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The Actor Search Tree Critic (ASTC) for Off-Policy POMDP Learning in Medical Decision Making

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Off-policy reinforcement learning enables near-optimal policy from suboptimal experience, thereby provisions opportunity for artificial intelligence applications in healthcare. Previous works have mainly framed patient-clinician interactions as Markov decision processes, while true physiological states are not necessarily fully observable from clinical data. We capture this situation with partially observable Markov decision process, in which an agent optimises its actions in a belief represented as a distribution of patient states inferred from individual history trajectories. A Gaussian mixture model is fitted for the observed data. Moreover, we take into account the fact that nuance in pharmaceutical dosage could presumably result in significantly different effect by modelling a continuous policy through a Gaussian approximator directly in the policy space, i.e. the actor. To address the challenge of infinite number of possible belief states which renders exact value iteration intractable, we evaluate and plan for only every encountered belief, through heuristic search tree by tightly maintaining lower and upper bounds of the true value of belief. We further resort to function approximations to update value bounds estimation, i.e. the critic, so that the tree search can be improved through more compact bounds at the fringe nodes that will be back-propagated to the root. Both actor and critic parameters are learned via gradient-based approaches. Our proposed policy trained from real intensive care unit data is capable of dictating dosing on vasopressors and intravenous fluids for sepsis patients that lead to the best patient outcomes.
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The Actor Search Tree Critic (ASTC) for Off-Policy
POMDP Learning in Medical Decision Making
Luchen Li
Imperial College London
Matthieu Komorowski
Imperial College London
A. Aldo Faisal
Imperial College London
Off-policy reinforcement learning enables near-optimal policy from suboptimal
experience, thereby provisions opportunity for artificial intelligence applications in
healthcare. Previous works have mainly framed patient-clinician interactions as
Markov decision processes, while true physiological states are not necessarily fully
observable from clinical data. We capture this situation with partially observable
Markov decision process, in which an agent optimises its actions in a belief
represented as a distribution of patient states inferred from individual history
trajectories. A Gaussian mixture model is fitted for the observed data. Moreover, we
take into account the fact that nuance in pharmaceutical dosage could presumably
result in significantly different effect by modelling a continuous policy through
a Gaussian approximator directly in the policy space, i.e. the actor. To address
the challenge of infinite number of possible belief states which renders exact
value iteration intractable, we evaluate and plan for only every encountered belief,
through heuristic search tree by tightly maintaining lower and upper bounds of the
true value of belief. We further resort to function approximations to update value
bounds estimation, i.e. the critic, so that the tree search can be improved through
more compact bounds at the fringe nodes that will be back-propagated to the root.
Both actor and critic parameters are learned via gradient-based approaches. Our
proposed policy trained from real intensive care unit data is capable of dictating
dosing on vasopressors and intravenous fluids for sepsis patients that lead to the
best patient outcomes.
1 Introduction
Many recent examples [
] have demonstrated that machine learning can deliver above-human
performance in classification-based diagnostics. However, key to medicine is diagnosis paired with
treatment, i.e. the sequential decisions that have to be made by clinician for patient treatment.
Automatic treatment optimisation based on reinforcement learning has been explored in simulated
patients for HIV therapy [
] using fitted-Q iteration, dynamic insulin dosage in diabetes using
model-based reinforcement learning [5], and anaesthesia depth control using actor-critic [6].
We focus on principled closed-loop approaches to learn a near-optimal treatment policy from vast
electronic healthcare records (EHRs). Previous works mainly modelled this problem as a Markov
decision process (MDP) and learned a policy of actions
π(a|s) = P(a|s)
based on estimated values
of possible actions
in each state
. [
] investigated fitted Q-iteration with linear function
approximation to optimise treatment of schizophrenia. [
] compared different supervised learning
methods to approximate action values, including neural networks, and successfully predicted the
weaning of mechanical ventilation and sedation dosages. In addition to crafting a reward function that
reflects domain knowledge, another avenue explored inverse reinforcement learning to recover one
from expert behaviours. For example, [
] proposed hemoglobin-A1c dosages for diabetes patients by
Preprint. Work in progress.
arXiv:1805.11548v3 [cs.AI] 3 Jun 2018
implementing Markov chain Monte Carlo sampling to infer posterior distribution over rewards given
observed states and actions. Further, multiple objective optimal treatments were explored [
] with
non-deterministic fitted-Q to provide guidelines on antipsychotic drug treatments for schizophrenia
patients. [
] inferred hidden states via discriminative hidden Markov model, and investigated a
Deep-fitted Q variant to learn heparin dosages to manage thrombosis.
