Introduction
Statistical methods for the analysis of data can be prediction, we conclude that the data are, in this
classed as descriptive or as probabilistic. The former respect, consistent with the hypothesis. Note,
methods include tabulation and graphical display, of though, that we cannot conclude that the hypothesis
great importance both in detailed analysis and also in is true, because there may be other hypotheses that
presentation of conclusions. Probability enters statis would have led to the same test data.
tical analysis in various ways. The most obvious is that While the general idea of significance tests follows
one recognizes explicitly that conclusions drawn from essentially the same steps (iiii) there are, however,
limited data are uncertain and that therefore it is a two important differences. First the observations are
good thing to measure and control probabilities of subject to nontrivial variability, natural random
drawing the wrong conclusions, partly, but by no variability and/or measurement 'errors' of various
means solely, as a precaution against overinterpreta kinds. Secondly the hypotheses are typically not
tion. The statistical significance test is the most widely scientific (biological) hypotheses, but rather
known device concerned with such probabilities and hypotheses about the values of parameters describing
is the subject of the present paper. 'true' values applying to populations of measure
The nature, use and misuse of significance tests ments. Of course, in some fields at least, these
have been much discussed in both statistical and parameters will be linked to scientific models or
nonstatistical circles. The view taken in this paper is interpretations of the system under study.
that such tests play an important but nevertheless We now adapt the procedure (i)(iii) as follows.
strictly limited role in the critical analysis of data. (i) Find a test statistic whose probability distri
There is an extensive mathematical literature on bution when the null hypothesis is true is known, at
the theory of such tests and on the distributions least approximately. Also the test statistic is to be
appropriate for special tests. The mathematics can such that large, or possibly extreme (large or small),
largely be separated from critical discussion of the values of the statistic point to relevant departures
underlying concepts, that being the concern of the from the null hypothesis.
present paper. (ii) Calculate the value of the test statistic for the
available data.
(iii) If the test statistic is in the extreme of its
Nature of statistical significance tests probability distribution under the null hypothesis,
there is evidence that the null hypothesis is untrue. If
The first element in a significance test is the formula the test statistic is in the centre of its distribution, the
tion of a hypothesis to be tested, often called the null data are consistent with the null hypothesis.
hypothesis. It may help to consider first how to pro More quantitatively, we calculate from the distri
ceed when random variation can be ignored. We bution of the test statistic, the probability P that a
might, for instance, be interested in a hypothesis deviation would arise by chance as or more extreme
about how some biological mechanism 'really works'. than that actually observed, the null hypothesis being
We would do the following: true. The value of P is called the (achieved) signifi
(i) Find one (or more) test observations (or sets of cance level. If P < 0.05, we say the departure is
observations) whose values can be predicted from the significant at the 0.05 level, if P < 0.01 that the
hypothesis under examination. For instance the departure is significant at the 0.01 level, and so on. In
hypothesis might predict that a certain set of relation applications it is nearly always enough to find P fairly
ships between 'response' and log dose are in fact roughly.
parallel straight lines. The test observations would A natural and fundamental question now arises.
then be such as to allow assessments of nonlinearity Why consider at all deviations more extreme than
and nonparallelism. that observed? Why assess a hypothesis partly on the
(ii) Make the relevant observations. basis of what has not been observed.' One answer is as
(iii) If the test observations do not agree with the follows. Suppose that we were to accept the observa
predictions, the hypothesis is rejected, or at least tions as just decisive evidence against the null
modified. If the test observations agree with the hypothesis. Then we would be bound to accept more
03065251/82/09032507 $01.00 © The Macmillan Press Ltd 1982
326 D.R. COX
extreme data as evidence against that hypothesis. Ponesided = prob {60, or 61, or. ,or 100 0.029,
Therefore P has a direct, though hypothetical, Ptwosided = prob (60, or 61, or. . . ,or 100; 0, or.
physical interpretation. It is the probability that the or 39, or 40; 0.057
null hypothesis would be falsely rejected when true,
were the data just decisive against the hypothesis. There has been some controversy as to which is
Note particularly that the interpretation is hypo appropriate when a priori we expect any difference to
thetical. In the first place, at least, we use P as a favour D and this expectation is confirmed in the
measure of evidence, not as a basis for immediate data. To an appreciable extent the matter is one of
tangible action (see also Appendix E). convention. In reading the literature, check to see
which has been used. In the present paper we use
twosided tests and leave the matter with the
following brief comments.
