A Dataset for N-ary Relation Extraction of Drug Combinations
Abstract
Combination therapies have become the standard of care for diseases such as cancer, tuberculosis, malaria and HIV.
However, the combinatorial set of available multi-drug treatments creates a challenge in identifying effective combination therapies available in a situation.
To assist medical professionals in identifying beneﬁcial drug-combinations, we construct an expert-annotated dataset for extracting information about the efﬁcacy of drug combinations from the scientiﬁc literature.
Beyond its practical utility, the dataset also presents a unique NLP challenge, as the ﬁrst relation extraction dataset consisting of variable-length relations.
Furthermore, the relations in this dataset predominantly require language understanding beyond the sentence level, adding to the challenge of this task.
We provide a promising baseline model and identify clear areas for further improvement.
We release our dataset and code 1 publicly to encourage the
NLP community to participate in this task.
Introduction
“ So far, many monotherapies have been tested, but have been shown to have limited efﬁcacy against
COVID-19 .
By contrast, combinational therapies are emerging as a useful tool to treat SARS-CoVinfection. ”
(Ianevski et al., 2021).
Indeed, combining two or more drugs together has proven to be useful for treatments of various medical conditions, including cancer (DeVita et al., 1975; Carew et al., 2008; Shuhendler et al., 2010),
AIDS (Bartlett et al., 2006), malaria (Eastman and
Fidock, 2009), tuberculosis (Bhusal et al., 2005), hypertension (Rochlani et al., 2017) and COVID19 (Ianevski et al., 2020).
In this work, we examine the clinically signiﬁcant and challenging NLP task of extracting known drug combinations from the scientiﬁc literature.
We present an expert-annotated dataset and baseline models for this new task.
Our dataset contains 1600 manually annotated abstracts, each mentioning between 2 and 15 drugs.
840 of these abstracts describe one or more positive drug combinations, varying in size from 2 to 11 drugs.
The remaining 760 abstracts either contain mentions of drugs not used in combination, or discuss combinations of drugs that do not give a combined positive effect.
From a clinical perspective, solving the drug combination identiﬁcation task will assist researchers in suggesting and validating complex treatment plans.
For example, when searching for effective treatments for cancer, knowing which drugs interact synergistically with the ﬁrst line treatment allows researchers to suggest new treatment plans that can subsequently be validated in-vivo and become a standard protocol (Wasserman et al., 2001;
Katzir et al., 2019; Ianevski et al., 2020;
Niezni et al., 2022).
From an NLP perspective, the drug combination identiﬁcation task and dataset pushes the boundaries of relation extraction (RE) research, by introducing a relation extraction task with several challenging characteristics:
Variable-length n-ary relations Most work on relation extraction is centered on binary relations (e.g. Li et al.
(2016), see full listing in §5), or on n-ary relations with a ﬁxed n (e.g. Peng et al.
In contrast, the drug combination task involves variable-length n-ary relations : different passages discuss combinations of different numbers of drugs.
For each subset of drugs mentioned in a passage, the model must predict if they are used together in a combination therapy and whether this drug combination is effective.
No type hints As noted by Rosenman et al.
(2020) and Sabo et al.
(2021), in many relation extraction benchmarks (Han et al., 2018;
Sabo et al., 2021;
Zhang et al., 2017), the argument types serve as
“We tried adding Nifedipine , as Labetalol combined to Prazosin did not reduce blood pressure.
[Figure]
Indeed, the addition produced a marked decrease in blood pressure.
No reduction of urinary NA excretion was observed in our patient during the addition of the Nifedipine therapy, suggesting that the decrease in blood pressure was not caused by suppression of NA release from pheochromocytoma tissue.”
“In Thailand , artesunate and artemether are the mainly used antimalarials for treatment of
NO_COMB severe or multidrug resistant falciparum malaria .”
an effective clue.
