 # Time-lagged conversion rates and cure models¶

Suppose in our population we have a subpopulation that will never experience the event of interest. Or, for some subjects the event will occur so far in the future that it’s essentially at time infinity. The survival function should not asymptically approach zero, but some positive value. Models that describe this are sometimes called cure models or time-lagged conversion models.

There’s a serious fault in using parametric models for these types of problems that non-parametric models don’t have. The most common parametric models like Weibull, Log-Normal, etc. all have strictly increasing cumulative hazard functions, which means the corresponding survival function will always converge to 0.

Let’s look at an example of this problem. Below I generated some data that has individuals who will not experience the event, not matter how long we wait.

:

%matplotlib inline
%config InlineBackend.figure_format = 'retina'

from matplotlib import pyplot as plt
import pandas as pd
plt.style.use('bmh')


:

N = 200
U = np.random.rand(N)
T = -(logit(-np.log(U) / 0.5) - np.random.exponential(2, N) - 6.00) / 0.50

E = ~np.isnan(T)
T[np.isnan(T)] = 50

:

from lifelines import KaplanMeierFitter
kmf = KaplanMeierFitter().fit(T, E)
kmf.plot(figsize=(8,4))
plt.ylim(0, 1);


It should be clear that there is an asymptote at around 0.6. The non-parametric model will always show this. If this is true, then the cumulative hazard function should have a horizontal asymptote as well. Let’s use the Nelson-Aalen model to see this.

:

from lifelines import NelsonAalenFitter

naf = NelsonAalenFitter().fit(T, E)
naf.plot(figsize=(8,4))

:

<matplotlib.axes._subplots.AxesSubplot at 0x1211ac7b8>


However, when we try a parametric model, we will see that it won’t extrapolate very well. Let’s use the flexible two parameter LogLogisticFitter model.

:

from lifelines import LogLogisticFitter

fig, ax = plt.subplots(nrows=2, ncols=2, figsize=(10, 6))

t = np.linspace(0, 40)
llf = LogLogisticFitter().fit(T, E, timeline=t)

llf.plot_survival_function(ax=ax)
kmf.plot(ax=ax)

llf.plot_cumulative_hazard(ax=ax)
naf.plot(ax=ax)

t = np.linspace(0, 100)
llf = LogLogisticFitter().fit(T, E, timeline=t)

llf.plot_survival_function(ax=ax)
kmf.plot(ax=ax)

llf.plot_cumulative_hazard(ax=ax)
naf.plot(ax=ax)

:

<matplotlib.axes._subplots.AxesSubplot at 0x12199d518>


The LogLogistic model does a quite terrible job of capturing the not only the asymptotes, but also the intermediate values as well. If we extended the survival function out further, we would see that it eventually nears 0.

## Custom parametric models to handle asymptotes¶

Focusing on modeling the cumulative hazard function, what we would like is a function that increases up to a limit and then tapers off to an asymptote. We can think long and hard about these (I did), but there’s a family of functions that have this property that we are very familiar with: cumulative distribution functions! By their nature, they will asympotically approach 1. And, they are readily available in the SciPy and autograd libraries. So our new model of the cumulative hazard function is:

$H(t; c, \theta) = c F(t; \theta)$

where $$c$$ is the (unknown) horizontal asymptote, and $$\theta$$ is a vector of (unknown) parameters for the CDF, $$F$$.

We can create a custom cumulative hazard model using ParametericUnivariateFitter (for a tutorial on how to create custom models, see this here). Let’s choose the Normal CDF for our model.

Remember we must use the imports from autograd for this, i.e. from autograd.scipy.stats import norm.

:

from autograd.scipy.stats import norm
from lifelines.fitters import ParametericUnivariateFitter

class UpperAsymptoteFitter(ParametericUnivariateFitter):

_fitted_parameter_names = ["c_", "mu_", "sigma_"]

_bounds = ((0, None), (None, None), (0, None))

def _cumulative_hazard(self, params, times):
c, mu, sigma = params
return c * norm.cdf((times - mu) / sigma, loc=0, scale=1)

:

uaf = UpperAsymptoteFitter().fit(T, E)
uaf.print_summary(3)
uaf.plot(figsize=(8,4))

<lifelines.UpperAsymptoteFitter: fitted with 200 observations, 119 censored>
number of subjects = 200
number of events = 81
log-likelihood = -386.053
hypothesis = c_ != 1, mu_ != 0, sigma_ != 1

---
coef  se(coef)  lower 0.95  upper 0.95       p  -log2(p)
c_      0.521     0.059       0.406       0.636 <0.0005    51.753
mu_    17.514     0.608      16.322      18.705 <0.0005   603.894
sigma_  5.398     0.425       4.564       6.232 <0.0005    80.823

:

<matplotlib.axes._subplots.AxesSubplot at 0x122376f28>


We get a lovely asympotical cumulative hazard. The summary table suggests that the best value of $$c$$ is 0.586. This can be translated into the survival function asymptote by $$\exp(-0.586) \approx 0.56$$.

Let’s compare this fit to the non-parametric models.