However, the true physiological state of the patient is not necessarily fully observable by clinical
measurement techniques. Practically, this observability is further restricted by the actual subset of
measures taken in hospital, restricting both the nature and frequency of data recorded and omitting
information readily visible to the clinician . Those latencies are especially salient in intensive care
units (ICUs). Strictly speaking, the decision making process acting on the patient state therefore
should be mathematically formulated as a partially observable MDP (POMDP). Consequently, the
true patient state is latent and thus the patient’s physiological belief state
can only be represented as
a probability distribution of the states given the history of observations and actions. Exhaustive and
exact POMDP solutions are computationally intractable because belief states constitute a continuous
hyperplane that contains infinite possibilities. We alleviate this obstruct by evaluating the sequentially
encountered belief states through learning both upper and lower bounds of their true values and
exploring reachable sequences using heuristic search trees to obtain locally optimal value estimates
. The learning of value bounds in the tree search is conferred via keeping back-propagating that
of newly expanded nodes to the root, which are usually computed offline and remain static. We model
the lower and upper value bounds as function approximators so that the tree search can be improved
through more accurate value bounds at the fringe nodes as we process the incoming data. Moreover,
to realise continuous action spaces (e.g. milliliter of medicine dripped per hour) we explicitly use
a continuous policy implemented through function approximation. We embed these features in an
actor-critic framework to update the parameters of the policy (the actor) and the value bounds (the
critic) via gradient-based methods.
2 Preliminaries
A POMDP framework can be represented by the tuple
{S,A,O,T,,R, γ , b0}
], where
is the state space,
the action space,
the observation space,
the stochastic
state transition function:
T(s0, s, a) = P(st+1 =s0|st=s, at=a)
the stochastic observation
Ω(o, s, a) = P(ot+1 =o|st+1 =s, at=a)
the immediate reward function:
R(s, a)
the discount factor indicating the weighing of present value of future rewards, and
b0the agent’s initial knowledge before receiving any information.
h= 0
h= 1
h= 2
h= 3
5 6
12 13
9 10
3 4
5 6
14 15
17 18 19
12 13
9 10
3 4
5 6
14 15
17 18 19
20 21 22
23 24 25
9 10
3 4
5 6
14 15
17 18 19
12 13
9 10
20 21 22
3 4
Fig. 1. (left)
Graphical model of POMDP.
Tree search. Each circle node represents a belief
state, each dotted node an action-belief-state pair. (a) select the best fringe node to expand; (b) expand
the selected node by choosing the action with the maximal upper value bound and considering all
possible observations, and back-propagate value bounds through all its ancestors to the root; (c) no
revision is required for previous choices on actions, expand the next best fringe node; (d) a previous
action choice (example is showing in horizon 1) is no longer optimal after the latest expansion, the
new optimal action is selected.
The agent’s belief state is represented by the probability distribution over states given historical
observations and actions,
bt(s) = P(s|b0, o1, a1, ..., at1, ot)
. Executing
in belief
and receiving
observation o, the new belief is updated through:
b0(s0) = τ(b, a, o) = ηΩ(o, s0, a)X
T(s0, s, a)b(s)(1)
where η=1
P(o|b,a)is a normalisation constant, and
P(o|b, a) = X
Ω(o, s0, a)X
T(s0, s, a)b(s)(2)
The optimal policy
P(a|b) = π(a|b)
specifies the best action to select in a belief, its value function
being updated via the fixed point of Bellman equation [13]:
v(b) = max
a∈A "RB(b, a) + γX
P(o|b, a)v(τ(b, a, o))#(3)
RB(b, a) = Ps∈S R(s, a)b(s)
is the probability-weighted immediate reward. Graphical model of a
fraction of POMDP framework is shown in Fig. 1 (left).
