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Title: Dose-response analysis using R / by Christian Ritz, Signe M. Jensen,
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Identifiers: LCCN 2019006744| ISBN 9781138034310 (hardback : alk.
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Contents

Preface ix

1 Continuous data 1
1.1 Analysis of single dose-response curves . . . . . . . . . . . . 2
1.1.1 Inhibitory effect of secalonic acid . . . . . . . . . . . 2
1.1.1.1 Fitting the model . . . . . . . . . . . . . . . 3
1.1.1.2 Estimation of arbitrary ED values . . . . . 6
1.1.2 Data from a fish test in ecotoxicology . . . . . . . . . 6
1.1.3 Ferulic acid as an herbicide . . . . . . . . . . . . . . 9
1.1.4 Glyphosate in barley . . . . . . . . . . . . . . . . . . 13
1.1.5 Lower limits for dose-response data . . . . . . . . . . 19
1.1.6 A hormesis effect on lettuce growth . . . . . . . . . . 23
1.1.7 Nonlinear calibration . . . . . . . . . . . . . . . . . . 26
1.2 Analysis of multiple dose-response curves . . . . . . . . . . 31
1.2.1 Effect of an herbicide mixture on Galium aparine . . 31
1.2.2 Glyphosate and bentazone treatment of Sinapis alba 35
1.2.2.1 A joint dose-response model . . . . . . . . . 36
1.2.2.2 Fitting separate dose-response models . . . 39

2 Binary and binomial dose-response data 43

2.1 Analysis of single dose-response curves . . . . . . . . . . . . 44
2.1.1 Acute inhalation toxicity test . . . . . . . . . . . . . 44
2.1.1.1 Link to ordinary logistic regression . . . . . 46
2.1.2 Tumor incidence . . . . . . . . . . . . . . . . . . . . . 47
2.1.3 Earthworm toxicity test: Abbott’s formula . . . . . . 49
2.1.4 Another earthworms toxicity test: Estimating the
upper limit . . . . . . . . . . . . . . . . . . . . . . . . 52
2.2 Analysis of multiple dose-response curves . . . . . . . . . . 53
2.2.1 Toxicity of fluoranthene under different ultraviolet
radiation . . . . . . . . . . . . . . . . . . . . . . . . . 54
2.2.2 Toxicity of different types of selenium . . . . . . . . . 57

3 Count dose-response data 63

3.1 Analysis of single dose-response curves . . . . . . . . . . . . 64
3.1.1 Counting number of fronds . . . . . . . . . . . . . . . 64
3.1.2 Counting offspring: Modeling hormesis . . . . . . . . 69

v
vi Contents

3.1.3 More counting offspring: Varying observation periods 73

3.2 Analysis of multiple dose-response curves . . . . . . . . . . 78
3.2.1 Counting bacteria colonies: Wadley’s problem . . . . 79

4 Multinomial dose-response data 85

4.1 Trichotomous data . . . . . . . . . . . . . . . . . . . . . . . 86
4.1.1 Insecticide residues . . . . . . . . . . . . . . . . . . . 86
4.1.2 Effect of two arboviruses on chicken embryos . . . . . 90

5 Time-to-event-response data 95
5.1 Analysis of a single germination curve . . . . . . . . . . . . 97
5.1.1 Germination of Stellaria media seeds . . . . . . . . . 97
5.2 Analysis of data from multiple germination curves . . . . . 102
5.2.1 Time to death of daphnias . . . . . . . . . . . . . . . 104
5.2.1.1 Step 1 . . . . . . . . . . . . . . . . . . . . . 104
5.2.1.2 Step 2 . . . . . . . . . . . . . . . . . . . . . 107
5.2.2 A hierarchical three-way factorial design . . . . . . . 109
5.2.2.1 Step 1 . . . . . . . . . . . . . . . . . . . . . 112
5.2.2.2 Step 2 . . . . . . . . . . . . . . . . . . . . . 114

6 Benchmark dose estimation 119

6.1 Binomial dose-response data . . . . . . . . . . . . . . . . . 120
6.1.1 Pathogens in food . . . . . . . . . . . . . . . . . . . . 120
6.1.2 Chromosomal damage . . . . . . . . . . . . . . . . . 124
6.1.3 Tumor incidence continued: Integration of historical
data . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
6.2 Continuous dose-response data . . . . . . . . . . . . . . . . 128
6.2.1 Toxicity of copper in an ecosystem with giant kelp . 129
6.2.2 Toxicity of an antituberculosis drug . . . . . . . . . . 133
6.3 Model averaging . . . . . . . . . . . . . . . . . . . . . . . . 135
6.3.1 Pathogens in food revisited . . . . . . . . . . . . . . 136
6.3.2 Toxicity of an antituberculosis drug revisited . . . . . 140