:

fig, ax = plt.subplots(nrows=2, ncols=2, figsize=(10, 6))

t = np.linspace(0, 40)
uaf = UpperAsymptoteFitter().fit(T, E, timeline=t)

uaf.plot_survival_function(ax=ax)
kmf.plot(ax=ax)

uaf.plot_cumulative_hazard(ax=ax)
naf.plot(ax=ax)

t = np.linspace(0, 100)
uaf = UpperAsymptoteFitter().fit(T, E, timeline=t)
uaf.plot_survival_function(ax=ax)
kmf.survival_function_.plot(ax=ax)

uaf.plot_cumulative_hazard(ax=ax)
naf.plot(ax=ax)

:

<matplotlib.axes._subplots.AxesSubplot at 0x121109438>


I wasn’t expect this good of a fit. But there it is. This was some artificial data, but let’s try this technique on some real life data.

:

from lifelines.datasets import load_leukemia, load_kidney_transplant

uaf.fit(T, E)
ax = uaf.plot_survival_function(figsize=(8,4))
uaf.print_summary()

kmf.fit(T, E).plot(ax=ax, ci_show=False)
print("---")
print("Estimated lower bound: {:.2f} ({:.2f}, {:.2f})".format(
np.exp(-uaf.summary.loc['c_', 'coef']),
np.exp(-uaf.summary.loc['c_', 'upper 0.95']),
np.exp(-uaf.summary.loc['c_', 'lower 0.95']),
)
)

<lifelines.UpperAsymptoteFitter: fitted with 42 observations, 12 censored>
number of subjects = 42
number of events = 30
log-likelihood = -118.60
hypothesis = c_ != 1, mu_ != 0, sigma_ != 1

---
coef  se(coef)  lower 0.95  upper 0.95      p  -log2(p)
c_      1.63      0.36        0.94        2.33   0.07      3.75
mu_    13.44      1.73       10.06       16.82 <0.005     47.07
sigma_  7.03      1.07        4.94        9.12 <0.005     25.91
---
Estimated lower bound: 0.20 (0.10, 0.39)


So we might expect that about 20% will not have the even in this population (but make note of the large CI bounds too!)

:

# Another, less obvious, dataset.

uaf.fit(T, E)
ax = uaf.plot_survival_function(figsize=(8,4))
uaf.print_summary()

kmf.fit(T, E).plot(ax=ax)
print("---")
print("Estimated lower bound: {:.2f} ({:.2f}, {:.2f})".format(
np.exp(-uaf.summary.loc['c_', 'coef']),
np.exp(-uaf.summary.loc['c_', 'upper 0.95']),
np.exp(-uaf.summary.loc['c_', 'lower 0.95']),
)
)

<lifelines.UpperAsymptoteFitter: fitted with 863 observations, 723 censored>
number of subjects = 863
number of events = 140
log-likelihood = -1458.88
hypothesis = c_ != 1, mu_ != 0, sigma_ != 1

---
coef  se(coef)  lower 0.95  upper 0.95      p  -log2(p)
c_        0.29      0.03        0.24        0.35 <0.005    433.78
mu_    1139.66    101.52      940.68     1338.63 <0.005     94.73
sigma_  872.26     66.24      742.44     1002.08 <0.005    128.86
---
Estimated lower bound: 0.75 (0.70, 0.79)


### Using alternative functional forms¶

An even simplier model might look like $$c \left(1 - \frac{1}{\lambda t + 1}\right)$$, however this model cannot handle any “inflection points” like our artificial dataset has above. However, it works well for this Lung dataset.

With all cure models, one important feature is the ability to extrapolate to unforseen times.

:

from autograd.scipy.stats import norm
from lifelines.fitters import ParametericUnivariateFitter

class SimpleUpperAsymptoteFitter(ParametericUnivariateFitter):

_fitted_parameter_names = ["c_", "lambda_"]

_bounds = ((0, None), (0, None))

def _cumulative_hazard(self, params, times):
c, lambda_ = params
return c * (1 -  1 /(lambda_ * times + 1))

:

# Another, less obvious, dataset.

saf = SimpleUpperAsymptoteFitter().fit(T, E, timeline=np.arange(1, 10000))
ax = saf.plot_survival_function(figsize=(8,4))
saf.print_summary(4)

kmf.fit(T, E).plot(ax=ax)
print("---")
print("Estimated lower bound: {:.2f} ({:.2f}, {:.2f})".format(
np.exp(-saf.summary.loc['c_', 'coef']),
np.exp(-saf.summary.loc['c_', 'upper 0.95']),
np.exp(-saf.summary.loc['c_', 'lower 0.95']),
)
)

<lifelines.SimpleUpperAsymptoteFitter: fitted with 863 observations, 723 censored>
number of subjects = 863
number of events = 140
log-likelihood = -1392.1610
hypothesis = c_ != 1, lambda_ != 1

---
coef  se(coef)  lower 0.95  upper 0.95      p  -log2(p)
c_      0.4252    0.0717      0.2847      0.5658 <5e-05   49.6941
lambda_ 0.0006    0.0002      0.0003      0.0009 <5e-05       inf
---
Estimated lower bound: 0.65 (0.57, 0.75)

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