in longitudinal clinical studies , where the change over time of an outcome is of interest , it is sometimes seen that the change is dependent on the initial value .
the change over time may be significantly larger in subjects who had really higher ( or lower ) initial values as compared to subjects whose initial values were closer to the population mean
. this differential effect may partly be due to a phenomenon known as regression to the mean .
in other words , since there is always within - subject variability , the initial value may have been high ( or low ) for certain subjects just by random chance , and upon remeasurement the outcome values for these subjects would have just 
regressed back to the true mean . for example , this phenomenon may be illustrated via the analysis results of data in a registry based on cystic fibrosis ( cf ) patients that was conducted by investigators at children 's hospital of philadelphia .
one of the goals of the study was to determine the rate of change of the pulmonary function as measured by percent of predicted forced expiratory volume in 1 second ( fev1% ) , over a 4-year period in a large cohort of children with cystic fibrosis .
cf foundation 's national cf patient registry data collected from 1991 to 1995 for 968 children ( 461 male ) aged 5 to 8 years with pancreatic insufficiency and fev1% between 60% and 140% were analyzed longitudinally . the significant decline in fev1% was found to be dependent on baseline fev1% ; children with initial fev1%  90 declined 2.6 u / y more than those with initial fev1% < 90 .
various methods have been proposed in the literature to account for regression to the mean .
these approaches may be broadly classified into two categories : 1 ) methods where the regression to the mean is estimated and then subtracted from or added to the observed change to estimate the true change ; 2 ) methods which check for the relationship between change and initial value via correlation or regression , where the correlation co - efficient or the regression co - efficient as the case may be adjusted for the regression towards mean . methods of the first type have been proposed and studied in[28 ] .
we present an estimator for the regression to mean when the underlying distribution for the measurements are non - normal .
gardener , james and davis[24 ] discussed estimators for regression to mean when the measurements are normally distributed with mean and variance that remain constant over time .
chinn and heller presented similar results when the mean and vari - ance were assumed to vary over time .
das and mulder investigated the effect when the measurements were not necessarily normal , however their method is not directly applicable to em - pirical distributions .
their method was made more usable for a practitioner / analyst by a method proposed in sheath and dobson where the regression to mean was estimated for empirical distributions using edgeworth series and saddle point approximations .
muller , abramson and azari propose an elegant nonparametric method for estimating the regression to the mean under fewer assumptions related to the underlying distributions . in this paper , das and mulder 's method
is made data - adaptive for empirical distributions via kernel estimation approaches , while retaining the original assumptions made by them .
we adopted the best approaches for kernel density and hazard function estimation in our methods .
this makes our approach extremely user friendly for a practitioner via the state of the art procedures and packages available in statistical softwares such as sas and r for kernel density and hazard function estimation .
in this paper we restrict our attention to the studies which measure only one additional value other than the initial value . following the notational convention in ,
let x1i and x2i be random variables representing the initial and follow - up measurements on the i subject , i = 1 , ... n , where x1i = mi + e1i and x2i = mi + e2i . here
mi , e1i , and e2i are mutually independent random variables representing the true value , measurement error or within - subject variability for the initial and follow - up measurements respectively .
we also assume that the mi 's are i.i.d . with mean  and variance  =  and el and e2
have the normal distributions n(0, ) , where  = ( 1  ). for the initial measurements x1i 's let xl denote the cut - off point for  large values ; that is all the subjects with initial measurements greater than xl are considered subjects with high initial value .
we further assume that all the x1i 's are i.i.d . with a probability density function g(x ) and
then the expression for evaluating the regression to the mean for the subjects with high initial values , as proposed by das and mulder is , we propose to estimate r(xl ) by two different approaches as outlined in sections 3 and 4 .
let g be a kernel density estimator for g and let  be the empirical distribution function for x1i 's greater than xl . then in section 3 , we propose an estimator   of r(xl ) given by let us denote .
