entropy

Article
Working with Convex Responses: Antifragility from Finance
to Oncology
Nassim Nicholas Taleb 1, * and Jeffrey West 2

1 Tandon School of Engineering, New York University, Brooklyn, NY 11201, USA

2 Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
* Correspondence: NNT1@nyu.edu

Abstract: We extend techniques and learnings about the stochastic properties of nonlinear responses
from finance to medicine, particularly oncology, where it can inform dosing and intervention. We
define antifragility. We propose uses of risk analysis for medical problems, through the properties of
nonlinear responses (convex or concave). We (1) link the convexity/concavity of the dose-response
function to the statistical properties of the results; (2) define “antifragility” as a mathematical property
for local beneficial convex responses and the generalization of “fragility” as its opposite, locally
concave in the tails of the statistical distribution; (3) propose mathematically tractable relations
between dosage, severity of conditions, and iatrogenics. In short, we propose a framework to
integrate the necessary consequences of nonlinearities in evidence-based oncology and more general
clinical risk management.

Keywords: convexity; dose response; antifragility

1. Introduction: Where the Idea of Antifragility Came From

The notions of fragility and antifragility were inspired by the payoffs and the intricacies
of financial derivatives. The concept was introduced in Taleb (2012) [1] and more formalized
in Taleb and Douady (2013) [2]. While, in the real world, many phenomena are intuitively
Citation: Taleb, N.N.; West, J.
known to benefit from an increase in “volatility” (that is, the standard deviation of a random
Working with Convex Responses:
variable, or the variability of a nonrandom one), only quantitative finance had names for
Antifragility from Finance to
such attributes, such as “long gamma” (where the financial “derivative” contract has a
Oncology. Entropy 2023, 25, 343.
positive local second mathematical derivative with respect to the underlying security),
https://doi.org/10.3390/e25020343
“long vega” (where the financial derivative has a positive first derivative with respect to the
Academic Editors: Alessandro standard deviation of the underlying security), and similar measures, always associated
Pluchino, Andrea Rapisarda and with some range of variation as these sensitivities are local and have, themselves, higher
Filippo Caruso derivatives. By “local” we refer to the fact that most payoff functions in finance are convex
Received: 26 September 2022 over a certain range, then linear or concave, with the second derivative changing in sign,
Revised: 23 January 2023 the so-called “higher Greeks” in [3]) Furthermore, finance links some nonlinear attributes
Accepted: 25 January 2023 of portfolios to the risk of “blowups”, that is, a loss large enough to be irreversible, such
Published: 13 February 2023 as irrecoverable financial ruin. Such quantitative and qualitative models of ruin can give
us a tractable generalizable definition of fragility. However, centrally, derivative risk
management, at its core, lies in distinguishing between the properties of a random variable
X and a payoff function f ( x ), almost always nonlinear.
Copyright: © 2023 by the authors. While Jensen’s inequality (on which more in Appendix B) is concerned with the
Licensee MDPI, Basel, Switzerland. first moment of the distribution, monotone convex (or concave) functions, and a static
This article is an open access article expectation operator, financial payoffs are more complicated; the first static moment, while
distributed under the terms and
relevant, is not the sole focus as:
conditions of the Creative Commons
Attribution (CC BY) license (https://
• The expectation must be conditioned on absence of “blowup”, that is, the left tail of
creativecommons.org/licenses/by/
the distribution must be constrained (see Geman et al., 2015) [4], which involves all
4.0/). higher moments of f ( x ).

Entropy 2023, 25, 343. https://doi.org/10.3390/e25020343 https://www.mdpi.com/journal/entropy

Entropy 2023, 25, 343 2 of 21

• The payoff functions are almost never monotone.

• Taking into account higher moments of the distributions is analogous to going beyond
second-order effects: third, fourth, etc.
Fragility, as defined in Taleb (2012) and Taleb and Douady (2013) [1], Ref. [2], is
related to how a system suffers from the variability of its environment beyond a certain
preset threshold (when the threshold is K, it is called K-fragility), see Figure 1, while
antifragility refers to when it benefits from this variability—in a similar way to as what
we saw quantitative finance calls “vega” for an option or a nonlinear payoff, that is, its
sensitivity to volatility or some similar measure of scale of a distribution. (Tail fragility
maps to a risk of financial ruin, while local fragility does not necessarily mean ruin). In [2]:

Simply, a coffee cup on a table suffers more from large deviations than from
the cumulative effect of some shocks—conditional on being unbroken, it has
to suffer more from “tail” events than regular ones around the center of the
distribution, the ‘at-the-money’ category. This is the case of elements of nature
that have survived: conditional on being in existence, then the class of events
around the mean should matter considerably less than tail events, particularly
when the probabilities decline faster than the inverse of the harm, which is
the case of all used monomodal probability distributions. Further, what has
exposure to tail events suffers from uncertainty; typically, when systems—a
building, a bridge, a nuclear plant, an airplane, or a bank balance sheet—are
made robust to a certain level of variability and stress but may fail or collapse if
this level is exceeded, then they are particularly fragile to uncertainty about the
distribution of the stressor, hence to model error, as this uncertainty increases the
probability of dipping below the robustness level, bringing a higher probability
of collapse. In the opposite case, the natural selection of an evolutionary process
is particularly antifragile, indeed a more volatile environment increases the
relative survival rate of robust species and eliminates those whose superiority
over other species is highly dependent on environmental parameters.