7 Hierarchical nonlinear models 145

7.1 Normally distributed dose-response data . . . . . . . . . . . 145
7.2 The R package medrc . . . . . . . . . . . . . . . . . . . . . 146
7.2.1 In vitro effects of the fungicide vinclozolin . . . . . . 147
7.2.2 Inhibition of photosynthesis in spinach . . . . . . . . 150
7.2.3 Herbicides with auxin effects . . . . . . . . . . . . . . 153
7.2.4 Drought stress resistance in Brassica oleracea . . . . 157

Appendix A Estimation 161

A.1 Nonlinear least squares . . . . . . . . . . . . . . . . . . . . . 162
A.2 Maximum likelihood estimation . . . . . . . . . . . . . . . . 163
A.2.1 Binomial dose-response data . . . . . . . . . . . . . . 164
A.2.2 Count dose-response data . . . . . . . . . . . . . . . 164
Contents vii

A.2.2.1 The Poisson distribution . . . . . . . . . . . 164

A.2.2.2 The negative-binomial distribution . . . . . 165
A.2.3 Time-to-event-response data . . . . . . . . . . . . . . 165
A.3 The transform-both-sides approach . . . . . . . . . . . . . . 166
A.4 Robust estimation . . . . . . . . . . . . . . . . . . . . . . . 166
A.5 Sandwich variance estimators . . . . . . . . . . . . . . . . . 167
A.6 Constrained estimation . . . . . . . . . . . . . . . . . . . . 168
A.7 Two-stage estimation for hierarchical models . . . . . . . . 168
A.7.1 Technical replicates . . . . . . . . . . . . . . . . . . . 169
A.7.2 Two-stage approaches . . . . . . . . . . . . . . . . . 169
A.7.3 Lindstrom-Bates algorithm . . . . . . . . . . . . . . . 170
A.8 Starting values and self-starter functions . . . . . . . . . . . 171
A.9 Confidence intervals . . . . . . . . . . . . . . . . . . . . . . 172
A.10 Prediction and inverse regression . . . . . . . . . . . . . . . 172
A.10.1 Effective dose . . . . . . . . . . . . . . . . . . . . . . 173
A.10.2 Relative potency . . . . . . . . . . . . . . . . . . . . 174

Appendix B Dose-response model functions 177

B.1 Log-logistic models . . . . . . . . . . . . . . . . . . . . . . . 178
B.1.1 Four-parameter log-logistic models . . . . . . . . . . 178
B.1.1.1 Three-parameter version . . . . . . . . . . . 179
B.1.1.2 Two-parameter version . . . . . . . . . . . . 179
B.1.1.3 E-max and Michaelis-Menten models . . . . 179
B.1.2 Extensions . . . . . . . . . . . . . . . . . . . . . . . . 180
B.1.2.1 Generalized log-logistic models . . . . . . . 180
B.1.2.2 A model with two slope parameters . . . . . 181
B.1.2.3 Hormesis models . . . . . . . . . . . . . . . 181
B.1.2.4 Two- and three-phase models . . . . . . . . 182
B.1.2.5 Fractional polynomial models . . . . . . . . 182
B.2 Log-normal models . . . . . . . . . . . . . . . . . . . . . . . 183
B.3 Weibull models . . . . . . . . . . . . . . . . . . . . . . . . . 184
B.3.1 Weibull type 1 models . . . . . . . . . . . . . . . . . 184
B.3.1.1 Exponential decay model . . . . . . . . . . 184
B.3.1.2 Other special cases . . . . . . . . . . . . . . 185
B.3.2 Weibull type 2 models . . . . . . . . . . . . . . . . . 185
B.3.2.1 Asymptotic regression . . . . . . . . . . . . 185
B.3.2.2 Other special cases . . . . . . . . . . . . . . 186
B.3.2.3 Generalized Weibull-2 model . . . . . . . . 186
B.4 Other types of models . . . . . . . . . . . . . . . . . . . . . 186
B.4.1 Gamma models . . . . . . . . . . . . . . . . . . . . . 186
B.4.2 Multistage models . . . . . . . . . . . . . . . . . . . . 186
B.4.3 NEC . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
B.4.4 Biphasic models with a peak . . . . . . . . . . . . . . 187
B.5 Fixing parameters . . . . . . . . . . . . . . . . . . . . . . . 188
viii Contents

