Joseph Rhine (1950)

1
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?????? ??????????
????????? ?.?.
???????? ????? ???????? ??. ?.?. ???????? ???
2
????? ?? ????????? ????? ? ???????????????
????????????? Joseph Rhine (1950)
????? ?. ????? ?????? ???????? ??????????
????? ?? ?? ?????????????? ????????????
??? ?????????? ??????????? ? ??????????? ??????
?? ??????????? ???? ???????????
3
??? ??????????
1- ?(100 ??? ?? ?????)
4
?????? ???? ?????? ? ??????? ??????
???? ?????? ??????? ?????, ?????????? ????????
??????? ?????? ?? ????? ??????? (????? ???????
? ????????)
? ?? ??????? ?? ????? ??????? ???????!!!
?????????? ???????? 9 ?????? 1 ?????
??????????? ????????? 9 ??? 10 ????? ? 10
????????? ??????
5
?????? ? ???????? 90-?? ?????????? ? ????????
multiple comparisons ?

• ? ????????????? ????????????? ????????????
  ???, ??? ???????, ?????????? 3-5 (??? 5-20)
  ??????????? ??????? (??? ????? ??? ????? ????????
  ?? ????? ??????????? ??? ???????????? ?????????)
• Genome-wide association ???????? ??????????
  ????? ??? ?????? ?????????? 500 000 SNP.
• ??? ?????? ?????????? 0.01 ????? ??????? 5000
  ?????? ??????????
• ????-???????????? (????????????
  ????????????) ??? ?????????? ? ??????????
  ??????, ?????????? ??????? ????????

?????????? ???????? ?????????? ??????
(????????????? ?????????) ??????? ? ??????????
????????? ????????
6
??? ??? ??????? ????????? ????????? ?????????
??????????
?????????? ??? ????????? ?????????????? ???????
?? 100 ?????? ? 20-????????? ??????????
Odd Ratio ????????? ??????, ?????????? ????
?????????????. ??? ?????????? ????? OR1
??????? ??????? ??????? (? ??????? 0.1)
?????? ???? OR1
??????? ????????
??? ??????? 1 ??????? 2
OR p
????? 3 ?????? ????????????? ?
???????????????!
1
2
3
4
7
??? ?? ???????? ????????? ?????????
??? ?????????? m ??????????? ??????????????
?????? ?? ?????? ?????????? ? , ??????????? ????
?? ?????? ?????????? ?????????? ?????? ????
1-(1-?)m lt 0.05
8
??????? ?????????? ??????????? ?????????? ??????
???????????? ???????????
??? ???????, ??????????????? ? ????????????
???????? (100) ??????? (100) OR p
??????? 1 1 7 7,45 0,0349
??????? 2 5 15 3,6 0,0253
?????? ??????? ?????????? ??????? p lt
0,05/20,025
9
??????? ?????????? ??????????? ?????????? ??????
???????????? ???????????
???? ??????? ?????, ?? ??????????? ? ????
???????
???????? (100) ??????? (100) OR p
??????? 1 1 7 7,45 0,0349
??????? ?????????? ? ??????? ????? 36 40 1,19 0,646
??????? ?????????? ??????? p lt 0,05/20,025
???, ??? ?? ?????!!!
10
Assessment of individual sensitivity to ionizing
radiation and DNA repair efficiency in a healthy
population F. Marcona, C. Andreoli, et al. Mut.
Res., 541 (2003)
????????
11
High-Throughput Detection of GST Polymorphic
Alleles in a Pediatric Cancer Population P.
Barnette, R. Scholl, et al. Cancer Epidemiology,
Biomarkers PreventionVol. 13, 304313, 2004
????????
13 ?????????
OR6,4 P0,007
8 ????? ???????????
?????????????? ?? ???????? GST ???????? ?? ????!
OR2,3 P0,018
12
Implication of Xenobiotic Metabolizing Enzyme
gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2)
Polymorphisms in Breast Carcinoma A. Khedhaier,
E. Hassen, et. al. BMC Cancer, 2008
??? ???? ??????? ????? ????????? ????????? ??
????, ??? ? ??????? ? ??????? ??????????
(?????????? ????????????? ?????????????)
microsomal Epoxide Hydrolase ???????? ?????? (?)
????????????? ?????????? ?????????? ????????
? ??????? 12 ????????? ?? ?????? 6 ? ????????
13