Continuous Control
Policy gradient method can go beyond the limit of a finite action space and
achieve continuous control. Instead of choosing actions based on action-value estimates, a policy
is directly optimised in the policy space. Our policy
π(a|s, u) = Factor(x(s),u)
is a function of
state feature vector
parameterised by weight vector
. The objective function measuring the
performance of policy
is defined as the value, or expected total rewards from future, of the start
J(π) = Eπ[G0|s0] = Eπ"T1
is the return
k=0 γkrt+k
t= 0
. According to policy gradient theorem [
the gradient of Jw.r.t. uis:
uJ(π) = 1X
qπ(st, a)uπ(a|st,ut) = EπGt
denotes the stationary distribution of states under policy
(i.e. the chance a state will
be visited within an episode).
qπ(st, at) = Eπ[Gt|st, at]
is the value of
in state
subsequently be updated through gradient ascent in the direction (with step size
) that maximally
increases J:
ut+1 =ut+αGt
3 Methodology
In this section, we introduce how our algorithm combines tree search with policy gradient/function
approximations to realise both continuous action space and efficient online planning for POMDP. We
will derive the components of our algorithm as we go along this section and provide an overview
flowchart in Fig. 2.
Heuristic Search in POMDPs
The complexity of solving POMDPs is mainly due to the curse of
dimensionality: a belief state in an
space is an
(|S| − 1)
-dimensional continuous simplex, with all
its elements sum to one, and curse of history, as it acknowledges previous observations and actions,
the combination of which grows exponentially with the planning horizon [
]. Exact value iteration
for Eq. 3 in conventional reinforcement learning is therfore computationally intractable.
The optimal value function
of a finite-horizon POMDP is piecewise linear and convex in the
belief state [
], represented by a set of
-dimensional convex hyperplanes, whose total amount
1uJ(π) = Ps∈S Pstat
π(s)Pa∈A qπ(st, a)uπ(a|st,ut) = EπPa∈A qπ(st, a)uπ(a|st,ut)=
EπhPa∈A π(a|st,ut)qπ(st, a)uπ(a|st,ut)
π(a|st,ut)i=Eπhqπ(st, at)uπ(at|st,ut)
grows exponentially. Most exhaustive algorithms for POMDPs are dedicated to learning either lower
bound [
] or upper bound [
] of
by maintaining a subset of the aforementioned
hyperplanes. Tree-search based solutions usually prunes away less likely observations or actions
[20, 21, 22], or expanding fringe nodes according to a predefined heuristic [23, 24, 25].
Our methodology is compatible with any tree-search based POMDP solution. Here we implement
on a heuristic tree search introduced in [
] to focus computations on every encountered belief (i.e.
plan at decision time) and explore only reachable sequences. Specifically, a search tree rooted at
the current belief
is built, whose value estimate is confined by its lower bound
ˆvL(bcurr )
upper bound
ˆvU(bcurr )
that after each step of look-ahead become tighter to the true optimal value
v(bcurr )
. Here we use subscript on the belief state to denote its temporal position within the episode
in environmental experience, and superscript the horizon explored for it in the tree search (analogous
for observation and action). At each update during exploration, only the fringe node that leads to the
maximum error on the root b0
curr is expanded:
curr = arg max
curr , h∈{0,...,H}"γhˆvU(bh
curr )ˆvL(bh
curr )
curr |bi
curr , ai
curr )πτ(ai
curr |bi
curr )#
is the maximum horizon explored so far,
curr )ˆvL(bh
curr )
the error on the fringe
i=0 P(oi
curr |bi
curr , ai
curr )πτ(ai
curr |bi
curr )
the probability of reaching it from the root, and
the time discount (Fig. 1 (right) (a)). Once a node is expanded, the estimates of value bounds of
all its ancestors are updated in a bottom-up fashion analogous to equation Eq. 3, substituting
as appropriate, to the root (Fig. 1 (right) (b)), and previous choices on actions in expanded
belief nodes along the path are revised (Fig. 1 (right) (c-d)) to ensure that the optimal action
curr for h∈ {0, ..., H }is always explored based on current estimates.
