Transcript The role of inherited factors in common cancers

Environmental and heritable factors
in the causation of cancer.
The genetic epidemiology of cancer:
Interpreting family and twin studies
Week 4, Stat 246, 2002
Background to and discussion of:
Lichtenstein et al, NEJM 343 2000: 78-84, and
Risch, Cancer Epi., Biom. & Prev. 10 2001:733-741
1
Science, July 27, 2001:
Genes Come to the Fore in New Cancer Analysis
Last summer, scientists in Sweden and Finland got a lot of
publicity when they published a paper, based on data from
mammoth Scandinavian twin studies, concluding that inherited
factors make a "minor contribution" to most cancers. But they
were using the wrong methodology, says genetic epidemiologist
Neil Risch of Stanford University.
Risch has done an analysis
that comes to the opposite conclusion: Genes play a strong role
in who gets cancer.
Risch looked at the same data as in the earlier study, headed by
Paul Lichtenstein of Sweden's
Karolinska Institute. In the model
Lichtenstein used to extract estimates of the relative
contributions of genes and environment to cancer liability,
environment nearly always won out. But
Risch says that was the
wrong model--one problem with it is that there aren't enough
people with rare cancers to produce meaningful
calculations. Risch instead looked at people in twin and family
studies who had developed cancer and then estimated the
likelihood that a first-degree family member would develop the
same cancer. He found that in "the great majority of cancers," a
family member was about twice as likely as the average person to
develop the cancer. If anything--contrary to
Lichtenstein's
conclusions--the genetic risk was higher for rarer cancers,
Risch reports in the July issue of Cancer Epidemiology
Biomarkers & Prevention. Prostate, colorectal, and breast
cancers are usually seen as having the strongest genetic
components. But the top three on
Risch's list are thyroid and
testicular cancers and multiple myeloma. The exercise means that
" we should be looking for susceptibility genes for all cancers,"
says Risch. Lichtenstein was on vacation and unavailable for
comment. But cancer epidemiologist
Sholom Wacholder of the
National Cancer Institute in Bethesda, Maryland, says
Risch's
work is "a reminder of the need to be cautious about
interpreting studies that attempt to distinguish
genetic and environmental factors."
2
The papers in brief
Lichtenstein et al (2000). Combined data on 44,788
pairs of twins listed in the Swedish, Danish and
Finnish twin registries in order to assess the risks of
cancer at 28 anatomical sites for the twins of persons
with cancer. Statistical modeling was used to estimate
the relative importance of heritable and environmental
factors in causing cancer at 11 of those sites.
Risch (2001). Offers a reassessment of the role of
genetic factors in cancer susceptibility generally and
for site-specific cancers in particular. Presents an
detailed critique of Lichtenstein et al (2000).
3
Summary of conclusions
Lichtenstein et al. “Inherited genetic factors make a minor contribution to
susceptibility to most types of cancers. This finding indicates that the
environment has the principal role in causing sporadic cancers.”
Risch. “ a) All cancers are familial to approximately the same degree, with
only a few exceptions; b) early age of diagnosis is generally associated
with increased familiality;c) familiality does not decrease with decreasing
prevalence of the tumor- in fact the trend is toward increasing familiality
with decreasing prevalence; d) a multifactorial (polygenic) threshold
model fits the twin data for most cancers less well than single gene or
genetic heterogeneity-type models; e) recessive inheritance is less likely
generally than dominant or additive models; f) heritability decreases for
rarer tumors only in the context of the polygenic model but not in the
context of single-locus or heterogeneity models; g) although the family
and twin data do not account for gene-environment interaction or
confounding, they are still consistent with genes contributing high 4
attributable risks for most cancer sites.”
Setting the scene, I
Lichtstenstein et al use the multifactorial (polygenic)
threshold (MFT) model, and infer the relative contributions of
heredity and environment within that model. Their analysis rests
on “the usual assumptions of a classic twin study (that there
was random mating, no interactions between genes and
environment, and equivalent environments for monozygotic
and dizygotic twins). Phenotypic variance was divided into a
component due to inherited genetic factors (heritability), a
component due to environmental factors common to both
members of the pair of twins (the shared environmental
component), and a component due to environmental factors
unique to each twin (the nonshared environmental
component)”.
5
Setting the scene, II
By contrast, Risch makes extensive use of familial risk ratios (FRRs).