However, argument types do not apply naturally to the drug combination task, in which all possible relation arguments are entities of the same type (drugs) and we need to identify speciﬁc subsets of them.
Long range dependencies The information describing the efﬁcacy of a combination is often spread-out across multiple sentences.
Indeed, our annotators reported that for 67% of the instances, the label could not be determined based on a single sentence, requiring reasoning with a larger textual context.
Interestingly, our experiments show that our models are not helped by the availability of longer context, showing the limitations of current standard modeling approaches.
This suggests our dataset can be a test-bed for models that attempt to incorporate longer context.
Challenging inferences As we show in our qualitative analysis (§4.2), instances in this dataset require processing a range of phenomena, including coordination, numerical reasoning, and world knowledge.
We hope that by releasing this dataset we will encourage NLP researchers to engage in this important clinical task, while also pushing the boundaries of relation extraction.
The Drug Combinations Dataset
A set of drugs in a biomedical abstract are classiﬁed to one of the following labels:
Positive combination (POS_COMB): the sentence indicates the drugs are used in combination, and the passage suggests that the combination has additive, synergistic, or otherwise beneﬁcial effects which warrant further study.
Non-positive combination (OTHER_COMB): the sentence indicates the drugs are used in combination, but there is no evidence in the passage that the effect is positive (it is either negative or undetermined).
Not a combination (NO_COMB): the sentence does not state that the given drugs are used in combination, even if a combination is indicated somewhere else in the wider context.
An example is given in the lower half of Figure 1, where each of the drugs Artesunate and Artemether is given in isolation, and no combination is reported.
Our primary interest is to identify sets of drugs that are positive combinations.
2. Relevant Context Size for Classifying Drug Combinations
When formulating the extraction task and designing our data collection methodology, we ﬁrst analyzed the locality of the phenomenon: to what extent are drug combinations are expressed in a single sentence, or is a larger context is needed?
We sampled 275 abstracts that contained known drug combinations according to DrugComboDB.
Analysis showed that 51% of these abstracts mentioned attempted drug combinations.
In 97% of the abstracts containing drug combinations, all participating drugs in the attempted combination could be located within a single sentence in the abstract (for an example, see the OTHER_COMB relation in Figure 1).
However, establishing the efﬁcacy of the combination frequently required a larger context (such as the context accompanying the
POS_COMB relation in Figure 1).
2. Task Deﬁnition
We deﬁne each instance in the Drug Combination
Extraction (DCE) task to consist of a sentence, drug mentions within the sentence, and an enclosing context (e.g. paragraph or abstract).
The output of the task is a set of relations, each consisting of a set of participating drug spans and a relation label (POS_COMB or OTHER_COMB).
Each subset of drug mentions not included in the output set is implicitly considered to have relation label NO_COMB.
More formally, DCE is the task of labeling an instance X
= { C, i, D } with a set of relation instances R , where C
=
( S 1 , ...S n ) is an ordered list of context sentences (e.g. all the sentences in an abstract or paragraph), 1 ≤ i ≤ n is an index of a target sentence S i
= ( w 1 , ..., w n ( i ) ) with n ( i ) words, and D = {( d 1 start , d 1 end ) , ..., ( d m start , d m end )} is a set of m >= 2 spans of drug mentions in
S .
The output is a set R = {
( c i , y i )}
where c i ∈ P ( D ) is a drug combination from P ( D ) , the set of all possible drug combinations, and y i ∈
{ POS_COMB , OTHER_COMB } is a combination label.
2. Evaluation Metric
We consider two settings: “Exact Match”, a strict version which considers identifying exact drug combinations, and “Partial Match”, a more relaxed version which assigns partial credits to correctly identiﬁed subsets.
We use standard precision, recall and F metrics for both settings.
For the partial-match case, we replace the binary 0 or 1 score for a given combination with a reﬁned score: shared _ drugs / total _ drugs .
If there are multiple partial matches with gold relations, we take the one with maximum overlap.