curr = arg max
a∈A "RB(bi
curr , a) + γX
curr , avUτ(bi
curr , a, o)#(8)
Eq. 8 is the deterministic tree policy
that guides exploration within the tree. Each expansion
leads to more compact value bounds at the root. Tree exploration is terminated when the interval
between the value bounds estimates at the root belief changes trivially or a time limit is reached.
Gaussian States
Observed patient information is modelled as a Gaussian mixture, each observation
being generated from one of a finite set of Gaussian distributions that represent genuine physiological
states. The total number of latent states is decided by Bayesian information criterion [
] through
cross-validation using the development set. The terminal state is observable and corresponds either
patient discharge or death. Eq. 1 can be further expressed as:
b0(s0) = ηPa(s0|o)Pa(o)
Ta(s0, s)b(s) = η0Pa(s0|o)
Ta(s0, s)b(s)(9)
The superscript
denotes a subset divided from the data according to the action taken during this
. The division into subsets enables parallel computations.
is the posterior
distribution of s0when observing ospeculated from the trained Gaussian mixture model.
The transition function
Ta(s0, s)
is learned by maximum a posteriori [
] to allow possibilities for
transitions that did not occur in the development dataset.
Prior knowledge on transitions is modelled by Griffiths-Engen-McCloskey (GEM) distributions
] according to relative Euclidean distances between state centroids, whose elements, if sorted,
decrease exponentially and sum to one, to reflect higher probabilities of transiting into similar states.
Specifically, a GEM distribution is defined by a discount parameter
and a concentration parameter
In our implementation,
a∈ A
are globally computed as
P(s0|o)o∈ O
, regardless of the
action leading to it, because the impact of the observation on the distribution of states is significantly more
substantial than the action administered.
, and can be explained by a stick-breaking construction: break a stick for the
-th time into two
parts, whose length proportions conform to a Beta distribution:
VkBeta(1 c1, c2+kc1),0c1<1, c2>c1(10)
Then the length proportions of the off-broken parts in the whole stick are:
pk=V1, k = 1
(1 V1)(1 V2)...(1 Vk1)Vk, k = 2,3, ... (11)
The probability vector
consisting of elements calculated from Eq. 11 constitutes a GEM distribution.
Including to Eq. 5 a baseline term
as a comparison with
reduces variance in gradient estimates without changing equality
. This baseline is required to
discern states, a natural candidate would be the state value or its parametric approximation
ˆv(s, w) =
Fcritic(x(s),w). Then Eq. 6 becomes:
ut+1 =ut+α[Gtˆv(st,wt)] uπ(at|st,ut)
The parametric policy
π(a|s, u)
is called the actor, and the parametric value function
ˆv(s, w)
The complete empirical return
is only available at the end of each episode, and therefore at
each update we need to look forward to future rewards to decide current theoretical estimate of
. A close approximation of
that is available at each decision moment and thus enables
more data-efficient backward-view learning is
t= (1 λ)P
n=1 λn1Gt:t+n
, with
specifying the relative decaying rate among returns available after various steps
. Since
(denoted as
), substituting
in Eq. 12
ut+1 =ut+αδteu
is the eligibility trace [
] for
, and is initialised to
for every episode. Analogous update rules
apply to the critic.
Actor Search Tree Critic
The history-dependent probabilistic belief state reflects the information
the agent would need to know about the current time step to optimise its decision. This belief state is
used as the state feature vector for the actor-critic, i.e.
x(s) = b
. This is based on the notion that state
mechanism is supposed to allow weight parameter to update towards similar directions by similar
samples, while similar situations have similar distributions of states, with each component in the
distribution implying the responsibility for updating corresponding component in the weight.