Appendix C R code for plots 191

C.1 Continuous dose-response data . . . . . . . . . . . . . . . . 191
C.1.1 Ferulic acid as an herbicide . . . . . . . . . . . . . . 192
C.2 Estimation of BMD . . . . . . . . . . . . . . . . . . . . . . 192
C.2.1 Pathogens in food . . . . . . . . . . . . . . . . . . . . 192
C.2.2 Toxicity of an antituberculosis drug . . . . . . . . . . 194
C.3 Hierarchical nonlinear models . . . . . . . . . . . . . . . . . 195
C.3.1 Inhibition of photosynthesis in spinach . . . . . . . . 196
C.3.2 Herbicides with auxin effects . . . . . . . . . . . . . . 196
C.3.3 Drought stress resistance in Brassica oleracea . . . . 197

Bibliography 199

Index 211
Preface

The history of dose-response analysis goes back many hundred years. One of
the more unusual applications is that numerous rulers had cupbearers who
tried the ruler’s food and drink to avoid poisoning and probably the demise
of the regent. The dose-response was the survival/health of the cupbearer.
In more recent times, dose-response analysis was applied to data from
controlled experiments where a limited number of doses of a toxic chemical
compound were to be compared to a control group (dose 0) in terms of binary
responses such as whether or not a treated insect was dead or alive after a
certain time period (Finney, 1949). Later dose-response analysis crystallized
into being a certain type of regression analysis. In the seminal work by Finney
(1971) it is explained how to carry out the estimation in the so-called probit re-
gression model through manual calculations. By the late 1970s dose-response
analysis had been extended to log-logistic models for continuous response
(Finney, 1979). In the beginning, such dose-response data were fitted through
linearization (e.g., Streibig, 1981, 1983). Later nonlinear estimation of such
models became available through add-ons and macros for spreadsheet pro-
grams (e.g., Vindimian et al., 1983; Caux and Moore, 1997). General-purpose
statistical software programs also included nonlinear estimation procedures
but without any specific focus on dose-response analysis.
By 2005 the first version of the extension package drc was developed for
the statistical programming environment R (R Core Team, 2018). Originally,
it was developed for nonlinear fitting of log-logistic models that were routinely
carried out in weed science (Ritz and Streibig, 2005). However, subsequently,
the package has been modified and extended substantially, mostly in response
to inquiries and questions from the user community. It has developed into a
veritable ecosystem for dose-response analysis (Ritz et al., 2015). Currently,
such extensive functionality for dose-response analysis does not exist in any
other statistical software. One of the problems that non-statistical scientists
were facing in the past was that guestimates of nonlinear regression parameters
had to be provided upfront before any estimation of parameters could take
place; this was an insuperable problem for many practitioners. To a very large
extent this problem has now been resolved in the package drc through the use
of so-called self-starter routines.
The development of dose-response analysis has undergone dramatic
changes from struggling with cumbersome more or less manual calculations
and transformations with pen and paper to the blink-of-an-eye estimation of
relevant parameters on any laptop.