• Bonferroni method creates more problems than it
  solves
• ????????? ?????? ????????? (Thomas Perneger,
  1998)

• ????????????? ?????? ??????? ?? ????? ??????.
  ??? ???????? ????? ????????. ?????? ?? ?????
  ?????? ?????????? ?? ????, ??? ?? ???-??
  ??????????!
• ??? ??????? ?????????? ?????? ???????? ? ???,
  ??? ??? ??????????? ???????? ??????????, ??????
  ?? ?????
• ??? ????????? ?????????? ??????????? ????????
  ???????????? ???????? ????? ??????, ???
• ????? ?????? ??????????? ????? ????? ????
• ???????? ?????????? ?, ???????, ??????

Bonferroni adjustments are, at best, unnecessary
and, at worst, deleterious to sound statistical
inference
14
?? ?????????? ?? ?????? molbiol.ru

• ?? ?? ????? ??????? ???? ?????????? ??-??
  ??????-?? ??? ??????????
• ?????????? ??????????? ? ?????????? ???
  ?????? ???
• ??????????????? ???????? ???????
• ???????????? ???????? ?? ?????? ???????
  ???????? Bonferroni
• ???? ?????????? ?????? ???, ?? ??????
  ?????????? ?????? ?????????

15
????-???? ?? ??????? ?????????????? ??????
??????????? ?????? ???????????? ?? ????????
?????? I ???? (????? ??????? ??????????), ?.?.
?? ???????? ?????????? ?????? ????????,
??????? ???????? ?????? ????????????? ??
?????????? ???????? 2 ??????? ?? ?????
??????????? ????????????
?????? I ???? (?) ??????????? ??????????
?????????? ??????? ???????? ???????????
?????????? ???????? ???, ??? ?? ??? ???????????
????????? ????????? ????????
?????? II ???? (?) ??????????? ???????
???????????? ??????? ???????? ??????????? ??
?????????? ???????????? ???????? ???????????
???????? ????????
? ??? ???? ???? ????????? ? ???????????
???????? ???????? (?????? II ????)
???????? ????? 1- ?????? II ????
??????????? ????????? ?????????? ???????
???????? ??????????? ?? ???????? ????????
16
???????? ?????????????? ??????

• ???????? 80 ????????? ??????????
• (???????? ??????? ?????? ? ????????
  ?????????)
• ?????????????? ???? - ??? ???? ? ??????
  ?????????
• (????., ???????? ???????????-????????)
• ????? ?????????? ?????????????????
• (???????? ??? ????????? ??????)
• ?? ?????? ??????? ????????? ?????????? ??????
  
• ????????? ???????? ??????????? ????????
  ???????????

17
?? ???? ??????? ?????? ?????????????? ???????

• ?? ??????? ??????? ???????????? ??????? ?
  ????????
• ??????
• ?? ??????? ???????
• ?????? I ? II ???? ?????????? ?? ???????. ?
  ?????
• ?????? II ???? ?????? ??? ??????????
  ?????? I ????
• (??????? ??????? ???????????? ??????
  ?????????? )