PDF
Fr

K
 f (x, σ) - f (x, σ + Δ)  x

K f(x)[Response]

Figure 1. Fragility below level K as indicative of survival. It is not quite symmetric because global
antifragility is conditioned on tail robustness (“to do well, one must first survive”). The Taleb and
RK RK
Douady (2013) [2] paper shows that the gap between f ( x, σ)dx and f ( x, σ + ∆)dx, where σ is
the scale of the distribution, is proportional to the concavity of f ( x ). Hence, without knowing the
distribution (PDF above), one can gauge such an effect by looking at the nonlinearity of f (.) below
the threshold K.
Entropy 2023, 25, 343 3 of 21

The paper above produced theorems linking the second derivative of f ( x ) in some
ranges of variation to sensitivity to the scale of the distribution of X. Thus, the same sensi-
tivity to the scale of the distribution can also express sensitivity to a stressor (dose increase)
in medicine or other fields in its effect on either tail. Thus, one single measure will allow us
to express with comfortable precision the exposure to the disorder cluster: (i) uncertainty,
(ii) variability, (iii) imperfect, incomplete knowledge, (iv) chance, (v) chaos, (vi) volatility,
(vii) disorder, (viii) entropy, (ix) time, (x) the unknown, (xi) randomness, (xii) turmoil, (xiii)
stressor, (xiv) error, and (xv) dispersion of outcomes. A positive (negative) sensitivity to
one means positive (negative) to all others in the group. Finally—and critically—the paper
showed that one does not need to have an exact probability distribution to obtain a useful
idea of the exposure, since these metrics are based on acceleration, which washes out up
to one order of magnitude the precision errors. Note that for multivariate situations, an
additive approach is used without any loss of effectiveness.
Asymmetry of Fragile/Antifragile: The opposite of globally fragile (with respect to
a random variable X) is not naively “antifragile”, but is both convex with respect to that
variable and has a left tail constraint. In probabilistic representation, f ( x ) must have a
positively skewed distribution. Furthermore, as with the fragile, antifragility is limited to a
specific range of variations, and with respect to a single random variable.
The rest of this article will present medicine and convexity, then apply the notions
of fragility–antifragility at two levels: efficient dosing in oncology and an examination
of iatrogenics as linked to convexity. Finally, in the appendix, we present an overview of
convex responses in medicine.
Note: we use, by convention, the term “convexity” or “convexity effect” in the presence
of consequential nonlinearity, which can be concave: if the harm function is defined as
positive, it shows as convex; if negative, it shows as concave. Finance uses the expression
“convexity bias” for both concave and convex responses (and with the possible additional
designation “positive” or “negative” convexity).

2. Medicine and Convexity

Medicine has much simpler payoffs than quantitative finance. Most are generalizations
around simple sigmoids, see Figure 2, which were described in the mapping in Taleb and
Douady (2013) [2] as belonging to the benign class: the distribution of f ( x ) is necessarily
thinner-tailed than that of X, owing to the boundedness of the function, dubbed more
“binary” than “vanilla”, see [5].
However, in spite of such simplicity, little work in medicine has been conducted
about probabilistic effects on convexity—almost always limited to first-order effects and
comparative statics. The probabilistic dimension of variability has been made explicitly in
some medical domains, for instance, there are a few studies connecting Jensen’s inequality
to patient responses with pulmonary ventilators: papers such as Brewster et al. (2005) [6],
Amato et al. [7], Funk (2004) [8], Arold et al. (2003) [9], Graham et al. (2005) [10], and
Mutch et al. (2007). To summarize the literature, continuous high pressures have been
shown to be harmful (leading to increased mortality), but episodic spikes of ventilation
pressures can be helpful with the recruitment of collapsed alveoli (natural breathing exhibits
some variability, with some breaths deeper than others). However, these papers stop at
Jensen’s inequality, and, further, explicit probabilistic formulations are still missing in other
domains where the applications of these techniques are most needed, such as intermittent
fasting, episodic energy deficit, uneven distribution of sub-groups (say, proteins), vitamin
absorption, moderate- and low-intensity training, fractional dosage, the comparative effects
of low-intensity and distributed interventions vs. intense and concentrated ones, the
chronic vs. the acute, and similar effects. As to the psychology literature, the notion
of overcompensation is present Den Hartigh and Hill (2022) [11]. The identification of
convexity is still confined to local responses and did not generalize to decision-making
under uncertainty and inferences concerning silent risks from the nonlinearity in dose
response. For instance, the results did not reach the obvious relation between tumor size
Entropy 2023, 25, 343 4 of 21

and the trade-offs of the intervention, or the extrapolation between the numbers needed to
treat (NNT) and the potential severity of the side effects.

f(x)

1.0

0.8

0.6

0.4

0.2

Figure 2. Simple (first-order) nonincreasing or nondecreasing sigmoids, defined as floored and

capped increasing functions. They map to the payoff in finance of a binary option with time left to
expiration. As the sigmoid loses smoothness (with the decreased time to expiration), it becomes, at
the limit, a Heaviside function, see Figure 3.

1.0

Converges to
the theta function 0.8
θ(x-K) [Heaviside]
at point K, similar to
0.6
a binary option
getting closer to
expiration 0.4

0.2

Figure 3. The smoothing of the Heaviside function as distribution or Schwartz function.

The connections we are investigating are necessary and mathematical: they work in
both directions. We can illustrate as follows:
• A convex response to energy balance over a fixed time window necessarily implies
gains from intermittent fasting in some situations and under some strict conditions
(that is, higher variance in the distribution of nutrients) over some range within the
limits of that time window;
• The presence of metabolic problems in populations that have a steady supply of food
intake, as well as evidence of human fitness to an environment that provides moderate
variations in the availability of food, both necessarily imply a concave response to
food within a range and time frame.
Entropy 2023, 25, 343 5 of 21

