## SYNOPSIS

use CombinePvals;

my $obj = CombinePvals->new ($reference_to_list_of_pvals);

my $pval = $obj->method_name;

my $pval = $obj->method_name (@arguments);

## DESCRIPTION

There are a variety of circumstances under which one might have a number of different kinds of tests and/or separate instances of the same kind of test for one particular null hypothesis, where each of these tests returns a p-value. The problem is how to properly condense this list of probabilities into a single value so as to be able to make a statistical inference, e.g. whether to reject the null hypothesis. This problem was examined heavily starting about the 1930s, during which time numerous mathematical contintencies were treated, e.g. dependence vs. independence of tests, optimality, inter-test weighting, computational efficiency, continuous vs. discrete tests and combinations thereof, etc. There is quite a large mathematical literature on this topic (see ``REFERENCES'' below) and any one particular situation might incur some of the above subtleties. This package concentrates on some of the more straightforward scenarios, furnishing various methods for combining p-vals. The main consideration will usually be the trade-off between the exactness of the p-value (according to strict frequentist modeling) and the computational efficiency, or even its actual feasibility. Tests should be chosen with this factor in mind.Note also that this scenario of combining p-values (many tests of a single hypothesis) is fundamentally different from that where a given hypothesis is tested multiple times. The latter instance usually calls for some method of multiple testing correction.

## REFERENCES

Here is an abbreviated list of the substantive works on the topic of combining probabilities.-
Birnbaum, A. (1954)
*Combining Independent Tests of Significance*, Journal of the American Statistical Association**49**(267), 559-574. -
David, F. N. and Johnson, N. L. (1950)
*The Probability Integral Transformation When the Variable is Discontinuous*, Biometrika**37**(1/2), 42-49. -
Fisher, R. A. (1958)
*Statistical Methods for Research Workers*, 13-th Ed. Revised, Hafner Publishing Co., New York. -
Lancaster, H. O. (1949)
*The Combination of Probabilities Arising from Data in Discrete Distributions*, Biometrika**36**(3/4), 370-382. -
Littell, R. C. and Folks, J. L. (1971)
*Asymptotic Optimality of Fisher's Method of Combining Independent Tests*, Journal of the American Statistical Association**66**(336), 802-806. -
Pearson, E. S. (1938)
*The Probability Integral Transformation for Testing Goodness of Fit and Combining Independent Tests of Significance*, Biometrika**30**(12), 134-148. -
Pearson, E. S. (1950)
*On Questions Raised by the Combination of Tests Based on Discontonuous Distributions*, Biometrika**37**(3/4), 383-398. -
Pearson, K. (1933)
*On a Method of Determining Whether a Sample Of Size N Supposed to Have Been Drawn From a Parent Population Having a Known Probability Integral Has Probably Been Drawn at Random*Biometrika**25**(3/4), 379-410. -
Van Valen, L. (1964)
*Combining the Probabilities from Significance Tests*, Nature**201**(4919), 642. -
Wallis, W. A. (1942)
*Compounding Probabilities from Independent Significance Tests*, Econometrica**10**(3/4), 229-248. -
Zelen, M. and Joel, L. S. (1959)
*The Weighted Compounding of Two Independent Significance Tests*, Annals of Mathematical Statistics**30**(4), 885-895.

## AUTHOR

Michael C. WendlCopyright (C) 2009 Washington University

This program is free software; you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation; either version 2 of the License, or (at your option) any later version.

This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details.

You should have received a copy of the GNU General Public License along with this program; if not, write to the Free Software Foundation, Inc., 59 Temple Place - Suite 330, Boston, MA 02111-1307, USA.

## GENERAL REMARKS ON METHODS

The available methods are listed below. Each of computational techniques assumes that tests, as well as their associated p-values, are independent of one another and none considers any form of differential weighting.## CONSTRUCTOR METHODS

These methods return an object in the CombinePvals class.## new

This is the usual object constructor, which takes a mandatory, but otherwise un-ordered (reference to a) list of the p-values obtained by a set of independent tests.

my $obj = CombinePvals->new ([0.103, 0.078, 0.03, 0.2,...]);

The method checks to make sure that all elements are actual p-values, i.e. they are real numbers and they have values bounded by 0 and 1.