when xl is a non - negative variable , u(x ) is similar to the hazard rate function used in survival analysis literature .
we may find an estimator (x ) of u(x ) via the state of the art kernel estimation techniques for hazard rate function .
this approach is outlined in section estimation of regression to the mean via a kernel estimator for u.
kernel density estimates have been studied extensively in literature and used in various applications , ever since they were proposed in for the initial values , x1i , i = 1 , ... n , the kernel density estimator of the probability density function g is given by where   for a 
( see for a good introduction to the ideas . ) a common way of measuring the estimation error of h(x ) is via the mean integrated squared error ( mise ) , mise ( h ) = e  ( h  g ) where  denotes the integration over the real line .
asymptotic mean integrated square error ( amise ) given by amise ( h ) = nh 
 r(k ) + h 
 r(  ) (  x 
 k / 2 ) , is a more useful criterion which provides simple insight into " good " bandwidths . here r( ) =   ( x)dx and  xk =  xk ( x)dx . the minimizer of amise ( h ) given by is a good approximation to hmise , the minimizer of mise , in many circumstances .
various methods that have been proposed for optimal bandwidth selection may be broadly classified as first generation and second generation methods .
the most popular among the first generation methods are rules of thumb , least squares cross - validation[1517 ] , and biased cross - validation .
second generation methods include solve - the - equation plug - in approach and smoothed bootstrap[2123 ] . as shown in , the method proposed in
is a stable and consistent method that outperforms all the other methods mentioned above . the idea behind this method is to choose the bandwidth that is a solution of the fixed point equation this is the bandwidth selection method that we use for the kernel density estimate (h ) .
this is also the default method in many statistical software packages including proc kde in sas version 9.0 .
for non - negative x1i , then the function u defined in section 2 is become the hazard function , if we interchange the  time to event variable with x1i and assume no  censoring. kernel based estimation methods of hazard function have received considerable attention in the statistical literature .
.   gave a generalized form to these estimators and studied the asymptotic properties of the generalized estimator .
adapting the generalized form to our notation for regression to mean estimator , we have as a kernel estimator for u. here x1(i ) 's denote the ordered sample of x1i 's . as in the case of kernel density estimation , an important problem when estimating the hazard function by kernel methods is the choice of the smoothing parameter ( that is , the bandwidth ) h. various methods
later , ( via simulation results ) and ( via theoretical insights ) have shown that least squares cross validation as a more appropriate approach .
a least squares cross - validation methods proposed in for density estimation was extended to uncensored hazard function estimation in and in . later extended these methods via a bootstrap selection of the smoothing parameter .
all the methods mentioned above are fixed - bandwidth fixed - kernel methods for estimating the hazard function .
when the data is not evenly distributed over the range of interest , the degree of smoothing achieved via a fixed - bandwidth method will not be uniform . using a varying bandwidth estimator which balances the local variance and local bias as suggested in rectifies the non - adaptive behavior of fixed - bandwidth estimators .
fixed kernel estimators do not take into account the so - called boundary effects ( that is , the bias problems ) near the endpoints of the support of the hazard function .
one way to overcome this problem is to change the kernels at the boundary[3638 ] .  
presented a class of boundary kernels which gave rise to smaller leading constants of the asymptotic mean squared error when estimating than other boundary kernels considered previously . confirmed the advantages of methods proposed in and over the previously published methods for estimating hazard function via kernel estimators
bootstrap techniques have gained tremendous popularity ever since it was introduced in the seminal paper .
let us denote by  our estimate of the regression to the mean via any of the methods proposed in sections 3 and 4 .
we may obtain the bootstrap estimate of standard error and bias via the following steps .
a nonparametric bootstrap sample is obtained by sampling with replacement from the empirical distribution of the original data . for each of the b bootstrap samples ,
we calculate our estimate of regression to the mean , denoted by   the bootstrap estimate of the standard error of is simply the standard deviation of   that is , the standard error of  is obtained as
we illustrate the methods described in this paper using percent predicted fev 1 measurements of 461 males in the cf registry obtained in the years 1991 and 1992 .