ix
x Preface

A unified framework
The dose does not necessarily need to be a chemical compound. We define a
dose (metameter) as any pre-specified amount of biological, chemical, or ra-
diation stimuli or stress eliciting a certain, well-defined response. Other kinds
of exposure or stress could also be imagined, e.g., time elapsed in germination
experiments. However, in any case, the dose is a non-negative quantity.
Specifically, we define the response evoked by a specific dose as the quan-
tification of a biologically relevant effect, and as such, it is subject to random
variation. The most common type is a continuous response such as biomass,
enzyme activity, or optical density. A binary or aggregated binary (binomial)
response is also frequently used to describe results such as dead/alive, immo-
bile/mobile, or present/absent (Van der Vliet and Ritz, 2013). The response
may also be discrete as in a number of events observed in a specific time inter-
val such as a number of juveniles, offspring, or roots (Ritz and Van der Vliet,
2009). We will have more examples in later chapters.
A key feature of dose-response analysis is that the experimenter or re-
searcher has to have some a priori idea about the type of model function that
would be relevant for the analysis of her/his dose-response data. In principle,
many nonlinear model functions could be considered for describing how the
average response changes over the range of doses considered. In practice, only
a limited number of functions are used in the majority of applications. Specif-
ically, we will focus on modeling average trends through mostly s-shaped or
related biphasic functions. These functions reflect an a priori basic under-
standing of the causal relationship between the dose and the response, e.g.,
when a dose increases the response decreases between certain limits referred
to as the lower and upper limits, respectively. S-shaped functions have turned
out to be extremely versatile for describing various biological mechanisms;
one key feature is that model parameters provide useful interpretations of
observed effects within a biologically plausible framework. Specifically, dose-
response analysis is often used for screening and ranking of compounds using
estimated effective or lethal doses such as ED50 or LD50 (e.g., WHO, 2005).
The full specification of a statistical dose-response model involves both
specifying the parametric model function and assumptions about the distri-
bution of the responses, i.e., how they randomly fluctuate around the average
value determined by an assumed model function. Distributional assumptions
depend on the type of response observed. However, the same model functions
may be meaningful for different types of responses, and this is the unify-
ing feature of dose-response analysis: It involves dose-response models that
are a collection of statistical models that have a certain mean structure in
common. This is not a mathematical definition in any sense, but rather a
definition driven by applications, which actually makes sense for a statisti-
cal methodology. Consequently, dose-response models encompass a range of
statistical models that could be classified as nonlinear regression, generalized
Preface xi

(non)linear regression, and parametric survival analysis. Perhaps this is one

reason for dose-response analysis being neglected by many statisticians, as
already pointed out many years ago (Finney, 1979).

What this book is and is not about

Nowadays the term dose-response is used in many different contexts. This book
is about fitting and interpreting results obtained from fitting fully parametric
nonlinear dose-response (regression) models. In short, this is how we define
dose-response analysis and this book is meant to provide an introduction
to this kind of dose-response analysis. We do not cover some areas of dose-
response analysis that are still under development and where functionality is
not yet available in R, such as dose-response analysis of data from mixture
experiments and models for handling measurement error.
Some methods, which used to be part of a dose-response analysis, are
intentionally not covered in the book: goodness-of-fit and lack-of-fit tests and
other statistical tests that are used for assessing model assumptions. We prefer
using statistical tests for evaluating research questions about differences.
This book neither covers analysis of variance of dose-response data nor
estimation of linear trends, which are sometimes, and in some fields, referred
to as dose-response analysis. In the past, and occasionally still, s-shaped dose-
response trends or parts of them were approximated by means of linear regres-
sion models, e.g., parallel-line and slope-ratio assays, but such approaches are
hardly needed anymore as was already pointed out a long time ago (Vølund,
1978). We also do not cover semi- or non-parametric approaches for modeling
dose-response data. Finally, Bayesian methods for dose-response analysis are
still in their infancy and not covered either.

How to read the book

The first five chapters deal with different types of dose-response data, and
they may be read in arbitrary order as they are only loosely connected. How-
ever, there is a gradient such that more complex examples will be encountered
in the later chapters. The last chapters are more specialized, covering recent
advances, and therefore also more technical but still example-based. In exam-
ples, we will most often report estimates with corresponding standard errors
in brackets, unless otherwise stated. We provide an appendix with more tech-
nical details and explanations for the interested reader, but most examples
should be self-contained.
xii Preface

Above we praised the fact that modern dose-response analysis may be

carried out in much the same way as linear regression analysis. This is indeed
true, but as the estimation is intrinsically nonlinear, it can occasionally happen
that the analysis is also less smooth and the user will need to provide more
input. This is, in particular, the case when fitting more complex dose-response
models. We provide some examples in Chapter 7.
Sometimes we analyze examples in the chapters in this book in several
ways. This allows us to compare different approaches. In practice, a single
approach should ideally be decided upon by the scientist’s knowledge of the
underlying biological mechanisms. We hope this book will be helpful in ac-
quiring an informed opinion about when to use which approach.