We compute recall as identified _ relations / all _ gold _ relations , and precision as correct _ relations / identified _ relations .
We consider two metrics, the averaged Positive Combination F1 score which compares
POS_COMB to the rest, and the averaged Any
Combination F1 score which counts correct predictions for any combination label (POS or OTHER) as opposed to NO_COMB.
The latter is an easier task, but still valuable for identifying drug combinations irrespective of their efﬁcacy.
2. Collecting Data for Annotation
To collect data for annotation we curated a list of 2411 drugs from DrugBank 4 and sampled from
PubMed a set of sentences which mention 2 or more drugs.
Analysis of the ﬁrst 50 sentences from this sample showed that only 8 / 50 of the sentences included mentions of drug combinations.
This meant that annotating the full sample will be costly, and will result in a dataset that’s highly skewed toward relatively trivial NO_COMB instances.
We therefore repeated this experiment, sampling sentences whose PubMed abstract included a trigger phrase.
5 48% of 50 sampled sentences included mentions of drug combinations.
Evaluating the coverage of the trigger list against a new sample of abstracts with known drug combinations showed that 90% of these new abstracts included one of the trigger words.
This suggests our trigger list is useful for fetching label-balanced data, without prohibitively restricting coverage and diversity.
Accordingly, we collected the majority of instances for annotation, 90%, using a basic search for sentences that contain at least two different drugs and whose abstract contains one of the trigger phrases.
To overcome the lexical restrictions imposed by our trigger list, we sample the remaining 10% of instances using distant supervision: fetching sentences containing pairs of drugs known to be synergistic according DrugComboDB, but whose abstract does not include one of our trigger phrases.
All data collecting queries were performed using the SPIKE Extractive Search tool (Shlain et al., 2020; Taub-Tabib et al., 2020).
The process is il- lustrated at the top of Figure 2.
2. The Annotation Process
Seven graduate students in biomedical engineering took part in the annotation task.
The students all completed a course in combination therapies for cancer and were supervised by a principled researcher with expertise in this ﬁeld.
We provided the participants with annotation guidelines which speciﬁed how the annotation process should be carried out (see Appendix A.1) and conducted an initial meeting where we reviewed the guidelines with the group and discussed some of the examples together.
Each of the participants had access to a separate instance of the Prodigy annotation tool (Montani and Honnibal, 2018), pre-loaded with the candidate annotation instances.
Once a session starts, the instances (containing of a sentence with marked drug entities, and its context) appear in a sequential manner, with no time limit.
For each instance we instructed the annotators to mark all subsets of drugs that participated in a combination, and for each subset to indicate its label (POS_COMB or
OTHER_COMB).
Moreover, we instructed them to indicate whether the context was needed in order to determine the positive efﬁcacy of the relation.
Despite the considerable time required for expert annotation, we collected annotations for 1634 passages.
Among these, 272 were assigned to at least
[Table]
two annotators. After further arbitration by the lead researcher, these were used for the test set.
The process is illustrated in the bottom part of Figure 2.
2. Inter-annotator Agreement
During the course of the task we calculated interannotator agreement multiple times to identify cases of disagreement and provide feedback to annotators.
Each time, a set of 25 instances were randomly selected and assigned to all annotators.
Agreement was calculated based on a pairwise F measure (with some modiﬁcations as described in §2.3) and averaged over all pairs of annotators (see discussion of alternative metrics in Appendix A.2).
Final agreement numbers, in Table 1, are satisfactory (Aroyo and Welty, 2013; Araki et al., 2018).
Contextualized Embedding "[...] of protein kinase C-alpha.
This study evaluated the response rate of the combination therapy of <<m>> aprinocarsen <</m>> , <<m>> gemcitabine <</m>> , and <<m>> carboplatin <</m>> in previously untreated patients with advanced non-small cell lung cancer…
[ 200 tokens later ] …
However, this combination resulted in severe thrombocytopenia in the majority of patients."