? ??????????? ?????? ??????? ???????? ?????
(??????????? ?? ???????? ????????) ??????
??????????
?????? I ???? (??????????? ?????????? ????????)
????? ??????? ?? ??????? ???????, ???? ???
???????? ?? ????????
??????? ?????? ???????? ??. ???? ???????????
(0033) ?????? I ???? 0 ? ?????? II ????
1
18
??????????? ?????? II ???? ?? ????? ?????? ???
????????????? ???????? ??????????
??? 100 ?????????? ???? ????, ????? ?????????????
?????????? ???? ?? ?????? ??????? ??????????,
?? ???????? 88 ????????!
??????????? ?????????? ??? ? OR2.7 ?? ????????
100 (case) ? 100 (control)
??? m100 ?????? ????? 0.88
??? 5 ?????????? ???????? 50 ????????
? ????????? ????? ??????????? ???????? ????????
????? 0.2
19
????? ??????? ???????? ?????????????? ???????
FDR-????????
False Discovery Rate control Benjamini, Hochberg
(1995)
??????????? ?????????? ???????? lt ??????
?????????? ?????? I ???? lt 0.05
20
???????? ???????? FDR (Benjamini, Hochberg, 1995)

• ????????????? ????? ?? ?????? p-???????
• p1 ? p2 ? ? pm.
• ??? ???????? FDR ?? ?????? a (???????? 0.05),
• ???????
• ??????? ???????? ????????? ??? j 1, , j.
• ??? j gt j ???????? ????????? ???????????

?????????? ????? ????
??????????? ??????? ??????????
???????? p ??? j-??? ????? (????)
????? ????? ?????? (?????)
21
?????? ????????????? ????????? ?? 10 ??????
??????????? ????? ? ??????? ?????????? p
????????? Bonferroni
0,005
0,005
0,005
0,005
0,005
0,005
0,005
0,005
0,005
0,005
????????? ?? FDR
0,005
0,010
0,015
0,020
0,025
0,030
0,035
0,040
0,045
0,050
???? pi
1 0,001
2 0,0055
3 0,01
4 0,015
5 0,02
6 0,04
7 0,3
8 0,5
9 0,6
10 0,8
???????? ???????? ????? ????????? ?? FDR
? ?????? ?????? ??? ? ??????????,
???????? ?????????? ????????? ???????? ????
?????? ?????????
?? ?????? ?????? ????? ??????,
????? ?????? ? ?.? .
? ??? ???!!!
??? 6-??? ????? p ?????? ????? ????????
???????? ???????? ??? ???????? ?? ???????????????
22
?? ?? ????? ? ????? ?????? m ????? ?????????,
? 0.05 (????????)
Bonferroni (1939) FDR (1995)
p1 ?/m ?/m
p2 ?/m 2?/m
p3 ?/m 3?/m
?/m
pi ?/m i?/m
?/m
pm ?/m ?
?????????? ???????????! ???????? FDR ????????
???????? ??????????, ???? ???? ?? ???? ????
????????????? ??????? p lt ?/m
23
?????? ?????????? 3051 ????? ??? ??????
????????Golub T.R. Molecular classification of
cancer class discovery and class prediction by
gene expression monitoring. // Science. 2001,
v.286.
????? ????? ? ?????? ??????? t-??????????
t-?????????? ??? ????????? ?????????? ???? ?
??????? ? ????????

• t-???? 1045 ?????, ??? ??????? plt0.05
• ????????? ?????????? 98 ????? ??? plt0.000016
• FDR 681 ?????, ??? ??????? FDRlt 0.05

24
??? ??????, ???? FDR ?? ?????????
Permutation tests ????????? ????????????
??????? case-control ? ???????????? ??????????
?? ?????????

• ? ???????? ???? ?????? ?????? ?????????
  ????????????
• ??????? case-control
• ????????? ?????? p-?????? ??? ??????? ????
  (pperm)
• ????????? ????????? N ??? (??????? 10000),
  ????????
• ??????, ????? pperm ?????? ?????????
  ???????? p
• ????????? ?????????????????? p ???