Our critic parameterises the lower and upper value bounds in the tree search, instead of parameterising
the value function as whole (as done in conventional actor-critic methods). Note that the value bounds
at the fringe nodes are here updated as we parse the data for off-policy reinforcement learning. In
previous works these bounds would have been computed offline and not improved during online
planning. We use linear representations for the value bounds:
ˆvL(b, wL) = wL T b, ˆvU(b, wU) = wU T b(15)
At each step
, a local (as opposed to a value function optimal to all belief states) optimal value is
estimated for the current belief
through heuristic tree search with fringe nodes values approximated
, denoted as
. The critic parameters are updated through stochastic
gradient descent (SGD) to adjust in the direction that most reduces the error on each training
example by minimising the mean square error between the current approximation and its target
t+1 =4wL
3Because Pa∈A B(s)uπ(a|s, u) = B(s)uPa∈A π(a|s, u) = B(s)u1 = 0,s∈ S.
t+1 =
t)ˆvL(bt,wL)wˆvL(bt,wL) =
is the step size for updating
. Similar for
. As the weight vector also has an impact on the
, which is ignored during SGD update, the update is by definition semi-gradient,
which usually learns faster than full gradient methods and with linear approximators (Eq. 15), is
guaranteed to converge (near) to a local optimum under standard stochastic approximation conditions
To ensure convergence, we set the step sizes at time step taccording to:
ti, βU
Fig. 2. ASTC algorithm flowchart.
To realise continuous action space,
the actor is modelled as a Gaussian
distribution, with a mean vector ap-
proximated as a linear function (for
simplicity of gradient computation)
of weights and belief state:
π(a|b, u) = N(uTb, σ2)(19)
is a hyperparameter for standard
deviation. In this circumstance the
gradient in Eq. 14 is calculated as:
uπ(a|b, u)
π(a|b, u)=1
The moment-wise error, or temporal
difference (TD) error that motivates update to actor in Eq. 13 is:
In off-policy reinforcement learning, as we use retrospective data generated by a behaviour policy
(being clinicians’ actual treatment decisions) to optimise a target policy
(being our actor), the
actor-critic approach is tuned via importance sampling on the eligibility trace [31]:
is the importance sampling ratio. Importance sampling mechanisms help
ensure that we are not biased by differences between the two policies in choosing actions (e.g. optimal
actions may look different than clinical actions taken).
4 Experimental Results
We both train and test our algorithm on synthetic and real ICU patients separately.
On Synthetic Data
We first synthesize a dataset where we have full access to its dynamics, from
which a true theoretic optimal policy
can be computed from fully model-reliant approaches such
as dynamical programming. Note that although with synthetic data, we choose to learn on an existing
(simulated) dataset, to test the algorithm’s capability of off-policy learning. The dataset is further
divided into two mutually exclusive subsets for algorithm development and test. The suboptimality
of our behaviour policy
that dictates actions during data generation, is systematically related to
with -greedy 6.
is actually equivalent to
, both
denote the environmental state at an identical
moment, depending on whether the agent’s notion is represented by belief or fully observable state.
decides the fraction of occasions when the agent explores actions randomly instead of sticking to the
optimal one.
In our synthetic data, the action space contains six discrete (categorical) actions. Observed data are
generated from a Gaussian mixture model, with state transition probabilities denser at closer states.
All parameters for data generation are unknown to the reinforcement learning agent.
Fig. 3.
Action selections in test set under proposed/optimal/behaviour (showing is
= 0.3
) policy
(synthetic data).
Fig. 3 visualises action selections under
, and
of the first 200 time steps (to avoid clutter)
in the test set. Note that the optimal and behaviour policies are discrete, while the target policy is
continuous. Strict resemblance between the target policy and the optimal policy can be observed.
And there is no trace of the target policy varying with the behaviour policy.