Finally, a short summary of the above is as follows. Convexity analysis in medicine is

in two dimensions; first, working with the nonlinearity of dosing, second, for risk analysis
for patients and groups.
Missing second-order effects: One frequent lacuna in the literature is ignoring the
second-order effects when making statements derived from from empirical data. One
example is dietary recommendations for food group composition rather than frequency.
Epidemiological interpretations of the Cretan diet relied solely on composition. A sim-
plified intuition of the second-order effect in nutrition is as follows. Eating once a day
vs., say, three times (in an isocaloric way) presents a difference if the response function
is nonlinear: an average of response functions is not a response function of an average.
However, frequency matters: the Eastern Orthodox Church has, with minor local variations,
around two hundred days of vegan fasts per year. This is an episodic protein deprivation;
fatty meats are consumed in lumps (on Sundays and holidays), which compensates for
such a deprivation (recall the threshold in Figure 4. As shown in the literature review in
Appendix A, there is a need for a mathematical bridge between studies of variability, say
Martin et al. (2006) [12] and Fontana et al. (2008) [13], on one hand, and the focus on compo-
sition—the Longo and Fontana studies, furthermore, narrow the effect of the frequency to a
given food type, namely proteins (Lee and Longo (2011) [14] “In the prokaryote E. coli, lack
of glucose or nitrogen (comparable to protein restriction in mammals) increase resistance
to high levels of H2 O2 (15 mm) (Jenkins et al., 1988) [15]”). Further, the computation of the
“recommended daily” units may vary markedly if one assumes necessary stochasticity.
Extracting past statistical attributes and frequencies: A central question is if we need a
certain dose of stressors, whether in intermittence of nutrition or necessary exercise, might
these represent the attributes of an “ideal” environment. Whether evolutionary or not, this
is the one to whose stochastic properties we are most adapted. We can, therefore, reverse
engineer the stochastic nature of such an “ideal” environment by finding the various
conditions that result from a reduction in stressors. We noted that papers such as Kaiser
(2003) [16] and Calabrese and Baldwin (2003), [17] do not bridge the results to the point
that hormesis may correspond to a “fitness dose”, beyond and below which one departs
from such an ideal dispersion of the dose x per time period.
Such a reverse engineering uses the visible dose–response curve to make inferences
about the ideal parametrization of the probability distribution of nutritional balance and
vice-versa. For example, assessing the benefits of episodic fasting and the length of win-
dows for neoplasms, insulin resistance, and other conditions can lead to understanding
some kind of “fitness” to an environment endowed with a certain structure of randomness,
either with the σ above or some more sophisticated attributes of the probability distribu-
tions (such as higher moments, hence different shapes). For example, if insulin resistance
can be reduced thanks to occasional deprivation (a certain variance), say one 24-h fast every
week, 3 days of fasting per trimester, and a complete week every five years, then we can
extract and parametrize a probability distribution of ancestral deprivations. A comprehen-
sion of the exact mechanism by which such intermittences work can be helpful but is not
needed given the robustness of the mathematical connection between the functional and
probabilistic.

Antifragility in Treatment Scheduling

In Figure 5, the input distribution of dose x is subject to the convexity (or concavity
or linearity) of the dose-response function, which influences the tail of the outcome distri-
bution. Importantly, an oncologist has “first-mover” advantage [18] and has the benefit
of prescribing an “even” treatment protocol with no variance (Figure 4, top row) or an
“uneven” treatment protocol with positive variance (Figure 4, bottom row).
In medical practice, treatment protocols are typically fixed with doses administered at
regular intervals (e.g., Figure 4). The distribution of dosing is unimodal (purple; continuous
dosing), or, at most, bimodal (green; intermittent dosing). Manipulation of dose volatility
when designing treatment protocols is under-utilized as a strategy in cancer treatment.
Entropy 2023, 25, 343 6 of 21

In place of a dose x, one can give, say, 120% of x, then 80% of x, with a more favorable
outcome if one is in a zone that benefits from unevenness. If antifragile, more unevenness
is more beneficial: 140% followed by 60% produces better effects [19].

Figure 4. Example treatment-scheduling protocols. (A) Input distribution of dosing is typically

unimodal (“even”) or bimodal (“uneven”). (B) Protocols are typically fixed, with doses administered
at regular intervals. It may be feasible to temporarily increase the dose (green), with periodic
treatment holidays. (C) Even treatment is optimal to maximize response for concavity; uneven
for convexity.

Figure 5. These three graphs (related to the convex (concave) transformations of random variables)
summarize and simplify our main idea; they show how we can go from the reaction or dose response
S( x ), combined with the probability distribution of x, to the probability distribution of S( x ) and its
properties: mean, expected benefits or harm, variance of S( x ). Thus, we can play with the various
parameters that can affect S( x ) and those that can affect the distribution of x, and extract results from
the output. S( x ), as we show, can take different forms (we chose a monotone convex or concave S( x ),
but a second-order mixed sigmoid can also be used).

3. Antifragility in Oncology
Across all treatment modalities, cancer treatment is intended to induce perturbations
to environmental conditions within a tumor leading to cell death, altering vasculature,
or impacting immune response. However, the most common treatment paradigm is the
Entropy 2023, 25, 343 7 of 21

“maximum tolerable dose” (MTD) dosing protocol, whereby the dose is maximized, and
only limited by tolerability, toxicity, and side effects. To re-phrase, oncology research is
implicitly focused on maximizing “first-order” treatment effects by increasing the cumula-
tive dose [20] or shortening the time between doses [21]. The “log-kill” law proposes an
MTD protocol for cytotoxic chemotherapy agents that decreases the amount of time over
which a cumulative dose is delivered as toxicity allows [22]. More recently, metronomic
therapy proposes frequent, low doses known to provide an anti-angiogenic effect during
chemotherapy, still implicitly optimizing a first-order effect of cumulative dose [23].
Oncology must consider convexity in strategizing treatment protocols. Although con-
vexity was not a consideration of initial clinical design, recent approaches have had success
in managing second-order effects through the practice of high/low dosing. Intermittent
high dosing of tyrosine kinase inhibitors (TKI) in HER2-driven breast cancers was adminis-
tered with concentrations of the drugs that would otherwise far exceed toxicity thresholds
if dosed continuously [24]. Continuous letrozole in combination with high-dose intermit-
tent ribociclib is currently in clinical trial (NCT02712723; ER-positive breast cancer) [25].
Intermittent high-dose erlotinib delays resistance in an EGFR-mutant non–small cell lung
cancer in vivo model [26,27]. Intermittent weekly EGFR-inhibitors reduced tumor load
in vivo, compared with daily regimens with identical cumulative doses [28]. Intermittent
“pulsatile” high-dose erlotinib once weekly maintains efficacy even after failure of low-
dose continuous treatment [29]. Ideal treatment protocols will maximize both first-order
effects (cumulative dose) and second-order effects (variance of dose delivered). Studies
mentioned previously provide evidence of the tolerability of temporary dose escalation by
also employing off-treatment periods to alleviate therapy toxicity.