??? ????? ?? ???????????? ?? ??????? ?????????
?????????? ????????. ?????? ????? ?? ??
???????? ????????????????, ?????????? ????????
?? ??????????
?????? ???? ?????? ??? ???? permutation test,
?????? ????????????? ???????????? (?
??????????? ?? ???????? ????????????? ??????
????????????)
25
Permutation test ????????????? ? ?????? ??
?????????? ?????????????? ? 10 SNP
???????????? ??????? case-control 10000 ???. ?
?????????? ???????? ????????? p
SNP ??????? ????????? ?????? ??????? ????????? ?????? OR p
SNP Case (100) Control (100) OR p
1 62 26 4,6 0,0001
2 19 6 3,7 0,009
3 31 14 2,8 0,011
4 20 8 2,9 0,023
5 11 4 3,0 0,071
6 23 13 2,0 0,096
7 44 30 1,8 0,103
8 54 39 1,8 0,120
9 59 53 1,3 0,571
10 40 41 1,0 0,911
p
0,000
0,010
0,007
0,025
0,109
0,098
0,058
0,067
0,476
1,000
Indulgentia
?? ??? ?????? ?? ??????
26
?????? Permutation test ??? ??????????

• ???????? ?????????? ? FDR ????????????, ??? ???
  ?????
• ??????????
• ???????????? ??????? case-control ?????????
• ?????????????? ????? ????? ???????
  
• (? ?????? ??????????? ????? ????? ???????
  ?????????
• ???????????? ?? ?????????)
• ????????? ?????????? ????????????? ????????
• ?????????
• ? ?????????? Permutation test ???????????
  ?????
• ?????????????, ??? Bonferroni ? FDR

27
??? ??????????? permutation tests?
?? ???????????? ? ??????????? ???????????.??
??????????? ???? ????????

• free
  30-day demo version
• https//www.dynacom.co.jp/e/products/package
  /snpalyze
• 
  FREE!!!
• http//statgen.ncsu.edu/powermarker/index.ht
  ml
• Free software environment for
  statistical computing
• ?????????? ???????
  HaploStats, SNPassoc ? ?????? ??.
• http//www.r-project.org/index.html

? ??? ?? ?????? ????? ??????!
28
?????? ? ???????? ?????????? ????????????!

• ????????? ????, ????????? ???????,
• ???????????? ?????????, ?????????? ????
• ? ??? ??? ????? ???
• ??????? ?? ????????? ? ??????????
• ???????? ?????????? ????? ?????????.
• ?????????? ? ??????????? ???????????
  ???????????!
• ???? ????? ??????? 3, ?? ??????
• ????? ??????????? ?????????? ltlt ?????
  ?????????

???????? ???????? ??? 3 ??????? 27 ?????????
?????????, ?? ???? 5-7 ?????????? ??????????? ?
???????? gt1
29
Soft ??? ?????? ? ???????????

• http//www.bios.unc.ed
  u/lin/hapstat/
• X. Sole, E. Guino, J. Valls, R. Iniesta1,
  V. Moreno (2006)
• http//bioinfo.iconcologia.net/index.php?m
  oduleSnpstats

30
SNPStats

• ???????????? ??????
• Allele and genotype frequencies
• Test for Hardy-Weinberg equilibrium
• Analysis of association with a response
  variable based on
• linear or logistic regression
• Multiple inheritance models co-dominant,
  dominant,
• recessive, over-dominant and additive
• Analysis of interactions (gene-gene or
  gene-environment)
  
• ????????????? ??????
• Linkage disequilibrium statistics
• Haplotype frequency estimation
• Analysis of association of haplotypes with the
  response
• Analysis of interactions (haplotypes-covariate)