Feedforward
OTHER_COMB 2. Resulting Dataset The dataset consists of 1634 annotated abstracts,split into 1362 train and 272 test instances. These include 1248 relations; 838 are POS_COMB and 410 are OTHER_COMB (with the same label ratio in the train and test sets).
591 sentences contain no drug combination, 877 contain one relation (either
POS_COMB or OTHER_COMB), and 166 contain two or more different combinations.
Among annotated relations, 900 are binary, 226 are 3-ary, 69 are 4-ary, and 53 are 5-ary or more.
For each instance in the resulting dataset we include the context-required indication provided by the annotators.
In 835 out of 1248 relations the annotator marked the context as needed which is 67% of the time, showing the importance of the context in the DCE task.
Experiments 3. Baseline Model Architecture
We establish a baseline model to measure the difﬁculty of our dataset and reveal areas for improvement.
For our underlying baseline model architecture, we adopt the PURE architecture from Zhong and Chen (2021), which is state-of-the-art on several relation classiﬁcation benchmarks, including the SciERC binary scientiﬁc RE dataset (Luan et al., 2018).
The PURE architecture, designed for 2-ary and 3-ary relation extraction, consists of three components.
First, special “entity marker" tokens are inserted around all entities in a candidate relation.
Next, these marker tokens are encoded with a contextualized embedding model.
Finally, the entity marker embeddings are concatenated and fed to a feedforward layer for prediction.
Unlike the original PURE architecture, we consider the more challenging case of extracting relations of variable arity.
To support this setting, we average the entity marker tokens in a relation rather than concatenate.
The ﬁnal baseline model architecture is shown in Figure 3.
For the contextual embedding component of this architecture, we experiment with four different pretrained scientiﬁc language understanding models (SciBERT (Beltagy et al., 2019), BlueBERT (Peng et al., 2019), PubmedBERT (Gu et al., 2020), and BioBERT (Lee et al., 2020)).
During training, we only ﬁnetune the ﬁnal *BERT layer.
We train each model architecture for 10 epochs on a single NVIDIA Tesla T4 GPU with 15GB of GPU memory, which takes roughly 7 hours to train for each model.
To our knowledge, there are no other models designed for variable-length N -ary relation extraction, so we consider no other baselines.
3. Domain-Adaptive Pretraining
Our baseline model architecture relies heavily on a pretrained contextual embedding model to provide discriminative features to the relation classiﬁer.
Gururangan et al.
(2020) showed that continued domain-adaptive pretraining almost always leads to signiﬁcantly improved downstream task performance.
Following this paradigm, we performed continued domain-adaptive pretraining (“DAPT”) on our contextual embedding models.
We acquired in-domain pretraining data using the same procedure used to collect data for annotation: running a SPIKE query against PubMed to ﬁnd abstracts containing multiple drug names [Table] and a “trigger phrase" (from the list in Appendix
A.3).
This query resulted in 190K unique abstracts.
We do not include any paragraphs from our annotated dataset.
We then perform domainadaptive training against this dataset using the
Huggingface Transformers library.
We train for 10 epochs using a learning rate of 5e-4, ﬁnetuning all *BERT layers and using the same optimization parameters speciﬁed by Gururangan et al.
This pretraining took roughly 8 hours using four 15GB NVIDIA Tesla T4 GPUs.
3. Relation Prediction
To apply the model to drug combination extraction, we reduce the RE task to an RC task by considering all subsets of drug combinations in a sentence, treating each one as a separate classiﬁcation input, and combining the predictions.
This poses two challenges: there may be a large number of candidate relations for a given document, and each relation is classiﬁed independently despite the combinatorial structure.
To handle these issues, we use a greedy heuristic of choosing the smallest set of disjoint relations whose union covers as many drug entities as possible in the sentence.
We do this iteratively: at each step, we choose the largest predicted relation that does not contain any drugs found in the relations chosen at previous iterations.
This greedy heuristic favors large (high arity) relations.