These are quantities denoted by R , where R denotes a relationship
(S=sib, O=offspring, DZ= dizygotic twin, etc), and whose values are the
risks of relatives of type R of affected individuals being themselves
affected (here by cancer), divided by the population prevalence.
A way to think of R is as pr(affected | R affected)/pr(affected), the ratio
of the probability (risk) of someone being affected, given that their
relative of type R is affected, divided by the unconditional probability of
that person being affected.
In this view, it is entirely analogous to the coincidence coefficient we
met in the study of interference.
If we denote the population prevalence of our trait by K, and the
frequency of affected pairs with relationship R by K2, then
R = K2 / K2 .
6
More on familial risk ratios
They can be estimated directly from family data, and
can also be studied theoretically, by calculating them
under different assumptions concerning penetrances
and susceptibility allele frequencies.
In particular, we can estimate R , where R = MZ and
R=DZ from twin data, and also study the behaviour of
these quantities under different genetic models, e.g.
a single rare dominant gene causing susceptibility, or
a recessive gene, whose susceptibility allele
frequency ranges from very common to very rare.
7
Points to consider when comparing two types of models
for the involvement of genes in disease susceptibility
How do the models relate to our current
understanding of genetics in general, and
that of disease susceptibility in particular?
How interpretable are the models’ parameters?
How do the models relate to available data?
Do they fit? Does their qualitative behaviour
reflect broadly observed trends?
8
Single factor models
Suppose that the levels of a quantitative trait in a population are
influenced by a gene at a locus at which two (unobserved)
alleles A and a are segregating.
Suppose further (with Weinberg and Hardy) that the population
frequencies of types AA, Aa and aa are, p2, 2pq and q2,
respectively, where 0<p<1, and q=1-p.
Finally, suppose that matings are at random in relation to
genotypes at this locus.
Then the joint distribution of a parental (P) genotype and that of
an offspring (O) at this locus is readily determined.
E.g. the mating AAAa has population frequency p2  2pq, and by
Mendel’s law of segregation, produces offspring with
genotypes 50% AA and 50% Aa. Calculations like this for all 9
mating-pair types lead to the table:
9
One-factor models: the joint distribution
of parent-offspring genotypes
Offspring genotype
Parental
genotype
AA
Aa
aa
AA
p3
p2q
0
Aa
p2q
pq
pq2
aa
0
pq2
q3
Exercise: Obtain the above table and the
corresponding table for full sibs.
10
One-factor models: parent-offspring correlation
Now suppose that deviations from the population mean of the trait for
individuals with genotypes AA, Aa and aa are u, v and w, respectively.
With Yule (1906) we put p=1/2. Then the correlation between the trait
values of P and O is
corr(P,O) = (u-w)2/ [2(u-w)2 + (u-2v+w)2].
Additivity: u+w=2v,
Dominance: v=w,
corr(P,O) = 1/2.
corr(P,O) = 1/3.
This calculation reconciled the Mendelian and Biometric schools at the turn
of the last century.
Exercise: Derive the above and obtain corr(S,S’) for full sibs S, S’ in the
same way. (Remember that u+2v+w=0. Why?) Redo with general allele
frequencies.
11
Multifactorial (polygenic) models
In general, we can postulate arbitrarily many segregating loci, with
arbitrary numbers of alleles, and arbitrary allele frequencies, though
still satisfying Hardy-Weinberg equilibrium, each locus contributing
independently to the quantitative trait, and repeat the analysis just
presented. This was done by RA Fisher in a 1918 paper which laid
out the framework that underlies the MFT model. One result is a
number of formulae like the following:
cov(MZ twins) = VA + VD , cov (DZ twins) = 0.5 VA + 0.25VD
where VA and VD are called the additive and dominance variances,
respectively. The total variance of the quantitative trait in this context
is V = VA + VD + VE , where VE is called the environmental
variance. An extra twist in twin studies is a further term VS for shared
family environment effects which are postulated to be uncorrelated
with the general environmental effects contributing to VE ..
In what follows, we suppose that VD = 0, and adopt the terminology
that calls H= VA /V the heritability of the quantitative trait.
12
Threshold models for disease susceptibility
The analysis of RA Fisher was all for quantitative traits. But most diseases
are qualitative traits: you get them, or you don’t. People wanted to use the
preceding framework for disease traits, and they did it by postulating an
unobserved liability to which the foregoing genetic analysis applies. They
then suppose an individual becomes affected when their liability exceeds a
threshold T. In practice, the population distribution of liabilities is always
assumed to be normal N(0,1), and T is determined by the population
prevalence K, e.g. if K = 1%, then T=2.33.