3.1. Defining (Local) Fragility in Oncology

Local fragility, F, is a measurable quantity, similar to the Jensen gap, defined as the
difference in the result of unevenness over evenness (with corresponding unevenness range
parameter λ):
f ( x + λ) + f ( x − λ)
F ( x, λ) = − f (x) (1)
2
Which property of cancer cells, f ( x ), is important in oncology? Here, we are interested in
the advantage of “uneven” high/low schedule over the “even” schedule. More precisely,
fragility is the difference between (1) a schedule of two constant doses (termed an “even”
dosing strategy), ~ X = { x, x } and (2) a schedule of a high dose followed by a low dose
(termed an “uneven” dosing strategy), ~ X = { x + λ, x − λ}. We consider the response to
two doses over an interval of time T, where the first dose is given at t = 0 and the second
dose is given at t = T/2. Given a tumor with an initial population size of n0 , the final size
of an exponentially growing population is given by:

n F (t) = n0 exp(γ( x )t), (2)

where γ( x ) is the decay rate of the population associated with a dose of x. Fragility can be
defined as:
       
T T T T
F ( x, λ) = n0 exp γ( x + λ) exp γ( x − λ) − n0 exp γ( x ) exp γ( x ) , (3)
2 2 2 2

which simplifies to:

   
T
F ( x, λ) = n0 exp (γ( x + λ) + γ( x − λ)) − exp(γ( x ) T ) . (4)
2

We are interested in the antifragile–fragile boundary, the point at which the population is
no longer fragile but antifragile. If F < 0, the cell population is antifragile by definition (a
Entropy 2023, 25, 343 8 of 21

benefit conferred to uneven dosing for minimizing tumor growth rate), and if F > 0, then
it is fragile. It follows that the previous equation will be negative if:

γ( x + λ) + γ( x − λ)
< γ( x ) (5)
2
Thus, the important domain for convexity is the dose-dependent growth rate, γ( x ). It is
an unfortunate common practice to normalize dose–response curves to obtain fractional
survival at the final time point (e.g., 1 − n F /n0 ), which obscures convexity. Drug-induced
growth rate inhibition (GR curves) has been introduced as a method to remove the artifac-
tual dependency of IC50 and Emax on the cellular division rate [30]. GR curves preserve
convexity, unlike fractional survival.

3.2. Fragility and Taylor Series Approximations

Antifragility is a “second-order” effect. This is shown by first taking a Taylor expansion
about x:
λ2 00
f ( x ± λ) = f ( x ) ± λ f 0 ( x ) + f ( x ) + O ( λ3 ) (6)
2
where O(λ3 ) represents all third-order or higher terms. Using this expansion, fragility can
be written:

λ2 00 λ2 00
 
1 0 0
F ( x, λ) = 2 f (x) − f (x) − λ f (x) − f (x) − f (x) + λ f (x) − f ( x ) + O ( λ3 ).
2 2 2
(7)
The zeroth-order terms and the first-order terms cancel out:

λ2 00
F ( x, λ) = − f ( x ) + O ( λ3 ) (8)
2
For small values of λ, fragility is proportional to the second derivative, and, thus, known
as a second-order effect. Next, we connect the concept to finite difference methods.

3.3. Fragility and Finite Differences

We can approximate the derivative of f ( x ) using finite differences. Here, we use the
well-known central difference approximation to the second derivative, f 00 ( x ), where h is
the width of the interval over which the finite difference is estimated (h > 0):

1
f 00 ( x ) = lim

2
f ( x + h) + f ( x − h) − 2 f ( x ) . (9)
h →0 h

The term on the right-hand side in brackets is related to fragility (Equation (1)), giving us
the relationship between F ( x, λ = h) and f 00 ( x ):

2
f 00 ( x ) = − lim F ( x, h), (10)
h →0 h2

This limit illustrates that f 00 ( x ) approaches F only when h is small. When the value of h is
large, the approximation is poor, and, therefore, we employ Equation (1). Figure 6 provides
an example of approximation error for the Hill function (see next section).
Entropy 2023, 25, 343 9 of 21

Figure 6. The second derivative is an approximation for fragility for low values of h. (A) Hill function,
H ( x ) (Equation (11)) shown for n = 10, E0 = 0, E1 = 100, and C = 10. Analytically derived
second derivative (Equation (12)) is shown in the bottom panel. (B) Difference between fragility and
second derivative at various dose values (red to blue) corresponding to panel A. As h → 0, the error
2
approaches zero: F ( x, h) − h2 ddxH2 → 0.

3.4. Applications of Hill Function

The Hill function is commonly used to describe drug pharmacodynamics [31], where
H ( x ) is the cell viability in response to a dose x.