A simple example (a) In some problems the twosided P is clearly
appropriate, because neither direction of e.fect is
Consider the following much simplified example. To biologically impossible.
compare a drug D with a placebo C, 100 patients each (b) It will be rather rare that a substantial observed
receive both drugs, in random order and with appro effect in an unexpected direction can be dismissed
priate design precautions. For each patient an assess without discussion. Further, retrospective explana
ment is made as to which is the more effective tions of unexpected effects can often be put forward.
treatment, ties not being allowed. It is observed that These are the arguments for regarding the twosided
for 60 patients D was better and for 40 patients C was test as the one for routine use.
better. (c) It is largely conventional whether one says that
Now the null hypothesis would typically be that the the twosided P is say 0.1 and the effect is in the
long runr proportion of preferences for D is 1/2. Other expected (or unexpected) direction, or whether one
null hypotheses could, however, arise; for instance if quotes the onesided P of 0.05.
a large independent study under comparable con Section 3 describes the nature of null hypotheses,
ditions had shown that 80% preferred D, another and we then go on to discuss various points of inter
interesting null hypothesis would be that the long run pretation.
proportion in the present study is 0.8.
The test statistic is the observed number of prefer
ences for D. Under the 50% null hypothesis the
probability distribution of the number of preferences The nature of null hypotheses
for D can be found; independence of the individuals is
assumed. The distribution, which is roughly a normal Clearly for significance tests to be of much use, sens
distribution of mean 50 and standard deviation 5, ible and interesting null hypotheses should be tested.
is that for the number of heads observed in 100 A full cla .ification of null hypotheses will not be
tosses of a 'fair' coin. The distribution could also be attempted, but it is useful to have the following types
found by computer simulation although, except in mind:
possibly for didactic reasons, this is a poor idea when (i) null hypotheses of a technical statistical charac
a mathematical treatment is available. In complicated ter to the effect that such and such special assump
problems however, where a mathematical treatment tions are satisfied, such as that distributions have a
is not available, it is a good idea to simulate data from particular mathematical form or that preliminary
a 'null' system close to that under study. Conformity transformation of data is unnecessary. We do not
of the 'real' with the 'simulated' data can be examined consider these further here;
at least informally. (ii) null hypotheses closely related to some scien
Now the probability P of a deviation as or more tific hypothesis about underlying biology, such as,
extreme than that observed is, at first sight, the in genetics, that two genes are on different
probability of observing 60, or 61, or. . . ,or 100 and chromosomes. These are of critical importance in
is about 0.029. certain kinds of research, but are perhaps of less
But there is a difficulty here; what if we observed direct importance in clinical trials, although in
not 60 preferences for D and 40 for C but 40 for D and complex trials with elaborate data, it may be
60 for C? If under those circumstances we would still feasible to formulate such hypotheses;
have examined consistency with the null hypothesis, (iii) null hypotheses of homogeneity. These
our significance level P must take account of extreme typically are that a certain effect is the same, for
fluctuations in both directions, the test becomes a example in several independent studies or in differ
socalled twotailed or twosided test and in this ent subgroups of patients. An emphasis in statis
instance P becomes 2 x 0.029 0.057.

tical work is frequently on designing and analysing
That is we have individual investigations so that these investiga
STATISTICAL SIGNIFICANCE TESTS 327
tions, in isolation, lead to convincing conclusions. from 52% to 58% and yet it might well be that these
Yet, clearly, judgment about any issue should would all be of little practical importance. In this
depend on all available information; the most instance the direction of the effect is firmly estab
convincing conclusions are those backed by several lished but its magnitude is such as to make the effect
independent studies and preferably by different of little practical importance; such instances of
kinds of evidence. Tests of homogeneity play some observational overkill are probably rare in clinical
role here. It is a reasonable comment on some trials.