On Retrospective ICU Data
We subsequently apply the methodology on the Medical Information
Mart for Intensive Care III (MIMIC-III) [
], a publically available de-identified electronic healthcare
record database of patients in ICUs of a US hospital. We include adult patients conforming to the
international consensus sepsis-3 criteria [
], and exclude admissions where treatment was withdrawn,
or mortality was undocumented. This selection procedure leads to 18,919 ICU admissions in total,
which are further divided into development and test sets according to proportions 4:1. Time series
data are temporally discritised with 4-hour time steps and aligned to the approximate time of onset
of sepsis. Measurements within the 4h period are either averaged or summed according to clinical
implications. The outcome is mortality, either hospital or 90-day mortality, whichever is available.
The maximum dose of vasopressors (mcg/kg/min) and total volume of intravenous fluids (mL/h)
administered within each 4h period define our action space. Vasopressors include norepinephrine,
epinephrine, vasopressin, dopamine and phenylephrine, and are converted to norepinephrine equiva-
lent. Intravenous fluids include boluses and background infusions of crystalloids, colloids and blood
products, and are normalised by tonicity. Patient variables of interest are constituted by demographics
(age, gender
, weight, readmission to ICU
, Elixhauser premorbid status), vital signs (modified
SOFA, SIRS, Glasgow coma scale, heart rate, systolic/mean/diastolic blood pressure, shock index,
respiratory rate, Sp
, temperature), laboratory values (potassium, sodium, chloride, glucose, BUN,
creatinine, Magnesium, calcium, ionised calcium, carbon dioxide, SGOT, SGPT, total bilirubin,
albumin, hemoglobin, white blood cells count, platelets count, PTT, PT, INR, pH, Pa
, PaC
, base
excess, bicarbonate, lactate), ventilation parameters (mechanical ventilation
, Fi
), fluid balance
(cumulated intravenous fluid intake, mean vasopressor dose over 4h, urine output over 4h, cumulated
urine output, cumulated fluid balance since admission), and other interventions (renal replacement
therapy 7, sedation 7).
Missing data in patient continuous variables are imputed via linear interpolations, binary variables
are interpolated via sample-and-hold. All continuous variables are normalised to
. To promote
patient survival (discharge from ICU), each transition to death is penalised by -10, each transition to
discharge is rewarded with +10. All non-terminal transitions are zero-rewarded.
Off-policy policy evaluation (OPPE) of the learned policy is usually conferred via importance
sampling, where one has to trade between variance and bias. [
] have extended this to
more accurate estimators to minimise estimation error sources for discrete action spaces. However,
importance-sampling based approaches usually assume coverage in the behaviour policy
possible in target policy
have to be possible in
) to calculate the importance sampling ratio, which
is mathematically meaningless in our case where both target and behaviour policies are continuous.
Instead of using OPE to provide theoretical policy evaluation, we focus on empirically evaluating our
learned policy by comparing how the similarity between clinicians’ decisions and our suggestions
7Binary variable.
Fig. 4.
Distributions of returns vs. action deviations. (Left) distributions of returns for different levels
of average absolute vasopressor deviations between clinicians and proposed policy per time step. The
uppermost subplot shows empirical outcomes from patients whose vasopressors actually received
deviated per time step less than
of overall vasopressor deviations (ascending) in the test set, and the
lowermost subplot higher than 2
3; (Right) intravenous fluid counterparts.
indicates patient outcomes: this provides an empirical validation and is commonly adopted [
for medical scenerios involving retrospective dataset.
Fig. 4 shows probability mass functions (histograms) of returns of start states (i.e.
being the length of that time series) in test set divided into three mutually exclusive groups according
to the average (per time step) absolute deviation from clinicians’ decision and the proposed dose in
terms of vasopressor or intravenous fluid within each episode (i.e. individual patient) respectively.
The boundaries between two adjacent groups are set to terciles (shown as the grey dotted vertical
lines in Fig. 5) of the whole test dataset for each drug to reflect equal weighing. It is observable that
for both drugs, higher returns are more likely to be obtained when doctors behave more closely to our
The distributions of action deviations between clinicians and the proposed policy in terms of each drug
for survivors and non-survivors with bootstrapping (random sampling with replacement) estimations
in Fig. 5 demonstrate that, among survivors our proposed policy captures doctors’ decisions most of
the time, while same is not true of non-survivors, especially for intravenous fluids.
