Bootstrapping is a method for statistical inference, which

focused on building a sampling distribution with the key idea of resampling the

originally observed data with replacement. The term bootstrapping, proposed by Bradley

Efron in his “Bootstrap methods: another look at the jackknife” published

in 1979, is extracted from the cliché of ‘pulling oneself up by one’s

bootstraps’. So, from the meaning of this concept, sample data is considered as

a population and repeated samples are drawn from the sample data, which is

considered as a population, to generate the statistical inference about the sample

data. The essential bootstrap analogy states

that “the population is to the sample as the sample is to the bootstrap samples”.

The bootstrap was divided into two methods, which are parametric and

nonparametric. Parametric bootstrapping assumes that the original data set is drawn

from some specific distributions, e.g. normal distribution. And the sample often has the

same size as the original data set.

Nonparametric bootstrapping is just the

one described in the beginning, which draws bootstrapping samples from the

original data. Bootstrapping is quite useful in non-linear regression and

generalized linear models. For small sample size, the parametric bootstrapping

method is highly preferred. In large sample size, nonparametric bootstrapping

method would be preferably utilized. For a further clarification of nonparametric

bootstrapping, a sample data set, A = {x1, x2, …, xk} is randomly drawn from

a population B = {X1, X2, …, XK} and K is much larger than k. The statistic T

= t(A) is considered as an estimate of the corresponding population parameter P

= t(B). Nonparametric bootstrapping generates the estimate of the sampling

distribution of a statistic in an empirical way. No assumptions of the form of the population

is needed. Next, a sample of size k is drawn from the elements of A with replacement,

which represents as A?1 =

{x?11,

x?12,

…, x?1k}.

In the resampling, a * is added to distinguish re-sampled data from original

data. Replacement is mandatory and supposed to be repeated typically 1000 or

10000 times, which is still increasing since computation power increases, otherwise

only original sample A would be generated. And for each bootstrap estimate of these samples, mean is

calculated to estimate the expectation of the bootstrapped statistics. Mean-T is the estimate of T’s bias. And T?, the bootstrap variance estimate, estimates the sampling variance of the population, P. Then

bootstrap confidence intervals can be constructed using either bootstrap

percentile interval approach or normal theory interval approach. Confidence

intervals by bootstrap percentile method is to use the empirical quantiles of the

bootstrap estimates, which is written as T?(lower) < P < T?(upper). More
specifically, it can be written as Tˆ ? (Tˆ ? upper – T*ˆ) ? P ? Tˆ + (T*ˆ + Tˆ ?lower).
Bootstrapping is an effective
method to doublecheck the stability of the model estimation results. It is much
better than the intervals calculated by sample variance with normality
assumption. And simplicity is bootstrapping's another important benefit. For
complicated estimators, such as correlation coefficients, percentile points,
for complex parameters in the distribution, it is a pretty simple way to generate
estimates of confidence intervals and standard errors. However, simplicity can also
bring up disadvantage for bootstrapping, which makes the important assumptions for
the bootstrapping easy to neglect. And bootstrapping is often over-optimistic and
doesn't assure finite sample size.
There are several types of bootstrapping schemes in the regression
problems. One typical approach is to resample residuals in the regression models.
The main procedure is firstly fit the original data set with the model, and generate
model estimates, ?ˆ and calculate residuals, ?ˆ; secondly randomly and repeatedly
sample the residuals (typically 1000 or 10000 times) to get K sets residuals of
size k and add each resampled residual to the original equation, generating
bootstrapped Y*; Finally use bootstrapped Y* to refit the model and get bootstrap
estimate ?ˆ?.
Another typical approach in the regression context is random-x resampling,
which is also called case resampling. We can either apply Monte Carlo algorithm,
which is to repeatedly resample the data of the same size as the original data
set with replacement, or identify any possible resampling of the data set. In
our case, before fitting regression model with the original predictor variable
and response pairs (xi, yi), for i = 1, 2, . . ., k, these data pairs are resampled
to get K new data pairs of size k. Then the regression model is fit to each of
these K new data sets. ?ˆ? is
generated from K parameter estimates.
Besides these two schemes in the regression, there are many other types
of bootstrap scheme. For example, Bayesian bootstrapping is a method which assigns
different weighting to the original data point to generate new data sets. And smooth
bootstrapping is to add mostly normally distributed random noise with zero mean
onto each replication. Gaussian process regression bootstrap and block
bootstrap can both be applied to deal with data with correlation. Wild
bootstrap is used in model indicating heteroskedasticity by resampling the
response variable based on the residuals values.
In the next section, I'm going to review the nonparametric bootstrapping
package in R with some examples in my research area-----population
pharmacokinetics analysis. In R, a package is called "boot", which provides various
sources for bootstrapping either a single statistic or a vector. To run the
boot function in the boot library, there are 3 necessary parameters:
1)
data, which can
be a vector, matrix, or data frame for bootstrap resampling;
2)
statistic, the
function that produces the statistic for bootstrapping. This function should
include the data set and an indices parameter, giving the selection of cases
for each resampling;
3)
R, the number of resampling
times.
The function boot() runs the statistic function for R
times. In each call, it generates a group of random indices with replacement to
select a sample. Then calculated statistics for each sample are collected in
the bootobject function. So the function boot() is used as bootobject <- boot(data= , statistic= , R=,
...). After seeing the satisfying plot, we use boot.ci(bootobject, conf=, type=
) to get confidence intervals.
Bootstrapping is prevalently used in the population analysis of clinical
trials in pharmaceutical/biotech industries. It is a pretty useful tool to
assess and control the model analysis stability. A good example is how
bootstrapping validates population pharmacokinetic (PK) model for sumatriptan,
a vasopressor used for the acute treatment of migraine attack. A single oral
dose of 50 mg was given to 26 healthy Korean male subjects. Plasma data were obtained
for pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 h post-dose.
Population PK analysis of sumatriptan was performed using plasma concentration
data by our software called NONMEM building models using differential equations.
Total 364 observations of plasma concentrations were successfully described by
a one-compartment model with first-order of both absorption with lag time and elimination,
and a combined transit compartment. The model scheme is shown as Figure 1 as
below:
Figure 1: The scheme of the final PK model of
sumatriptan
The final model was validated through a 1000-time resampling
bootstrapping. The procedure was conducted with 1000 datasets resampled from
the original dataset. The median and 90% confidence intervals of parameters were
shown in the Table 1 to compare with the final parameter estimates. Results
from the visual prediction check with 1000 simulations
Table 1: NONMEM estimated Parameters
and Bootstrap Results
were assessed by visual comparison of the gray area of 90%
prediction interval from the simulated data with an overlay of the circled raw
data. Any excess of data going outside the gray area indicates that the
estimates were not robust.
Figure 2: Visual
predictive check plot of the model from time 0 to 12 h after a single oral
administration of 50 mg sumatriptan. Circles represent the raw data set: the
90% confidence interval of the 1000 times simulations (gray area), and observed
concentration (solid line) of the 5th, median, and 95th percentiles.
Our conclusion is that the
final model and its estimated parameter were sufficiently robust and stable by
the assessment of the bootstrapping. All estimated parameter from the final
model were within the 95% bootstrap confidence intervals.

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