statistical analyses that not enough emphasis is (iii) The strong implication of (ii) is that, for
placed on the combination of evidence from important effects at least, it is necessary to calculate
several sources. socalled confidence limits for the magnitude of
(iv) Finally, and perhaps most commonly, there effects and not just values of P. This is of crucial
are hypotheses that assert the equality of effect of importance. It is very bad practice to summarise an
two or more alternative treatments, for example, a important investigation solely by a value of P.
drug and a placebo. One way of looking at such (iv) Failure to achieve an interesting level of
hypotheses is that they divide the possible true significance in a study does not mean that the topic
states of affairs into two (or more) qualitatively should be abandoned. Significance tests are not
different regimes. So long as the data are consistent intended to inhibit the free judgment of investigators.
with the equality of two treatments, the data do not Rather they may on the one hand warn that the data
firmly establish the sign of any difference between alone do not establish an effect, and hence guard
them. From this point of view significance tests against overinterpretation and unwarranted claims,
address the question: how firmly do the data estab and on the other hand show that an effect is reason
lish the direction of such and such an effect? ably firmly proved.
(v) If an effect is established as clearly correspond
ing to a bigger difference than can be accounted for by
Some comments on interpretation chance, two conditions have to be satisfied before the
difference can be given its facevalue interpretation
There follow a number of miscellaneous comments as, say, an improvement due to the new drug under
on the interpretation of significance tests. test. One condition is that the calculation of statistical
(i) There are clear distinctions between statistical significance is technically sound in that no unreason
significance and the more important notions of bio able detailed assumptions have been made in
logical significance and practical significance. Statis computing the probabilities. The most common fault
tical significance is concerned with whether, for is, in effect, to overlook an important source of
instance, the direction of such and such an effect is variability and thereby to underestimate the un
reasonably firmly established by the data under certainty in the conclusions. It is a key role of careful
analysis. Biological significance is concerned with design to ensure that, so far as is feasible, all major
underlying scientific interpretation in terms of more sources of uncertainty are controlled and that their
fundamental mechanisms. Practical significance is magnitude can be assessed. Specialised statistical
concerned with whether an effect is big enough to advice may be needed on this point. This is related to
affect practical action, e.g. in the treatment of the second and more serious possibility that the effect
patients. The three kinds of significance are linked is a bias or systematic error and not a genuine
but in a relatively subtle way. 'treatment' effect. Biases are relatively much more
(ii) Failure to achieve an interesting level of statis likely in observational studies, and comparisons
tical significance, i.e. the observation of values involving historical rather than concurrent controls,
reasonably consistent with the null hypothesis, does than in carefully controlled experiments involving
not mean that practically important differences are randomisation and, so far as feasible, firmly enforced
absent. Thus in the Example of Section 2 the observa 'blindness'. To a very limited extent biases can be
tion of 55 preferences for D and 45 for C would lead to investigated and corrected by more elaborate statisti
Ptwosided = 0.37 and to the conclusion that the data are cal analysis (see Appendix D).
just such as to be expected if the null hypothesis were (vi) Pooling of information from independent
true. On the other hand it can be shown that long run studies is very important, subject to tests of homo
effects ranging from 45% to 65% preferences for D geneity. If there is clear evidence of heterogeneity
are consistent with the data (at the 5% significance between studies this needs to be explained in subject
level) and, depending entirely on the context, these matter terms if at all possible.