When pairs of individuals are being considered, the joint distribution of their
liabilities is always assumed to be bivariate normal BN(0,0; 1,1; ), where
 is the appropriate multiple (1.0 for MZ, O.5 for DZ twins) of the additive
variance, which here is just the heritability, as the total variance is 1.
Thus from a knowledge of the prevalence and the heritability of the liability
of a disease trait, and the relationship between two individuals, we could
calculate the chance under the MFT model that neither, one and not the
other, or both will be affected (see later).
In practice, the reverse is done: from the frequencies of such concordant
and discordant relative pairs, people can estimate heritability under the
13
MFT model, and this is exactly what Lichtenstein et al (2000) did.
MFT models for disease susceptibility
Now let’s get to the MFT model used in their
analysis by Lichtenstein et al. As you see from p.
81 of their paper, their data for a particular type of
cancer, say stomach cancer, comes in the form of
counts for male and female MZ and DZ twin pairs,
namely a concordant affected pairs, b and c both
half the number of discordant pairs (one affected,
one unaffected) , and d=n-a-b-c concordant
unaffected pairs. They find it convenient to form a
22 table with entries a, b, c and d. These counts
were also stratified by country in their analysis, but
presented in aggregated form in the paper.
14
Lichtenstein et al’s analysis of
1211 sets of 22 tables
For each country (3), sex (2) and zygosity (2), and each of
11 cancer sites or types, L et al have a 22 table of counts.
+ + a b
- c d
Here a is the number of concordant affected twin pairs, etc.
Suppose that this table corresponds to DZ twins, say, from
a country where the liability threshold for affectedness is T, and
the components of variance in the bivariate normal model for the
liability are VA (additive), VS (shared environment), and VE
(nonshared environment), all adding to 1. The correlation for DZ
twins’ liabilities is  = 0.5 VA +VS , with 1.0 instead of 0.5 for MZ
twins. Their joint analysis of 12 22 tables for a given site or type
assumes country-dependent thresholds, but common,
15
sex-specific variance components.
Summary data and results for
stomach cancer
Twin pairs a b+c RR CI
Concordance
Men
MZ 6 131 9.9 (4.1-23.6) 0.08
Men
DZ 8 256 6.6 (3.2-13.8) 0.06
Women MZ 5 92 19.7(7.5-51.6) 0.10
Women DZ 4 198 6.2 (2.2-17.1) 0.04
VA = 0.28 (0.00-0.51) (not sig. diff from 0)
VS = 0.10 (0.00-0.34)
VE = 0.62 (0.49-0.76)
16
2
Goodness-of-fit  = 8.9 on 38 d.f.
Comment on relative risks
L et al calculate a conventional odds ratio
they term relative risk R = ad/bc from the 22
table entries, plus a confidence interval for R,
as well as a twin concordance 2a/(2a+b+c)
for the absolute risk.The second makes sense,
but the first doesn’t, as the division of
discordants into two equal-sized groups to
form the 22 table is artificial. They should be
using Risch’s DZ and MZ ,see later.
17
Comment on the model fitting and
residual degrees of freedom
What should the residual d.f. be? I count 12 =
3 (countries) x 2 (sexes) x 2 (twin types) sets of either 3 (my
view) or 4 numbers: a=#concordant affected, b+c (or b, c)
discordants, and d=n-a-b-c concordant unaffecteds. I say 3
here, as there is no real way to split the discordants, since twins
are unlabelled. So I get 36 numbers, actually only 24 freely
varying ones, since one of each triple is determined by the other
2 and n. The other calculation gives 48, but really only 36.
How many parameters are estimated? I count 3 thresholds, and
either 2 or 4 freely varying variance components (say additive
and shared environment) the remainder comes by subtracting
the first two from 1. The number 2 is right if we have pooled
across sexes, as Table 3 suggests, otherwise 4 for sex specific
analyses.
However, not one of 24, 36 or 48 minus 3+2 or 3+4 gives 38!
18
Any ideas?
Some comments from the paper
“The statistical model we used provided an
excellent fit to the observed data.”
“Although the model fitting can be used to
estimate the magnitude of the heritable
component of susceptibility to cancer, it
cannot reveal how this component acts or
how it interacts with other factors.”
“…we cannot exclude a modifying effect of
environment on the genetic component found
in our analyses of twins.”