E1 − E0
H (x) =  n + E0 (11)
1 + Cx

where n is the Hill shape parameter, E0 and E1 are the minimal and maximal response
(respectively), and C is the half-maximal response (the EC50 value). The second derivative
can be written:

( E1 − E0 )nC n x n−2 (n − 1)C n − (n + 1) x n

d2 H
= . (12)
dx2 ( C n + x n )3

Figure 6A shows a sample Hill function and corresponding second derivative. Figure 6B
2
illustrates decreasing error between the numerical (F) and analytical ( ddxH2 ) as h → 0. The
d2 H
error scales like h2 , as predicted in Equation (10). The inflection point, found where dx2
= 0,
defines the boundary between convex and concave regions.
1/n
n−1

∗
x =C (13)
n+1

It can be shown that as n increases, x ∗ → C. Importantly, x ∗ determines the boundary

between the antifragile and fragile regions of f ( x ). Benefit can, thus, be derived from
uneven dosing if x < x ∗ . The inverse implies that uneven treatment schedules provide
no additional benefit. For a discussion on relaxing the assumption of fixed treatment
schedules (e.g., Figure 4) using a probability density function describing dose distribution,
see Appendix C, Equations (A4) and (A5).
As shown in Figure 5, the input distribution passing through convex dose response
(e.g., on the Hill function below its inflection point) results in a left-tailed outcome distribu-
tion, and a concave response function results in a right-tailed distribution.
Entropy 2023, 25, 343 10 of 21

Thus, we have defined as locally antifragile a situation in which, over a specific interval
[ a, b], either the expectation rises with the scale parameter of the probability distribution as
in Equation (A2), or the dose response is convex (on average) over the same range. The
designation in Taleb (2012) [1] meant to accurately describe such situations: anything that
gains from an increase in stochasticity or variability (since the scale parameter represents
both). Terms such as “resilience”, since they were not mapped mathematically, are vague
and even confusing as they meant either resistance or gains from stressors, depending on
context. Figures 7 and 8 illustrates the threshold effect of the asymmetric response, and
gives the intuition of how they can be described as as antifragile.

Figure 7. (A) How a fractional intervention is more effective to surpass a threshold than a constant
dosage of the same average. This is akin to stochastic resonance (in physics), by which the presence
of noise causes the signal to rise above the detection threshold. For instance, genetically modified BT
crops produce a constant level of pesticide, which appears to be much less effective than occasional
manual interventions to add doses to conventional plants. The same may apply to antibiotics,
chemotherapy, and radiation therapy [32]. (B) How more variance impacts the exceedance over the
threshold. If threshold ≥ mean, we have convexity, and the variance increases the payoff more than
variations in the mean. Such an effect is proportional to the remoteness of such threshold. Note that
the harm function is defined as positive.

Two distributions of the same mean

P>K
Intensity
0.15
Lower
PROBABILITY SPACE
variance

Higher 0.10
variance
(blue)
0.05

σ
0.5 1.0 1.5 2.0 2.5 3.0

Figure 8. (Left) A time series illustration of how a higher variance (hence scale), given the same mean,
allow more spikes, hence an antifragile effect. We have random paths of two gamma distributions
1
of the same mean, different variances, X1 ∼ G (1, 1) and X2 ∼ G ( 10 , 10), showing higher spikes
and maxima for X2 . The effect depends on the norm ||.||∞ , more sensitive to tail events, even more
than just the scale which is related to the norm ||.||2 . (Right) Representation of antifragility of (Left)
in distribution space: we show the probability of exceeding a certain threshold for a variable, as a
function of σ, the scale of the distribution, while keeping the mean constant.

3.5. The First-Order Sigmoid Curve

Next, we outline the variety of sigmoids as catalogued by [33]. Define the sigmoid or
sigmoidal function as having membership in a class of function S, S : R → [ L, H ], with
Entropy 2023, 25, 343 11 of 21

additional membership in the C2 class (twice differentiable), monotonic nonincreasing or

nondecreasing, that is let S0 ( x ) be the first derivative with respect to x: S0 ( x ) ≥ 0 for all x
or S0 ( x ) ≤ 0. Thus, we have:

as x → +∞;

H
S( x ) = ,
L if x → −∞.

which can of course be normalized with H = 1 and L = 0 if S is increasing, or vice versa,

or alternatively H = 0 and L = −1 if S is increasing. We can define the simple (or first-
order) sigmoid curve as having equal convexity in one portion and concavity in another:
∃k > 0 s.t. ∀ x1 < k and x2 > k, sgn(S00 ( x1 )) = −sgn(S00 ( x2 )) if |S00 ( x2 )| ≥ 0.
Now, all functions starting at zero will have three possible properties at inception, as
in Figures 9 and 10: concave, linear, and convex. The point of our discussion is the latter
becoming sigmoid. Although few medical examples appear, under scrutiny, to belong to
the first two cases, one cannot exclude them from analysis. We note that given that the
inception of these curves is zero, no linear combination can be initially convex unless the
curve is convex, which would not be the case if the start of the reaction is at a level different
from zero.

Figure 9. (A) Every (relatively) smooth dose response with a floor has to be initially convex, hence
prefers variations. (B) Every (relatively) smooth dose response with a ceiling has to be concave while
approaching the ceiling, hence prefers stability.

Response

At inception

1-concave

2-linear

3-convex

Dose

Figure 10. The three possibilities at inception.

There are many sub-classes of functions producing a sigmoidal effect. Examples

include:
• Pure sigmoids with smoothness characteristics expressed in trigonometric or exponen-
tial form, f : R → [0, 1]:
1  κx  1
f ( x ) = tanh +
2 π 2
Entropy 2023, 25, 343 12 of 21

1
f (x) =
1 − e− ax
• Gompertz functions (a vague classification that includes above curves but can also
mean special functions).
• Special functions with support in R such as the error function f : R → [0, 1]
 
1 x
f ( x ) = − erfc − √
2 2

• Special functions with support in [0, 1], such as f : [0, 1] → [0, 1]

f ( x ) = Ix ( a, b),

where I(.) (., .) is the beta regularized function.