31
SNPstats ? ???????? ?????????? ???? ? 3 SNP
(?????? ?.?. ???????? ? ?.?. ???????????, ???
2008)
Haplotype association with response (n164, crude analysis) Haplotype association with response (n164, crude analysis) Haplotype association with response (n164, crude analysis) Haplotype association with response (n164, crude analysis) Haplotype association with response (n164, crude analysis) Haplotype association with response (n164, crude analysis) Haplotype association with response (n164, crude analysis) Haplotype association with response (n164, crude analysis) Haplotype association with response (n164, crude analysis)
  COMT GSTP1 MTHFR Freq OR (95 CI) P-value    
1 L A C 0.2719 1 ---    
2 H A C 0.1996 2.69 (1.02 - 7.12) 0.048    
3 H G C 0.1155 0.10 (0.01 - 1.26) 0.076    
4 L G C 0.1059 3.22 (0.95 - 10.93) 0.062    
5 H A T 0.099 2.08 (0.77 - 5.60) 0.15    
6 L G T 0.0906 1.50 (0.49 - 4.62) 0.48    
7 L A T 0.0773 3.24 (0.67 - 15.68) 0.15    
8 H G T 0.0402 13.88 (1.21 - 158.65) 0.036    
Global haplotype association p-value 0.033 Global haplotype association p-value 0.033 Global haplotype association p-value 0.033 Global haplotype association p-value 0.033 Global haplotype association p-value 0.033 Global haplotype association p-value 0.033 Global haplotype association p-value 0.033 Global haplotype association p-value 0.033 Global haplotype association p-value 0.033
?? ??????????? ?????? ?? ???????????? ????????
??????????!
32
?????? ?? ??????? ???????????? ?????????? ??
??????????????? ??????????

• ????? ?? ??????????? ??????? ???????
• ????? ?????????? ??????? ????????? ????? ?
• ??????????? ??????
• ????? ???????????? ?????? ????????????????
• ??? ?????? ? ???????? ???????.
• ???? ???? ?? ???? ????????? ???????? ?????
  ????
• ??????????, ?? ? ??? ?????? FDR. ?
  ????????? ??????
• ??? ?? ???????? ??? ????????????????
  ?????????????
• ?????.

33
??????? ??????????? ????? ? ???? ??????????????
!!! ? ????????????? ??????????? ?????
??????????? ????????????????? ???????? rubanovich_at_
vigg.ru
34
Bonferroni, FWER, FDR ? ??? ?????

• Bonferroni ???????????? FWER
• (family-wise error rate), ?.?.,
  ???????????
• ???? ?? ?????? ?????????? ????????
• ?????????? ???? ? ???????????????
• FDR ??? ???????? ??????? ????
• ?????-??????????????? ????? ????? ????
• ?????, ??? ??????? ?????????? ???????
• ????????.

35

• Association between Common Variation in 120
  Candidate Genes and Breast Cancer Risk
• P. Pharoah, J. Tyrer1
  et al. PLoS Genetics, 2007.
• 710 SNP (120 genes), Case - 4400,
  Control 4400.
• ??????
  ??????????
• 104 SNP ? 8 ????? ??????????? ??????????
  ????????
• 112 SNP ? 18 ????? ???????? ?????????? ?????

??????? ?? ????????? ? ??????????

• ???????????? ????????? ?? ????????????
  ???????
• ????????? ????????? ?????, ?? ??????? ??
  ???????? ?????
• SNP (?? ??????? ??????????????? ?????????)
  
• ????????????? ???????????? ???????????? ???
• ? ?????????????? ?????? ????
  ??????????????

36
????????? ?????? ??? ?????? ?????????? 0.05
?????? ??????? ? ????? ? ???????? ?????????
????? ??????? ? ???????? ??????????? ????? ??????? ? ????? ??? ???????? ??????? ?? ???????? ??????????? ????? ??????? ? ????? ??? ???????? ??????? ?? ???????? ??????????? ????? ??????? ? ????? ??? ???????? ??????? ?? ????????
????? ??????? ? ???????? u-???? ?2 ?????
0 2 4 5
1 6 7 7
2 8 9 9
3 10 11 10
4 12 12 12
5 13 13 13
6 15 15 15
7 16 16 16
8 18 18 18
9 19 19 19
10 21 21 20
20 35 35 33
30 47 47 46
???? ? ???????? ??? ?????????, ?? ??? ??????????
??????? ? ????? ?? ?????? ????
?????? 5 ?????????? ?? ????, ??????? ?????? ??
?????????? 100 ??? 1000