might correspond to differences of practical impor (vii) If a number of independent studies are done,
tance. By constrast with 1000 patients a split 550 for D possibly in different centres, and only those yielding
and 450 for C would be a highly significant departure an effect significant at say the 0.05 level are reported,
from the null hypothesis (twosided 0.0018), the
=
it is clear that a distorted picture may emerge. The
range of preference for D consistent with the data is criterion for publication should be the achievement of
328 D.R. COX
reasonable precision and not whether a significant entirely legitimately, examine several measures of
effect has been found; it may be, however, that response: death rate (all causes), death rate
investigations yielding interesting new conclusions (particular causes), 'minor' critical event rate, and
merit publication in greater detail than investigations so on. Quite clearly if many different effects are
whose outcome is predominantly negative or con examined it is quite likely that a superficially quite
firmatory, but that is a separate issue. significant result will emerge. Individual P values
will apply to each effect in isolation, but to judge
whether there is overall evidence of an effect, a
The choice of tests and levels: multiple testing: choice socalled allowance for selection is essential in
of sample size judging significance. A rough rule is to multiply the
smallest P value by the number of effects examined
A question frequently asked is 'what significance before selecting the most significant. For instance
level should be used, 0.05, 0.01 or what?' The view suppose that an overall analysis of a clinical trial
taken in the previous discussion is that the question comparing drug D with placebo C shows little
does not arise, at least in the sense that we may use the evidence of a difference. Analyses are made for
observed value of P as a measure of the conformity of men and women, for 'young' and 'old' patients and
the data with the null hypothesis. What overall for two different Centres, say taking the 8 com
interpretation is made or what practical action is binations of sexageCentre. The older women at
taken depends not only on the significance level P, Centre 2 show a difference significant at about the
but also on other information that may be available, 0.05 level. But this is the largest out of 8 com
including biological plausibility on the magnitude of parisons and therefore, after the rough correction
effect present and, in a decisiontaking context, on for selection, is to be assigned a value of P of about
the consequences of various modes of action. 8 x 0.05 = 0.4, i.e. it is just such as would be
Nevertheless some rough guide for qualitative expected by chance. Note that if the investigation
interpretation is useful and the following seems fairly had been set up specifically to investigate older
widely accepted, sensible, and leads to some women in Centre 2, P = 0.05; the magnitude of the
standardization of procedure: effect is the same in both context. This general
point is especially important because major trials
P I : accord with the null hypothesis is as good are complex with many measures of response,
as could reasonably be expected; categories of patient etc.
(iii) The third possibility is that essentially the
same scientific issue is tackled by trying a number
P ' : there is, for most purposes, overwhelming of tests similar in spirit but different in detail. Thus
100 evidence against the null hypothesis; to compare two samples one might consider the t
intermediate: there is some evidence against the null test, the sign test, the Wilcoxon test, the Fisher and
hypothesis. Yates score test, and so on. Each is appropriate
under slightly different conditions and usually,
except possibly for the sign test, the results will be
Values of P should be quoted approximately and rigid very similar; the differences arise primarily from
borderlines avoided. Thus in terms of the interpreta the relative weights attached to extreme observa
tion of data it would be absurd to draw a rigid border tions. This blunderbuss procedure of trying many
line between P = 0.051, not significant at the 0.05 tests is wrong if what is done is concealed. In
level, and P = 0.049, significant at the 0.05 level, even principle, for each specific scientific question there
though in decisionmaking contexts with strictly should be a single test in the light of the error struc
limited data such borderlines do have to be adopted. ture present. If a search through a number of test
Some special problems arise when several statis statistics is carried out, an allowance for selection is
tical tests are applied to the same data. We can dis essential. The simple correction outlined above is
tinguish a number of situations: much too crude, being really appropriate for statis
(i) Scientifically quite separate questions can be tically independent tests rather than for closely
addressed from the same data. This raises no related tests. If the procedure were used, which is
special problems. Note, however, that if one of the not recommended, computer simulation to attain
analyses led to doubts about data quality, the other the appropriate correction for selection seems the
analyses would become suspect too. most practicable procedure.
(ii) The data may be searched by examining (iv) A rather more specialised issue concerns the
different kinds of effect and ultimately focusing normal use of significance tests in trials in which the
attention on the most significant. For instance one possibility of stopping the trial before its nominal
might classify the patients in various ways (age, sex, completion date is determined at least in part by
etc.) to look for differential effects. Or we may, formal datadependent rules. We regard this topic,
STATISTICAL SIGNIFICANCE TESTS 329
traffic between biological understanding and more laboratory systematic differences can in principle be
empirical studies should be twoway; to disregard all estimated and eliminated, provided of course the
empirical studies in conflict with prior expectation rather disastrous situation is avoided wherein, say
would be very dangerous. biochemical measurements in the two treatment arms
are made in two different laboratories. External
D. Biases can be more important than random evidence on the degree of standardization achieved
errors and biases are not susceptible to statistical will always be valuable.
analysis. Biases are indeed likely to be relatively Biases of the third kind, concerned with treatment
important in large studies, where the effect of random implementation, are in some ways the most awkward.
