfatter udvælgelse som den ene af den mindst ene tærskelværdi af en risiko-cutoff-værdi svarende til et datapunkt på ROC-kurven, som er nærmere ved et øverste venstre hjørne af diagrammet end noget som helst andet datapunkt på ROC-kurven, hvor hvert datapunkt på ROC-kurven svarer til en forskellig risiko-cutoff-værdi, og/eller som desuden omfatter a) bestemmelse af en position på ROC-kurven, som er nærmest ved et øverste venstre hjørne af diagrammet, og bestemmelse af en sensitivitet og specificitet, som svarer til denne position; b) analyse af scorerne for hvert medlem af casegruppen og kontrolgruppen for at identificere en risiko-cutoff-værdi, hvis sensitivitet og specificitet er nærmest ved den sensitivitet og specificitet, der svarer til positionen, hvor den risiko-cutoff-værdi, hvis sensitivitet og specificitet er nærmest ved den sensitivitet og specificitet, der svarer til positionen, er den ene af den mindst ene tærskelværdi.
12. Fremgangsmåde ifølge krav 6, hvor den relative risiko udregnes for en given risiko-cutoff-værdi ved en fremgangsmåde, der omfatter a) bestemmelse af en procentdel af medlemmerne af casegruppen, som har en score, der er mindst lige så stor som den givne risiko-cutoff-værdi; b) bestemmelse af en procentdel af medlemmerne af kontrolgruppen, som har en score, der er mindst lige så stor som den givne risiko-cutoff-værdi; og c) dividering af den under a) bestemte procentdel med den under b) bestemte procentdel for at udregne den relative risiko.
13. Fremgangsmåde ifølge krav 1, hvor bestemmelsen af en score for individet desuden omfatter a) bestemmelse af en genotype for individet ved flerheden af biallele polymorfe loci, hvor genotypen er valgt fra gruppen bestående af homozygot med hensyn til en associeret allel, heterozygot og homozygot med hensyn til en ikke-associe-ret allel; b) tildeling af en første værdi til hvert af de polymorfe loci, der har en genotype, som er homozygot med hensyn til en allel, som ikke er den associerede allel; c) tildeling af en anden værdi til hvert af de polymorfe loci, der har en genotype, som er heterozygot; d) tildeling af en tredje værdi til hvert af de polymorfe loci, der har en genotype, som er homozygot med hensyn til den associerede allel; e) opsummering af de værdier, der er bestemt i trin b) til d) for alle de polymorfe loci, hvorved der bestemmes en score for individet.
14. Fremgangsmåde ifølge et hvilket som helst af kravene 1 eller 13, som er en computerimplementeret fremgangsmåde.
15. Fremgangsmåde ifølge et hvilket som helst af kravene 1,13 eller 14, hvor de værdier, som tildeles de associerede alleler baseret på størrelsen af effekten på risiko for allelerne, er baseret på frekvensen af allelerne i en case- og en kontrolpopulation.
16. Fremgangsmåde ifølge krav 1, som forud for trin (a) omfatter genotypebestemmelse af en prøve, som er opnået fra individet, for at opnå den genotypiske information.
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| US20150025861A1 (en) * | 2013-07-17 | 2015-01-22 | The Johns Hopkins University | Genetic screening computing systems and methods |
| KR20180021234A (ko) | 2013-08-12 | 2018-02-28 | 제넨테크, 인크. | 보체-연관 상태의 치료를 위한 조성물 및 방법 |
| JP2017515811A (ja) | 2014-05-01 | 2017-06-15 | ジェネンテック， インコーポレイテッド | 抗ｄ因子抗体変異体及びその使用法 |
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| US10152298B1 (en) * | 2015-06-29 | 2018-12-11 | Amazon Technologies, Inc. | Confidence estimation based on frequency |
| CN108289951A (zh) | 2015-10-30 | 2018-07-17 | 豪夫迈·罗氏有限公司 | 抗-因子d抗体和缀合物 |
| CN108472382A (zh) | 2015-10-30 | 2018-08-31 | 豪夫迈·罗氏有限公司 | 抗-因子d抗体变体缀合物及其用途 |
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| CN106951730A (zh) * | 2017-03-21 | 2017-07-14 | 为朔医学数据科技（北京）有限公司 | 一种基因变异致病等级确定方法及装置 |
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| US20140018258A1 (en) | 2014-01-16 |
| US20090087854A1 (en) | 2009-04-02 |
| ES2671119T3 (es) | 2018-06-05 |
| EP2198381A1 (en) | 2010-06-23 |
| AU2008304485A1 (en) | 2009-04-02 |
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