Fig. 5.
Distribution of action deviations with bootstrapping for all survivors, non-survivors, and
overall patients in test set are plotted separately, with terciles for each drug plotted as two grey dotted
vertical lines, separating the whole test set into three groups with equal patient numbers.
5 Conclusion
This article provides an online POMDP solution to take into account uncertainty and history infor-
mation in clinical applications. Our proposed policy is capable of dictating near-optimal dosages in
terms of vasopressor and intravenous fluid in a continuous action space, to which behaving similarly
would lead to significantly better patient outcomes than that in the original retrospective dataset.
Further research directions include investigating inverse reinforcement learning to recover the reward
function that clinicians were conforming to, modelling states/observations to non-trivial distributions
to more appropriately extract genuine physiological states, and phrasing the problem into a multi-
objective MDP to absorb multiple criteria.
Our overall aim is to develop clinical decision support systems that provision clinicians dynami-
cal treatment planning given previous course of patient measurements and medical interventions,
enhancing clinical decision making, not replacing it.
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Deep learning algorithms, in particular convolutional networks, have rapidly become a methodology of choice for analyzing medical images. This paper reviews the major deep learning concepts pertinent to medical image analysis and summarizes over 300 contributions to the field, most of which appeared in the last year. We survey the use of deep learning for image classification, object detection, segmentation, registration, and other tasks and provide concise overviews of studies per application area. Open challenges and directions for future research are discussed.
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Skin cancer, the most common human malignancy, is primarily diagnosed visually, beginning with an initial clinical screening and followed potentially by dermoscopic analysis, a biopsy and histopathological examination. Automated classification of skin lesions using images is a challenging task owing to the fine-grained variability in the appearance of skin lesions. Deep convolutional neural networks (CNNs) show potential for general and highly variable tasks across many fine-grained object categories. Here we demonstrate classification of skin lesions using a single CNN, trained end-to-end from images directly, using only pixels and disease labels as inputs. We train a CNN using a dataset of 129,450 clinical images-two orders of magnitude larger than previous datasets-consisting of 2,032 different diseases. We test its performance against 21 board-certified dermatologists on biopsy-proven clinical images with two critical binary classification use cases: keratinocyte carcinomas versus benign seborrheic keratoses; and malignant melanomas versus benign nevi. The first case represents the identification of the most common cancers, the second represents the identification of the deadliest skin cancer. The CNN achieves performance on par with all tested experts across both tasks, demonstrating an artificial intelligence capable of classifying skin cancer with a level of competence comparable to dermatologists. Outfitted with deep neural networks, mobile devices can potentially extend the reach of dermatologists outside of the clinic. It is projected that 6.3 billion smartphone subscriptions will exist by the year 2021 (ref. 13) and can therefore potentially provide low-cost universal access to vital diagnostic care.
We present new methodology based on Multi-Objective Markov Decision Processes for developing sequential decision support systems from data. Our approach uses sequential decision-making data to provide support that is useful to many different decision-makers, each with different, potentially time-varying preference. To accomplish this, we develop an extension of fitted-Q iteration for multiple objectives that computes policies for all scalarization functions, i.e. preference functions, simultaneously from continuous-state, finite-horizon data. We identify and address several conceptual and computational challenges along the way, and we introduce a new solution concept that is appropriate when different actions have similar expected outcomes. Finally, we demonstrate an application of our method using data from the Clinical Antipsychotic Trials of Intervention Effectiveness and show that our approach offers decision-makers increased choice by a larger class of optimal policies.