Acknowledgment
We are fortunate in having some colleagues and experts, Florent Baty, Andrew
Kniss, Andrea Onofri, Janine Wong, and Ming Yi, who kindly agreed to read
sections or the entire manuscript. We are grateful for their valuable comments
and correction of the substance and language. We would stress, however, that
all these helpful people are in no way responsible for any mistakes which still
occur; these are ours alone.
1
Continuous data

In this chapter, we show examples of how to analyze dose-response data that

are continuous. It is a common type of dose-response data obtained in biol-
ogy, toxicology, and many other fields. Specifically, a continuous response is a
quantitative measurement that may take any value within a certain (possibly
unlimited) range and is usually expressed in a quantitative unit such as colour,
length, mass, and volume.
For continuous dose-response data, we will assume a statistical model
where each response value y may be decomposed into two additive contri-
butions. One contribution is determined or predicted by the corresponding
dose through the assumed model function f , i.e., it will be the same contri-
bution every time the same dose is applied; it is a fixed contribution for each
dose. This contribution corresponds to the average response for a given dose.
The other contribution is random, i.e., it will change from one replicate to
the next, modifying the average response value in an unpredictable way. The
randomness may, however, be characterized by a probability distribution that
quantifies how likely the contribution is to take values in any given interval
of response values. As these random contributions will modify the average
response by adding or subtracting some value, we say that the probability
distribution is centered around the mean (response). This statistical model
may be written in the following way:

yi = f (xi , β) + εi , i = 1, . . . , n (1.1)

with the fixed and random contributions adding up to the observed response
value for each pair of dose and response (xi , yi ), for a total of n measurements.
It is common to assume that the random contributions, the εi ’s in Equa-
tion (1.1), follow a mean-zero normal distribution with an unknown residual
standard deviation, which also is a model parameter to be estimated from
the data. The residual standard error is a measure of the variation between
measurements beyond what is explained by the assumed dose-response model
function. We will also address how to deal with dose-response data that do not
fully satisfy the above assumptions (see Subsection 1.1.3 and Subsection 1.1.4
for examples).
The model specification in Equation 1.1 relies on the assumption that the
variation between replicates is the same for all doses (referred to as variance
homogeneity). In this case, estimation may be carried out using nonlinear

1
2 Dose-response analysis using R

least squares (see Section A.1 for more details) as the dose-response model is
a special case of a nonlinear regression model (Ritz and Streibig, 2008).
In the examples below we will only specify the model function f and im-
plicitly assume that a statistical model is defined through Equation (1.1).
However, we will also address situations where the assumptions of normality
and variance homogeneity are not fulfilled.
In this chapter, we use the following extension packages:

library(drc)

library(devtools)
install_github("DoseResponse/drcData")
library(drcData)

library(boot)

library(lmtest)

library(metafor)

library(sandwich)

1.1 Analysis of single dose-response curves

In the first example there are no replicates per dose, i.e., only a single response
is obtained per dose. It can occur as a consequence of the experimental design,
which may be a good thing if it means that more doses and fewer replicates
were used. It can also happen because averages over the replicates were cal-
culated per dose; this is a waste of data and should be avoided: All replicates
should enter the analysis as shown in Subsection 1.1.2 and Subsection 1.1.3.

1.1.1 Inhibitory effect of secalonic acid

We want to carry out a dose-response analysis for the dataset secalonic
shown below.

secalonic

## dose rootl
## 1 0.000 5.5
## 2 0.010 5.7
Continuous data 3

## 3 0.019 5.4
## 4 0.038 4.6
## 5 0.075 3.3
## 6 0.150 0.7
## 7 0.300 0.4

Dose-response data were obtained from an experiment assessing the inhibitory

effect of secalonic acid on plant growth (Gong et al., 2004). The response values
(in the variable named rootl) are root lengths in cm, and the dose values
(dose) are in mM. Replicates were averaged per dose (as already pointed out
above, this is in general not a good idea).

1.1.1.1 Fitting the model

In weed science a four-parameter log-logistic model is often used to describe
dose-response relationships. We can use the model fitting function drm(),
which is the pivotal function in the package drc for fitting dose-response mod-
els. Specifically, the response is specified on the left-hand side of the tilde (∼)
as the root length (rootl). The independent variable, which is denoted dose,
is supplied to the right of the tilde. Next, we specify the dataset where the vari-
ables named dose and rootl are to be found using the argument data. The
argument fct = LL.4() specifies a four-parameter log-logistic model where
both lower and upper limits have to be estimated from the data. For contin-
uous dose-response data it is not necessary to specify the argument type as
the default is type = "continuous". We store the resulting model fit in an
object named secalonic.LL.4:

secalonic.LL.4 <- drm(rootl ~ dose,

data = secalonic,
fct = LL.4())