• Special functions with support in [0, ∞)
 x
f ( x ) = Q a, 0,
b
where Q(., ., .) is the gamma regularized function.
• Piecewise sigmoids, such as the CDF of the Student distribution
  
1 α 1
 2 I 2α
 , x≤0
x +α 2 2 
f (x) =

 2 I x2 12 , α2 + 1
 1
x>0
x2 +α

We note that the “smoothing” of the step function, or Heaviside theta θ (.) produces a
sigmoid (in a situation of a
distribution or convoluted with a test function with compact
π + 2 , with κ → ∞, see Figure 3.
support), such as 12 tanh κx 1

3.6. Some Necessary Relations Leading to a Sigmoid Curve

Let f 1 ( x ) : R+ → [0, H ] , H ≥ 0, of class C2 be the first-order dose-response function,
satisfying f 1 (0) = 0, f 10 (0)| = 0, and limx→+∞ f 1 ( x ) = H, monotonic nondecreasing, that
is, f 10 ( x ) ≥ 0 ∀ x ∈ R+ , with a continuous second derivative, and analytic in the vicinity of
0. Then, we conjecture that:
A-There is a zone [0, b] in which f 1 ( x ) is convex, that is, f 100 ( x ) ≥ 0, with the implication
that ∀ a ≤ b a policy of variation of dosage produces beneficial effects:

α f 1 ( a) + (1 − α) f 1 (b) ≥ f 1 (αa + (1 − α)b), 0 ≤ α ≤ 1.

(The acute outperforms the chronic).

B-There is a zone [c, H ] in which f 1 ( x ) is concave, that is, f 100 ( x ) ≤ 0, with the implica-
tion that ∃d ≥ c a policy of stability of dosage produces beneficial effects:

α f 1 (c) + (1 − α) f 1 (d) ≤ f 1 (αc + (1 − α)d).

(The chronic outperforms the acute).

4. The Generalized Dose–Response Curve

Let S N ( x ): R → [k L , k R ], S N ∈ C ∞ be a continuous function possessing derivatives
(n)
SN


( x ) of all orders, expressed as an N-summed and scaled standard sigmoid function:
N
a
S N (x) , ∑ 1 + e(−kbk x+ck ) (14)
i =1

where ak , bk , ck are scaling constants ∈ R, satisfying:

Entropy 2023, 25, 343 13 of 21

1. S N (−∞) = k L , and
2. S N (+∞) = k R , and (equivalently for the first and last of the following conditions)
∂2 S N ∂2 S N ∂2 S N
3. ∂x2
≥ 0 for x ∈ (−∞, k1 ) , ∂x2
< 0 for x ∈ (k2 , k >2 ), and ∂x2
≥ 0 for x ∈ (k >2 , ∞),
with k1 > k2 ≥ . . . ≥ kN .
By increasing N, we can approximate a continuous function’s density in a metric space,
see Cybenko (1989) [34].
The shapes at different calibrations are shown in Figure 11, in which we combined
different values of N = 2 S2 ( x; a1 , a2 , b1 , b2 , c1 , c2 ), and the standard sigmoid S1 ( x; a1 , b1 , c1 ),
with a1 = 1, b1 = 1, and c1 = 0. As we can see, unlike the common sigmoid , the asymptotic
response can be lower than the maximum, as our curves are not monotonically increasing.
The sigmoid shows benefits increasing rapidly (the convex phase), then increasing at a
slower and slower rate until saturation. Our more general case starts by increasing, but the
reponse can actually be negative beyond the saturation phase, though in a convex manner.
Harm slows down and becomes “flat” when something is totally broken.

Figure 11. Generalizing the Dose–Response Curve, S2 ( x; a1 , a2 , b1 , b2 , c1 , c2 ), S1 ( x; a1 , b1 , c1 ) The con-

vex part in the increasing section is what we call “antifragile”.

Antifragility and Heterogeneity

Tumors are composed of a heterogeneous collection of subpopulations with varied
treatment sensitivity. Given N non-interacting populations, the fragility of the total popula-
tion is given by the sum of each subpopulation i’s fragility, Fi , weighted by its frequency
within the total population, wi , such that ∑i wi = 1.

N
F ( x̄, σ ) = ∑ wi Fi (x̄, σ) (15)
i

where fragility Fi for a single population is given by Equation (1).

The simplest case of a heterogeneous mixture of two populations, sensitive (with
associated dose response H1 ( x )) and resistant (H2 ( x )), is shown in Figure 12A. In the case
that each dose response, Hi , is non-increasing, then the mixed dose response will also be
non-increasing, but changes in convexity may occur. As seen in Figure 12A, the mixed
dose response has an internal plateau (shown for w = 0.5). Local convexity (fragility) may
switch signs multiple times.
Entropy 2023, 25, 343 14 of 21

Figure 12. Relationship between convexity and mixed, heterogeneous populations. (A) Dose response
shown for sensitive (green) and resistant (red) cell lines. When mixed, dose response is a weighted
average of each (Equation 15; black). (B) Fragility shown for sensitive (green) and resistant (red) cell
lines. When mixed, fragility (black) switches from locally convex to locally concave multiple times.

5. Nonlinearities and Medical Iatrogenics

Next, we connect nonlinearity to iatrogenics (that is, harm done by the healer) for
medicine in general, broadly defined as all manner of net deficit of benefits minus harm
from a given intervention.
The Taleb and Douady (2013) [2] theorems state:
• Convexity for a dose-response function increases fragility (from the expansion of the
left tail in response to the increase in the scale of the distribution).
• Detection of a nonlinearity allows the prediction of fragility and helps formulate
probabilistic decisions without much knowledge of the probability distribution beyond
minimum standard attributes.
• The presence of concavity in the tails of the distribution implies a silent risk.
This approach was used in stress testing by the International Monetary Fund (IMF),
where the degree of concavity in the tail was used as an indicator of the severity of tail
exposure, see Taleb, Canetti et al. [35]. Such a method can transfer to medicine as the
convexity of the dose response can be estimated via titration applied to Equation (1).