19
A cautionary remark
“…the study of twins, from being regarded as
one of the easiest and most reliable kinds of
researches in human genetics, must now be
regarded as one of the most treacherous.”
From L S Penrose, Outline of human genetics
Heinemann, 1959, quoted in
Pak Sham, Statistics in human genetics
Arnold, 1998.
20
Additional references
Michael C Neale and Lon R Cardon Methodology for
genetic studies of twins and families Kluwer, 1992.
A very comprehensive treatise on the methods of Lichtenstein et al (2000).
Arthur S. GOLDBERGER and Leon J. KAMIN
Behavior-Genetic Modeling of Twins: A Deconstruction
SSRI Working Paper #9824 University of Wisconsin, 1998.
http://www.ssc.wisc.edu/econ/archive/wp9824.htm
As it says, a deconstruction.
21
Risch’s critique: a beginning
First, some facts about the familial risk ratios.
If genetic susceptibility is attributable to a single (rare)
dominant gene, then P = O = S =DZ = (MZ +1)/2, and
so RMD = (DZ -1)/ (MZ-1) = 2.
If susceptibility is attributable to a recessive gene, then
P = O < S = DZ. For a recessive model, RMD is usually
>2, depending on the allele frequency. For a rare allele,
RMD = 4, but diminishes toward 2 if the allele is very
common. (Exercise: Derive these facts.)
22
Proofs of results on previous page
As in the calculation on p.10, we need to enumerate all 9
mating-pair types, and their population frequencies, and
then calculate the chance that they have 2 affected sibs,
under a singe rare dominant gene model. Then we form
RMD . The algebra is ugly, apart from the quantity K=
p2+2p(1-p). Clearly (why?) MZ = 1/K, while DZ is a quartic
polynomial in p. If we go directly to RMD = (MZ -1)/ (DZ-1),
we see that it is K(1-K)/(K2-K2). The numerator and
denominator are both quartics in p, but we only need the
leading terms, which are 2p and p, respectively, so that for
small p their ratio is 2 (Why?).
Exercise: Obtain the second result cited on p.22.
23
Penetrance functions
Recall that penetrance is the chance of being affected,
given genotype, and can be written xi for genotype i.
Various new penetrance functions can be built up from
single locus penetrances. Examples include:
with phenocopies: x’i = min(1, xi +)
multi-locus models: (here i, j, k..refer to different loci)
Multiplicative: xijk… = xi xj xk….
Additive
xijk… = min(1, xi+xj +xk+….)
Genetic heterogeneity xijk.. =1-(1-xi)(1-xj)(1- xk)(…
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Non-genetic cases, more than one gene.
How do the foregoing calculations change if there is a
proportion of non-genetic cases (so-called phenocopies)
of our disease, or if more than one gene influences
susceptibility.Risch asserts that phenocopies “do not
influence the predictions given above”. Can you see
why?
Further, he asserts that if we have locus heterogeneity , the
same predictions hold, and that this is also true if we
have additivity of risks (penetrances).
On the other hand, if epistasis (interaction) is present
among different loci, e.g. if penetrances are multiplicative,
things can be very different.
See Risch’s 1990 paper for fuller details on these issues.
25
Familial relative risks and the MFT model
We saw a few pages back that DZ = K2 / K2 where
K2 is the probability of both twins having liabilities
exceeding the threshold T, a bivariate normal integral,
whose correlation  is 0.5VA + VS. Risch’s Table 1
relates K, VA = H, DZ and MZ when VS = 0, and
draws two important conclusions:
•
For a fixed value of  , the heritability H decreases
with decreasing K;
•
For the MFT model, RMD is always > 2, and
increases directly with heritability H and inversely
26
with prevalence K.
MZ , DZ and the MFT model with
shared environment
We are interested in the impact of shared
environment on RMD under the MFT model.
This isn’t dealt with very neatly by Risch, who
says: “For the case where the shared familial
environment is equivalent between MZ and
DZ twin pairs, RMD will be attenuated: if
RMD = 2 without an equivalent shared
environment, then R’MD < 2 with it.”
To investigate this we recalculate Risch’s
Table 1 with a shared environment term in
the variance.