The first argument supplied to the function drm() is a model formula relating
the response to the predictor. The second argument data is specifying the
dataset where the variables rootl and dose are found. R will not automat-
ically look for variables in the dataset secalonic because they are not in
the search path and it is a good habit to specify the relevant dataset every
time a model is fitted. The third argument fct specifies the dose-response
model function that we want to fit. As there are 7 different doses, a four-
parameter model may easily be fitted (usually as many doses as parameters
are said to be required, but less will also do sometimes, possibly depending
on the choice of model function and the number of replicates). The built-in
function LL.4() in drc provides the four-parameter log-logistic model that
is commonly used in toxicology (see Section B.1 for more details). In short,
this model has four parameters: a lower limit, an upper limit, a parameter
corresponding to ED50, and a parameter for the relative slope at the dose
equal to ED50 (see Figure 1.1).
4 Dose-response analysis using R

Note that upon execution of the above R lines, no output is produced.

All information on the model fitted to the data is stored in the object named
secalonic.LL.4, which is our choice for an informative name for the model
fit; you are invited to use other names.
A plot of the observed response (rootl versus dose) and the corresponding
fitted dose-response curve is obtained using the plot method.
Apart from the first argument (the model object secalonic.LL.4), the
arguments in plot govern the layout of the plot. While the arguments xlab,
ylab and ylim are self-explanatory (or see the help page ?par for graphical
parameters), the arguments bp and broken require a little more explanation.
broken indicates the presence or absence of a break in the dose axis, in or-
der to display that both 0 and the logarithm axis are shown and bp sets the
value on the dose axis where the axis breaks. A break is needed in situations
where zero concentrations/doses (x values) are combined with a logarithmic
x-axis. The default value of bp is usually quite sensible, but in this particular

plot(secalonic.LL.4,
bp = 1e-3, broken = TRUE,
ylim = c(0, 7),
xlab = "Dose (mM)",
ylab = "Root length (cm)")

7
6
Root length (cm)

5
4
3
2
1
0

0 0.01 0.1

Dose (mM)

FIGURE 1.1
The four-parameter log-logistic model fitted to dose-response data from the
dataset secalonic is plotted together with the original data (no replicates).
Continuous data 5

instance we must choose a smaller value to ensure that the bp value is smaller
than all positive concentrations/doses (otherwise some observations are not
displayed!). The argument log = "" may be used to switch off the default
logarithmic dose axis.

A summary of the fit is obtained using the summary method when applied
to the model fit secalonic.LL.4:
summary(secalonic.LL.4)

##
## Model fitted: Log-logistic (ED50 as parameter) (4 parms)
##
## Parameter estimates:
##
## Estimate Std. Error t-value p-value
## b:(Intercept) 2.6542086 0.6962333 3.8122 0.0317398 *
## c:(Intercept) 0.0917852 0.3747246 0.2449 0.8223012
## d:(Intercept) 5.5297495 0.2010300 27.5071 0.0001055 ***
## e:(Intercept) 0.0803547 0.0078829 10.1935 0.0020121 **
## ---
## Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1
##
## Residual standard error:
##
## 0.2957497 (3 degrees of freedom)

The output shows the type of model that was fitted and the parameter esti-
mates for the four model parameters together with the corresponding (esti-
mated) standard errors. Briefly, the parameter b, c, d, and e refer to the slope
parameter for a dose equal to e, which is the dose resulting in a reduction
halfway between the upper limit d and the lower limit c, which is also called
ED50. We refer to Subsection B.1.1 for more details about the four-parameter
log-logistic model.
For each parameter, there are also t-values, which are parameter esti-
mates divided by their standard error, and the resulting p-values, looked up
in an appropriate t distribution; each of them corresponds to testing the null
hypothesis that the parameter is equal to 0 (not necessarily a relevant null
hypothesis to consider). The estimated residual variance is also shown, al-
though it is hardly reported in any publications, but it may still be useful
for understanding variation in the experiment. Possibly, the most interesting
parameter in the summary output is the parameter estimate for e; it is equal
to 0.08 (0.0079).
We also see that the estimated lower limit, which is equal to 0.0918 with a
standard error of 0.375, is not significantly different from zero (p-value = 0.82),
possibly indicating that a three-parameter log-logistic model (with an assumed
lower limit of 0) would also fit the data. However, such ad hoc data-driven