5.1. Effect Reversal

Radiation might be beneficial in small doses, with reversal later on. In Neumaier
et al. (2012) [36] titled “Evidence for formation of DNA repair centers and dose-response
nonlinearity in human cells”:

The standard model currently in use applies a linear scale, extrapolating cancer
risk from high doses to low doses of ionizing radiation. However, our discovery
of DSB clustering over such large distances casts considerable doubts on the
general assumption that risk to ionizing radiation is proportional to dose, and
instead provides a mechanism that could more accurately address risk dose
dependency of ionizing radiation.

Therefore, low-level radiation may cause hormetic overreaction, producing protective

effects. Also see Tubiana et al. (2005) [37]. Bharadwaj and Stafford (2010) present similar
general sigmoidal effects in hormonal disruptions by chemicals [38].
Entropy 2023, 25, 343 15 of 21

5.2. Nonlinearity of NNT and the Consequences

Below are applications of convexity analysis in decision-making in dosage, shown
in Figures 13 and 14. In short, it is fallacious to translate a policy derived from acute
conditions and apply it to milder ones. Mild conditions are different in treatment from an
acute ones. Likewise, high risk is qualitatively different from mild risk.

Severity

Treatment
breakeven

Iatrogenics

Tumor Size

Figure 13. Drug benefits when convex to numbers needed to treat (NNT) in the left part, with gross
iatrogenics invariant to condition (the constant line). We are assuming a standard sigmoidal benefit
function.

PDF

Benefits

Noise

Iatrogenics

Response

Figure 14. Unseen risks and mild gains: translation of Figure 13 into a probabilistic representation,
showing to the skewness of a decision involving iatrogenics when the condition is mild. This also
gives the intuition of the Taleb and Douady [2] translation theorems from concavity for S( x ) into
probabilistic attributes.

There is active literature on “overdiagnosis”, see Kalager et al. (2012) [39] and Morell
et al. (2012) [40]. The point is that treating a tumor that does not kill reduces life expectancy;
hence the need to balance iatrogenics and risk of cancer. An application of nonlinearity can
shed some light on the approach and clarify the public debate [1].
In a similar spirit of avoiding over-treatment, adaptive therapy in metastatic castrate-
resistant prostate cancer (clinical trial NCT02415621) has illustrated the feasibility of ir-
regular treatment protocols based on algorithms that react to tumor response. Adaptive
treatment protocols maintain a stable population of sensitive cells in order to suppress the
emergence of resistance [41,42]. Resistance, in some cases, is similar to the irreconcilable
ruin of a financial “blowup” as patients may develop multi-drug resistance to structurally
or functionally different drugs. The irreversibility of such clinical outcomes is similar to
that of financial ruin, a tail fragility situation from which the agent cannot exit. Adaptive al-
gorithms decrease the cumulative dose administered to a patient, lessening the selection for
resistance [43]. While it is not an explicitly stated goal of adaptive therapy, these schedules
increase both intra- and inter-patient dosing variance [44].
Entropy 2023, 25, 343 16 of 21

Last year (2022) saw the publication of calls from within the FDA to revamp the
dose-finding protocols to be suitable for targeted therapies [45]. Traditional dose selection
protocols invented for use with cytotoxic chemotherapies may not apply to targeted ther-
apies that have exposure–response curves which plateau at low toxicities to the patient.
Differences in convexity between chemotherapies and newly developed targeted therapies
lead to differing outcomes in diminished returns of dose escalation and differing curvature
of dose–response curves.

Author Contributions: N.N.T. and J.W. contributed equally to this work. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not Applicable.
Data Availability Statement: Not Applicable.
Acknowledgments: Yaneer Bar Yam and participants in the International Conference On Complex
Systems, Boston, 2018, where early ideas leading to this paper were presented [33] (synthesized in
the appendices), as well as Luke Pierik, Sandy Anderson, Maximilian Strobl, and Andriy Marusyk.
Conflicts of Interest: The authors declare no conflicts of interest.

Appendix A. Antifragility Indirectly Detected in the Various Literature

Table A1 reviews the medical literature on embedded antifragility, defined as indirectly
producing evidence of benefits from the “disorder cluster”.

Table A1. Review of medical research on embedded antifragility

Field Papers
Kaiser (2003) [16] , Rattan (2008) [46], Calabrese and Baldwin
Mithridatization and hormesis
(2002, 2003a, 2003b) [17,47,48], Aruguman et al. (2006) [49].
Caloric restriction and hormesis Martin, Mattson et al. (2006) [12]
Longo et al. (2010) [50], Safdie et al. (2009) [51], Raffaghelo et al.
Cancer treatment and fasting
(2010), [52], Lee et al. (2012) [53]
Aging and intermittence Fontana et al. [54]
Anson, Guo, et al. (2003) [55], Halagappa, Guo, et al. (2007) [56],
Stranahan and Mattson (2012) [57]. The long-held belief that the
For brain effects
brain needed glucose, not ketones, and that the brain does not
go through autophagy, has been progressively replaced.
Fabrizio et al. (2001) [58]; SIRT1, Longo et al. (2006) [59],
Yeast and longevity under restriction
Michan et al. (2010) [60]
Taylor (2008) [61], Lim et al. (2011) [62], Boucher et al.
(2004) [63]; diabetes management by diet alone, early insights in
Wilson et al. (1980) [64]. Couzin (2008) [65] gives insight that
blood sugar stabilization does not have the effect anticipated
(there need to be stressors). The ACCORD study (Action to
Diabetes, remission or reversal Control Cardiovascular Risk in Diabetes) found no benefits
from lowering blood glucose levels. Synthesis, Skyler et al.
(2009) [66], old methods, Westman and Vernon (2008) [67].
Bariatric (or other) surgery as alternative to intermittent fasting:
Pories (1995) [68], Guidone et al. (2006) [69],
Rubino et al. 2006 [70]
Entropy 2023, 25, 343 17 of 21

Table A1. Cont.