27
Risch’s Table 1 expanded : MZ
K/H
0.050
0.040
0.030
0.025
0.020
0.015
0.010
0.005
0.003
0.001
0.20 0.25 0.30 0.35 0.40
2.10 2.46 2.85 3.29 3.77
2.24 2.66 3.13 3.65 4.22
2.44 2.94 3.52 4.17 4.89
2.57 3.14 3.79 4.53 5.38
2.75 3.40 4.16 5.03 6.03
3.00 3.78 4.69 5.76 7.01
3.39 4.38 5.56 6.98 8.66
4.19 5.64 7.46 9.72 12.48
5.18 7.29 10.04 13.56 18.03
6.89 10.26 14.90 21.16 29.45
0.45
4.30
4.86
5.71
6.33
7.17
8.44
10.63
15.82
23.62
40.28
0.50
4.88
5.57
6.62
7.40
8.47
10.09
12.94
19.85
30.56
54.26
28
Risch’s Table 1 expanded : DZ
K/H
0.050
0.040
0.030
0.025
0.020
0.015
0.010
0.005
0.003
0.001
0.20
1.49
1.54
1.61
1.66
1.72
1.80
1.93
2.16
2.43
2.83
0.25
1.63
1.70
1.80
1.86
1.95
2.06
2.24
2.57
2.97
3.58
0.30
1.77
1.87
2.00
2.08
2.19
2.35
2.58
3.04
3.60
4.49
0.35
1.93
2.05
2.21
2.32
2.46
2.66
2.96
3.58
4.33
5.59
0.40
2.10
2.24
2.44
2.57
2.75
3.00
3.39
4.19
5.18
6.89
0.45 0.50
2.27 2.46
2.44 2.66
2.68 2.94
2.85 3.14
3.06 3.40
3.37 3.78
3.86 4.38
4.87 5.64
6.16 7.29
8.44 10.26
29
Risch’s Table 1 expanded : RMD
K/H
0.050
0.040
0.030
0.025
0.020
0.015
0.010
0.005
0.003
0.001
0.20
2.26
2.30
2.35
2.39
2.43
2.49
2.58
2.74
2.93
3.21
0.25
2.33
2.38
2.44
2.49
2.54
2.62
2.73
2.95
3.20
3.58
0.30
2.39
2.45
2.53
2.58
2.65
2.74
2.89
3.16
3.48
3.98
0.35
2.46
2.53
2.62
2.68
2.76
2.87
3.05
3.38
3.77
4.40
0.40
2.52
2.60
2.71
2.78
2.88
3.00
3.21
3.60
4.07
4.83
0.45
2.59
2.68
2.80
2.88
2.99
3.14
3.37
3.83
4.38
5.28
0.50
2.66
2.76
2.89
2.99
3.11
3.28
3.54
4.06
4.70
5.75
30
Risch’s Table 1 with shared env : MZ
K/H
0.20 0.25 0.30 0.35 0.40 0.45 0.50
0.050 2.85 3.29 3.77 4.30 4.88 5.51 6.21
0.040 3.13 3.65 4.22 4.86 5.57 6.36 7.22
0.030 3.52 4.17 4.89 5.71 6.62 7.65 8.79
0.025 3.79 4.53 5.38 6.33 7.40 8.60 9.96
0.020 4.16 5.03 6.03 7.17 8.47 9.94 11.61
0.015 4.69 5.76 7.01 8.44 10.09 11.99 14.16
0.010 5.56 6.98 8.66 10.63 12.94 15.63 18.76
0.005 7.46 9.72 12.48 15.82 19.85 24.68 30.45
0.003 10.04 13.56 18.03 23.62 30.56 39.10 49.57
0.001 14.90 21.16 29.45 40.28 54.26 72.13 94.81
31
Risch’s Table 1 with shared env : DZ
K/H
0.050
0.040
0.030
0.025
0.020
0.015
0.010
0.005
0.003
0.001
0.20
2.10
2.24
2.44
2.57
2.75
3.00
3.39
4.19
5.18
6.89
0.25
2.27
2.44
2.68
2.85
3.06
3.37
3.86
4.87
6.16
8.44
0.30 0.35 0.40 0.45 0.50
2.46 2.65 2.85 3.07 3.29
2.66 2.89 3.13 3.38 3.65
2.94 3.22 3.52 3.83 4.17
3.14 3.46 3.79 4.15 4.53
3.40 3.77 4.16 4.58 5.03
3.78 4.22 4.69 5.21 5.76
4.38 4.94 5.56 6.24 6.98
5.64 6.50 7.46 8.53 9.72
7.29 8.58 10.04 11.69 13.56
10.26 12.40 14.90 17.80 21.16
32
Risch’s Table 1 with shared env : RMD
K/H
0.050
0.040
0.030
0.025
0.020
0.015
0.010
0.005
0.003
0.001
0.20
1.69
1.71
1.75
1.78
1.81
1.85
1.91
2.03
2.16
2.36
0.25
1.80
1.83
1.88
1.91
1.95
2.01
2.09
2.25
2.43
2.71
0.30
1.90
1.94
2.00
2.04
2.09
2.16
2.27
2.47
2.71
3.07
0.35
2.00
2.05
2.12
2.17
2.23
2.31
2.44
2.69
2.99
3.44
0.40
2.09
2.15
2.23
2.29
2.36
2.46
2.62
2.92
3.27
3.83
0.45
2.18
2.25
2.35
2.41
2.50
2.61
2.79
3.14
3.56
4.23
0.50
2.27
2.35
2.46
2.54
2.63
2.76
2.97
3.38
3.87
4.65
33
Evidence of familiality in cancer
Risch’s Table 2 contains values of 1 , the familial
relative risk for 1st degree relatives, at about 25
sites, using data from Utah, and values of O and
S for data from Sweden. In about 10 cases, there
is a separate 1 for early onset cancers.