variation is controlled by the averaging of responses A conventional answer is that the usual comparison in
over a large number of patients. It is one of the a randomized clinical trial tests the total con
primary objectives of careful design to eliminate sequences of being assigned to one treatment arm
biases, by balancing or by randomizing (with con rather than to the other. Thus subsidiary effects, such
ceaiment) all important sources of variability. In as differences in general level of care, different levels
observational studies, for instance when historical of compliance, unacceptability of side effects, etc. are
controls are used instead of the much more desirable part of the consequences of the treatments under
randomized concurrent controls, biases are appreci study. From this point of view, biases are spirited
ably more likely and certainly the main sources of away by definition. It is clear that this approach may
potential bias should be examined and if necessary sometimes be quite unsatisfactory, both scientifically
adjustments calculated. In broad terms, if the source and for decision making about the treatment of
of bias can be identified and is short of a total con individual patients. If the conditions of this
founding with the treatment effect under study, then experiment are quite different from those obtaining
there is a possibility of largely removing the bias by in practical use, what is sometimes called an external
suitable statistical analysis. On general grounds it is, systematic error arises. Practical ways of dealing with
of course, very undesirable that interpretation should these matters of 'treatment bias' are not well
depend in an essential way on elaborate analysis: developed. In principle, if properties associated with
direct appreciation of the meaning and limitations of treatment administration and subsequent care can be
the data is thereby inhibited. measured, they may be either deliberately varied by
Biases are of three broad types: (i) those arising design or alternatively measured for each patient or
from systematic differences between the two (or for small groups of patients and their effect on the
more) arms of the trial, involving patient character major response assessed by suitable analysis. The
istics on entry; (ii) those concerned with the difficulties of measuring accurately such aspects as
procedures for measurement of response and other compliance are well known.
variables; (iii) those concerned with the implementa
tion of the treatment and with the care of the patient E. The Bayesian approach to statistical tests allows
during any subsequent period of observation. the incorporation of external evidence, that is always
Randomization is intended to ensure the absence available, and avoids the conceptual difficulties of
of the first kind of bias. Sometimes, however, ordinary significance tests. It would be out of place in
randomization may be defective; further, in observa the present paper to write at length on the founda
tional studies appreciable differences may arise tions of statistical inference. These foundations have
between a new 'treated' group and a historical control for many years been under active discussion and
group and these will need adjustment by some debate: such discussion should be taken as evidence
process of standardization, for example by analysis of of the intellectual vigour of the subject and not at all
covariance. Significance tests are now more complex as implying an unsoundness in application.
but not different in principle. A major concern is that Briefly, significance tests as described in the main
once it is clear that two groups are unbalanced with part of the paper aim to summarise what the data tell
respect to an observed property (e.g. age or sex) the about consistency with a hypothesis or about the
possibility of a difference with respect to an un direction of an effect. The Pvalue has, before action
measured though important property is enhanced. or overall conclusion can be reached, to be combined
This would lead to a bias not removable by analysis. with any external evidence available and, in the case
Biases connected with measurement can arise of decisionmaking, with assessments of the con
either when 'blindness' is impossible or seriously sequences of various actions. Clearly the Pvalue is a
ineffective or when different observers, laboratories, limited aspect: note also point (iii) of some comments
etc. are involved. It is difficult to suggest an effective on interpretation where the importance of calculating
practical method of dealing with the first kind of bias: limits of error for the magnitude of an effect is
independent confirmation of particularly sensitive stressed.
observations may sometimes be feasible, possibly on It appears superficially very attractive to
a sample of patients. Interobserver and inter strengthen interpretation and to bring in the external
STATISTICAL SIGNIFICANCE TESTS 331
information, by use of the socalled Bayesian of diagnosis, external information is in the form of a
approach. In my opinion, there is room for different statistical frequency, and then there is no dispute that
approaches in different contexts, but the arguments the Bayesian approach should be applied.)
are fairly persuasive against the Bayesian tests in most Finally in problems in which the direction of an
applications to the analysis and interpretation of effect is under study and the external information is
data. First it may often help to keep separate the relatively weak, the onesided P value is approxi
impact of data and external information. Secondly, to mately the (Bayesian) probability that the time effect
put the external information in the required quanti has the opposite sign to the effect in the data and the
tative form raises formidable conceptual and practical two approaches are largely reconciled.
difficulties. (In some cases, such as certain problems