Importance: Deep learning is a family of computational methods that allow an algorithm to program itself by learning from a large set of examples that demonstrate the desired behavior, removing the need to specify rules explicitly. Application of these methods to medical imaging requires further assessment and validation. Objective: To apply deep learning to create an algorithm for automated detection of diabetic retinopathy and diabetic macular edema in retinal fundus photographs. Design and setting: A specific type of neural network optimized for image classification called a deep convolutional neural network was trained using a retrospective development data set of 128 175 retinal images, which were graded 3 to 7 times for diabetic retinopathy, diabetic macular edema, and image gradability by a panel of 54 US licensed ophthalmologists and ophthalmology senior residents between May and December 2015. The resultant algorithm was validated in January and February 2016 using 2 separate data sets, both graded by at least 7 US board-certified ophthalmologists with high intragrader consistency. Exposure: Deep learning-trained algorithm. Main outcomes and measures: The sensitivity and specificity of the algorithm for detecting referable diabetic retinopathy (RDR), defined as moderate and worse diabetic retinopathy, referable diabetic macular edema, or both, were generated based on the reference standard of the majority decision of the ophthalmologist panel. The algorithm was evaluated at 2 operating points selected from the development set, one selected for high specificity and another for high sensitivity. Results: The EyePACS-1 data set consisted of 9963 images from 4997 patients (mean age, 54.4 years; 62.2% women; prevalence of RDR, 683/8878 fully gradable images [7.8%]); the Messidor-2 data set had 1748 images from 874 patients (mean age, 57.6 years; 42.6% women; prevalence of RDR, 254/1745 fully gradable images [14.6%]). For detecting RDR, the algorithm had an area under the receiver operating curve of 0.991 (95% CI, 0.988-0.993) for EyePACS-1 and 0.990 (95% CI, 0.986-0.995) for Messidor-2. Using the first operating cut point with high specificity, for EyePACS-1, the sensitivity was 90.3% (95% CI, 87.5%-92.7%) and the specificity was 98.1% (95% CI, 97.8%-98.5%). For Messidor-2, the sensitivity was 87.0% (95% CI, 81.1%-91.0%) and the specificity was 98.5% (95% CI, 97.7%-99.1%). Using a second operating point with high sensitivity in the development set, for EyePACS-1 the sensitivity was 97.5% and specificity was 93.4% and for Messidor-2 the sensitivity was 96.1% and specificity was 93.9%. Conclusions and relevance: In this evaluation of retinal fundus photographs from adults with diabetes, an algorithm based on deep machine learning had high sensitivity and specificity for detecting referable diabetic retinopathy. Further research is necessary to determine the feasibility of applying this algorithm in the clinical setting and to determine whether use of the algorithm could lead to improved care and outcomes compared with current ophthalmologic assessment.
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Importance Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.Objective To evaluate and, as needed, update definitions for sepsis and septic shock.Process A task force (n = 19) with expertise in sepsis pathobiology, clinical trials, and epidemiology was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Definitions and clinical criteria were generated through meetings, Delphi processes, analysis of electronic health record databases, and voting, followed by circulation to international professional societies, requesting peer review and endorsement (by 31 societies listed in the Acknowledgment).Key Findings From Evidence Synthesis Limitations of previous definitions included an excessive focus on inflammation, the misleading model that sepsis follows a continuum through severe sepsis to shock, and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria. Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. The task force concluded the term severe sepsis was redundant.Recommendations Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less.Conclusions and Relevance These updated definitions and clinical criteria should replace previous definitions, offer greater consistency for epidemiologic studies and clinical trials, and facilitate earlier recognition and more timely management of patients with sepsis or at risk of developing sepsis.
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Importance sampling is an essential component of off-policy model-free reinforcement learning algorithms. However, its most effective variant, weighted importance sampling, does not carry over easily to function approximation and, because of this, it is not utilized in existing off-policy learning algorithms. In this paper, we take two steps toward bridging this gap. First, we show that weighted importance sampling can be viewed as a special case of weighting the error of individual training samples, and that this weighting has theoretical and empirical benefits similar to those of weighted importance sampling. Second, we show that these benefits extend to a new weighted-importance-sampling version of offpolicy LSTD(λ). We show empirically that our new WIS-LSTD(λ) algorithm can result in much more rapid and reliable convergence than conventional off-policy LSTD(λ) (Yu 2010, Bertsekas & Yu 2009).