## EXACT ENUMERATIVE PROCEDURES FOR STRICTLY DISCRETE DISTRIBUTIONS

When all the individual p-vals are derived from tests based on discrete distributions, the ``standard'' continuum methods cannot be used in the strictest sense. Both Wallis (1942) and Lancaster (1949) discuss the option of full enumeration, which will only be feasible when there are a limited number of p-values and their range is not too large. Feasibility experiments are suggested, depending upon the type of hardware and size of calculation.## exact_enum_arbitrary

This routine is designed for combining p-values from completely arbitrary discrete probability distributions. It takes a list-of-lists data structure, each list being the probability tails*ordered from most extreme to least extreme*(i.e. as a probability cummulative density function) associated with each individual test. However, the ordering of the lists themselves is not important. For instance, Wallis (1942) gives the example of two binomials, a one-tailed test having tail values of 0.0625, 0.3125, 0.6875, 0.9375, and 1, and a two-tailed test having tail values 0.125, 0.625, and 1. We would then call this method using

my $pval = $obj->exact_enum_arbitrary ( [0.0625, 0.3125, 0.6875, 0.9375, 1], [0.125, 0.625, 1] );

The internal computational method is relatively straightforard and described in detail by Wallis (1942). Note that this method does ``all-by-all'' multiplication, so it is the least efficient, although entirely exact.

## exact_enum_identical

This routine is designed for combining a set of p-values that all come from a single probability distribution.

NOT IMPLEMENTED YET

## TRANSFORMS FOR CONTINUOUS DISTRIBUTIONS

The mathematical literature furnishes several straightforward options for combining p-vals if all of the distributions underlying all of the individual tests are continuous.## fisher_chisq_transform

This routine implements R.A. Fisher's (1958, originally 1932) chi-square transform method for combining p-vals from continuous distributions, which is essentially a CPU-efficient approximation of K. Pearson's log-based result (see e.g. Wallis (1942) pp 232). Note that the underlying distributions are not actually relevant, so no arguments are passed.

my $pval = $obj->fisher_chisq_transform;

This is certainly the fastest and easiest method for combining p-vals, but its accuracy for discrete distributions will not usually be very good. For such cases, an exact or a corrected method are better choices.

## CORRECTION PROCEDURES FOR DISCRETE DISTRIBUTIONS: LANCASTER'S MODELS

Enumerative procedures quickly become infeasible if the number of tests and/or the support of each test grow large. A number of procedures have been described for correcting the methodologies designed for continuum testing, mostly in the context of applying so-called continuity corrections. Essentially, these seek to ``spread'' dicrete data out into a pseudo-continuous configuration as appropriate as possible, and then apply standard transforms. Accuracy varies and should be suitably established in each case.
The methods in this section are due to H.O. Lancaster (1949), who discussed
two corrections based upon the idea of describing how a chi-square transformed
statistic varies between the points of a discrete
distribution.
Unfortunately, these methods require one to pass some extra information
to the routines, i.e. not only the CDF (the p-val of each test), but the
CDF value associated with the next-most-extreme
statistic.
These two pieces of information are the basis of
interpolating.
For example, if an underlying distribution has the possible tail values of
0.0625, 0.3125, 0.6875, 0.9375, 1 and the test itself has a value of
0.6875, then you would pass *both* 0.3125 *and* 0.6875 to the
routine.
*In all cases, the lower value, i.e. the more
extreme one, precedes higher value in the argument
list.*
While there generally will be some extra inconvenience in obtaining
this information, the accuracy is much improved over Fisher's
method.

## lancaster_mean_corrected_transform

This method is based on the mean value of the chi-squared transformed statistic.

my $pval = $obj->lancaster_mean_corrected_transform (@cdf_pairs);

Its accuracy is good, but the method is not strictly defined if one of the tests has either the most extreme or second-to-most-extreme statistic.

## lancaster_median_corrected_transform

This method is based on the median value of the chi-squared transformed statistic.

my $pval = $obj->lancaster_median_corrected_transform (@cdf_pairs);

Its accuracy may sometimes be not quite as good as when using the
average, but the method is strictly defined for *all* values of the
statistic.

## lancaster_mixed_corrected_transform

This method is a mixture of both the mean and median methods. Specifically, mean correction is used wherever it is well-defined, otherwise median correction is used.

my $pval = $obj->lancaster_mixed_corrected_transform (@cdf_pairs);

This will be a good way to handle certain cases.

## additional methods

The basic functionality of this package is encompassed in the methods described above. However, some lower-level functions can also sometimes be useful.
*exact_enum_arbitrary_2*

Hard-wired precursor of *exact_enum_arbitrary* for 2
distributions.
Does no pre-checking, but may be useful for
comparing to the output of the general
program.

*exact_enum_arbitrary_3*

Hard-wired precursor of *exact_enum_arbitrary* for 3
distributions.
Does no pre-checking, but may be useful for
comparing to the output of the general
program.

*binom_coeffs*

Calculates the binomial coefficients needed in the binomial (convolution) approximate solution.

$pmobj->binom_coeffs;

The internal data structure is essentially the symmetric half of the appropriately-sized Pascal triangle. Considerable memory is saved by not storing the full triangle.