He derives 3 observations from these numbers:
•
Apart from a few exceptions, the FRRs are all
rather similar, being around 2 in both studies. All
the FRRs are >1, and in the majority of cases,
between 1.5 and 3.0.
•
There is no decline in FRR with decreasing
frequency of the cancer site, if anything, the
reverse.
•
Increased family recurrence associated with early
34
diagnosis.
Evidence from the twin data of
Lichtenstein et al (2000)
Risch is able to use the Lichtenstein et al data to
estimate his MZ and DZ , see later for how it is
done. For the stomach cancer data, he finds:
K = 1%, MZ = 8.49, DZ = 5.96 , and RMD = 1.51,
(see next slide).
Doing this for a number of sites (results in Table 3),
he finds that the values of MZ and DZ are reasonably
consistent across sites and do not decrease with K.
Risch goes on to fit a constant risk ratio model to the
data, excluding female breast cancer. The results are
given in Table 4 , and simply formalize the obvious.
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Twin relative risk calculations
Suppose that in a population we have a concordant
twin pairs, (i.e. both affected with the given cancer),
b+c discordant pairs (one affected, one unaffected),
and d concordant unaffected twin pairs, n=a+b+c+d.
Since K2 = 2a/2n, and K = (2a+b+c)/2n, we have
R = Twin RR = K2 / K2 = 2a/2n / [(2a+b+c)/2n]2
= 4an / (2a+b+c)2 .
(In Risch p.737 a=c and b+c=d)
For stomach cancer, male MZ twins have a=6,
b+c=131 and n=7,231. We find that MZ = 8.49.
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Risch’s conclusions from his reanalysis
of data from Lichtenstein et al.
“… the conclusion that rarer cancers are less heritable is
strictly a consequence of the MFT model and is not robust
to violations from that model.”
“Thus the observed value of RMD conforms poorly to the
predictions of the MFT model but extremely well to the
single locus or additive genetic model”
“Hence the conclusion of a significant shared twin
environmental component may simply be a consequence
of using the wrong genetic model..”
(There are some important comments about age-structure which we’ll pass
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over for the moment.)
Heritability versus Attributable Risk.
Heritability is used as a measure of the importance of
genetic effects in the context of the MFT model. Small values
lead to the conclusion that genetic effects are minor relative
to environmental impacts. But what if the MFT does not
apply?
Epidemiologists use relative risk RR (risk to exposed versus
unexposed individuals) and PAF (proportion of disease
prevented by elimination from the population of the risk
factor). Table 5 presents the values of RRHet and PAF for 2
values of MZ and DZ and allele frequencies ranging from
0.001 to 0.10. It shows that the PAF can range from small
values to 100%, depending on disease allele frequency.
Similarly, quite high values of RRHet can arise.
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Conclusions
In my view, Risch has demonstrated that his
conclusions are justified, in particular, that the
MFT model is not a helpful framework within
which to assess the contribution of heredity
to cancer.
For more on FRRs, see: N. RISCH
Linkage strategies for genetically complex
traits. I. Multi-locus models.
Am. J. Hum, Genet. 46: 222-228, 1990.
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Acknowledgement
Many thanks to Ingileif Hallgrímsdóttir for
helping out with class this week.
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