Field Papers
Trabelsi et al. (2012) [71], Akanji et al. (2012). Note that the
Ramadan time window is short (12 to 17 h) and possibly fraught
Ramadan and effect of fasting with overeating so conclusions need to take into account energy
balance and that the considered effect is at the low-frequency
part of the timescale.
Caloric restriction Harrison (1984), Wiendruch (1996), Pischon (2008)
Autophagy for cancer Kondo et al. (2005) [72]
Autophagy (general) Danchin et al. (2011) [73], He et al. (2012) [74]
Fractional dosage Wu et al. (2016) [75]
Many such as Schnohr and Marott (2011) [76], intermittent
Jensen’s inequality in exercise
extremes vs. moderate physical activity.
Yaffe and Blackwell (2004) [77], Alzheimer and
hyperinsulenemia, Razay and Wilcock (1994) [78]; Luchsinger,
Cluster of ailments
Tang, et al. (2002) [79], Luchsinger Tang et al. (2004) [80] Janson,
Laedtke, et al. (2004) [81].
For the different results from the two types of stressors, short
and chronic, Dhabar (2009) “A hassle a day may keep the
pathogens away: the fight-or-flight stress response and the
Benefits of some type of stress (and convexity of the effect) augmentation of immune function” [82]. For the benefits of
stress on boosting immunity and cancer resistance (squamous
cell carcinoma), Dhabhar et al. (2010) [83],
Dhabhar et al. (2012) [84], Ansbacher et al. (2013) [85]
Rook (2011) [86], Rook (2012) [87] (auto-immune diseases from
Iatrogenics of hygiene and systematic elimination of germs absence of stressors), Mégraud and Lamouliatte (1992) [88] for
Helyobacter Pilori and incidence of cancer.

Appendix B. Simple Convexity and Its Effects

To eliminate ambiguity, let us define convexity. Let f (.) be the response function, and
f : R+ → R be a twice-differentiable function. If, over a range x ∈ [ a, b], over a set time
∂2 f ( x )
period ∆t, ∂x2 ≥ 0, or more practically (by relaxing the assumptions of differentiability),
2 ( f ( x + ∆x ) + f ( x − ∆x )) ≥ f ( x ), with x + ∆x and x − ∆x ∈ [ a, b ], then there are benefits
1

or harm from the unevenness of distribution, depending on whether f is defined as positive

or favorable or modeled as a harm function (in which case one needs to reverse the sign for
the interpretation).
We can generalize to comparing linear combinations: ∑ αi = 1, 0 ≤ |αi | ≤ 1,
∑ i f ( xi )) ≥ f (∑(αi xi )); thus, we have situations where, for x ≤ b − ∆ and n ∈ N,
( α
f (nx ) ≥ n f ( x ). This last property describes a “stressor” as having higher intensity than
zero: there may be no harm from f ( x ), yet there will be some at higher levels of x.
Now, if X is a random variable with support in [ a, b] and f is convex over the interval
as per above, then
E( f ( x )) ≥ f (E( x )), (A1)
which is commonly known as Jensen’s inequality, see Jensen(1906) [89], Figure 4. Further
(without loss of generality), if its continuous distribution with density ϕ( x ) and support
in [ a, b] belongs to the location scale family distribution, with ϕ( σx ) = σϕ( x ) and σ > 0,
then, with Eσ , the indexing representing the expectation under a probability distribution
indexed by the scale σ, we have:

∀σ2 > σ1 , Eσ2 ( f ( x )) ≥ Eσ1 ( f ( x )) (A2)

Entropy 2023, 25, 343 18 of 21

The last property implies that the convexity effect increases the expectation operator. We
R f (b) φ( f (−1) (y))
can verify that since f (a) y 0 (−1) dy is an increasing function of σ. A more simple
f (f (y))
approach (inspired by mathematical finance heuristics) is to consider 0 ≤ δ1 ≤ δ2 ≤ b − a,
where δ1 and δ2 are the mean expected deviations or, alternatively, the results of a simplified
two-state system, each with probability 12 :

f ( x − δ2 ) + f ( x + δ2 ) f ( x − δ1 ) + f ( x + δ1 )
≥ ≥ f (x) (A3)
2 2
This is, of course, a simplification here, since dose response is rarely monotone in its
nonlinearity, as we will see in later sections. However, we can at least make claims in a
certain interval [ a, b] and it can produce useful heuristics.
What are we measuring? Clearly, the dose (represented on the x line) is hardly
ambiguous: any measurable quantity can suffice, such as systolic blood pressure, ejection
fraction, caloric deficit, pounds per square inch, temperature, etc. The response, harm
or benefits, f ( x ), on the other hand, need to be equally precise, with nothing vague,
such as hazard ratios, some quantifiable index of health, median life expectancy, and
similar quantities. If one cannot express the response quantitatively, then such an analysis
cannot apply.

Appendix C. Relaxing the Assumption of Fixed Treatment Schedules

We can relax the assumption of fixed treatment schedules (e.g., Figure 4). Given some
input probability density function describing the distribution of dose, p( x ), the probability
density can be determined for the Hill function analytically. Let X (dose concentration)
and Y = H ( X ) be random variables. The probability density function transformation,
P(y( a) ≤ Y < y(b)), is given by:
Z b Z f (b)
dx
P = p( x )dx = p( x (y)) dy (A4)
a y( a) dy
Z b  −1 !  −(n+1)
E1 − E0 C ( E1 − E0 ) E0 − E1
  
n n
= p C −1 dy (A5)
a y − E0 n( E0 − y)2 E0 − y

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