the correlation between the measurements from years 1991 and 1992 was found to be 0.55 and variance of the 1991 measurements was 323.3 .
the proc mixed procedure in sas with a random intercept was used separately for subjects with the initial value ( that is , 1991 measurement ) greater than and less than or equal to 90 .
for the subjects with initial value above 90 , the intercept was 106.76 and the slope was -8.69 with standard errors 0.97 and 1.38 respectively and for the subjects with initial value below or equal to 90 , the intercept was 77.00 and the slope was 1.37 with standard errors 1.08 and 1.54 respectively .
we suspect that the regression to the mean plays a significant role in the change seen in subjects with high initial value . plots .
1a : scatter plot of fev% of male subjects at years 1991 and 1992 , 1b : box plots of fev% in years 1991 and 1992 .
1c : linear mixed effects model fit for subjects with initial measurement > 90 and for subjects with initial measurement  90 .
we assess the regression to the mean in subjects with initial measurements greater than 90 via the two methods described in this paper . for the method in the section 3
, we used the gaussian kernel along with the plug - in bandwidth selection method described in to estimate g. this was done via proc kde in sas .
the regression to the mean via this method was estimated to be -4.78 with bootstrap standard error of 0.85 . since the percent predicted fev1 measurements is a non - negative variable , we were also able to estimate the regression to the mean via the method described in section 4 .
we used the varying kernel , varying bandwidth method suggested in with the epanechnikov boundary kernel to estimate u. this was done using the muhaz r package .
( see section 4 for more details . ) the regression to mean estimate via this method was seen to be -5.21 with bootstrap standard error of 1.02 .
the regression to the mean estimate by both the methods are comparable in this case . via the first method we see that 55% of the change in percent predicted fev1 between 1991 and 1992 is due to the regression to the mean effect and by the second method we see that 60% of the change is attributable to regression to the mean .
we propose two approaches for estimating das and mulder 's expression of regression to the mean for non - normal population .
our first approach is based on a kernel density estimation method and our second approach is based on kernel estimation approaches for hazard rate function .
the estimates in both the methods may be easily obtained via the state of the art techniques available in popular statistical software such as sas and r. we also calculate the bootstrap standard error for estimates . applying our methods to fev
% data from cystic fibrosis foundation 's national patient registry showed that both the regression to the mean estimates are within the margin of bootstrap standard error estimates .
as in das and mulder 's original paper , our methods are restricted to calculating the regression to the mean when there are only two time points .
extension of these methods to longitudinal studies with more than two time points is an area of future research .
 background : part of the change over time of a response in longitudinal studies may be attributed to the re - gression to the mean . 
 the component of change due to regression to the mean is more pronounced in the subjects with extreme initial values . 
 das and mulder proposed a nonparametric approach to estimate the regression to the mean.aim:in this paper , das and mulder 's method is made data - adaptive for empirical distributions via kernel estimation approaches , while retaining the orig - inal assumptions made by them.results:we use the best approaches for kernel density and hazard function estimation in our methods . 
 this makes our approach extremely user friendly for a practitioner via the state of the art procedures and packages available in statistical softwares such as sas and r for kernel density and hazard function estimation . 
 we also estimate the standard error of our estimates of regression to the mean via nonparametric bootstrap methods . finally , our methods are illustrated by analyzing 
 the percent predicted fev1 measurements available from the cystic fibrosis foundation 's national patient registry.conclusion:the kernel based approach presented in this article is a user - friendly method to assess the regression to the mean in non - normal populations . 
Introduction
An estimate for regression to the mean in non-normal popula-tions
Estimation of regression to the mean via a kernel estimator for 
Estimation of regression to the mean via a kernel estimator for 
Bootstrap estimates of standard error
Application to percent predicted FEV1 measurements in cystic fibrosis patients
Concluding remarks