Nonetheless, we empirically ﬁnd this method is helpful for extracting high-precision drug combinations from our model architecture.
3. Rule-based baseline
To further validate that the trigger words do not introduce bias to our task, we consider an additional baseline based on the following rule: if a trigger word is found in the same sentence with multiple drugs, this set of drugs is tagged as POS_COMB.
Results 4. Effect of Pretrained LMs and Domain-Adaptive Pretraining
We show results of our baseline model architectures in Table 2.
For each model, we report the mean and standard deviation of each metric over four identical models trained with different seeds.
Among the four base scientiﬁc language understanding models in our experiments, we observe
PubmedBERT to be the strongest on every metric.
We additionally ﬁnd that domain-adaptive pretraining provides signiﬁcantly improvements for every base model, consistently giving 5-10 points of improvement on Positive Combination F1 score.
The value of domain-adaptive pretraining supports our observation that encoding domain knowledge is critical to solving this new task.
The rule-based approach underperformed all learned models (30 F1 points under our strongest model, PubmedBERT-DAPT).
This shows this task cannot be reduced to keyword identiﬁcation.
4. Qualitative Error Analysis
We identify classes of challenges that make this task difﬁcult, both in terms of human annotation and machine prediction.
Coordination Ambiguity: A known linguistic challenge is the ambiguity that stems from vague coordination.
In cases where explicit combination words (e.g. combination, plus, together with, etc)
[Table]
are not used, it may be unclear whether two drugs are being used together or separately. For example in “These ﬁndings may help clinicians identify patients for whom acamprosate and naltrexone may be most beneﬁcial” it is unclear if acamprosate and naltrexone are being described in combination or as independent treatments, leading to either a POS label for the former or NO_COMB for the latter.
Numerical and Relative Reasoning:
In some cases, the effect of a treatment is described in relative or numerical terms, rather than an absolute claim.
Consider the example, “The infection rate in the control group was 3.5% and in the treated group 0.5%.” .
Here, the reader must compare the control vs experimental groups and deduce that the experimental outcome is positive, because the treatment yields a lower infection rate.
Domain Knowledge: Similarly, classifying relations in this dataset may require an understanding of domain knowledge.
In “Growth inhibition and apoptosis were signiﬁcantly higher in BxPC-3,
HPAC, and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib ” , one must understand that having higher values of Growth inhibition and apoptosis in speciﬁc cells is a positive outcome, in order to classify this combination as positive.
Context related Complications: The following are kinds of complications found when the evidence lies in the wider part of the context.
Coreference: Anaphoric or coreferential reasoning is sometimes needed to understand the efﬁcacy of the combination e.g. “it was demonstrated that they could be combined with acceptable toxicity.” .
Contradicting Evidence: the reader often must infer a conclusion given opposing claims within a given abstract.
This can happen as combinations can be referred as e.g. toxic but effective .
Long Distance: The target sentence can be far—up to 41 sentences apart—from the evidence sentence, making it difﬁcult for even humans to process.
4. Quantitative Error Analysis
To probe this task, we analyze the performance of our strongest model—the one using a PubmedBERT base model tuned with domain-adaptive pretraining—along different partitions of test data.
We trained with four random seeds and perform comparisons using a paired multi-bootstrap hypothesis test where bootstrap samples are generated by sampling hierarchically over the four random seeds and the subsets of the test set (Sellam et al., 2021).
We use 1000 bootstrap samples in each test.
Do models leverage context effectively?
Each relation in our dataset consists of entities contained within a single sentence, but labeling the relation frequently requires extra-sentential context to make a decision.
In our dataset, annotators record whether or not each relation requires paragraph-level context to label, reporting that 67% of drug combinations required context to annotate.
To understand the extent that models make use of paragraph-level context, we trained and evaluated our PubmedBERT-based model using varying amounts of extra-sentential context around the sentence containing drug entities.
In Table 3, we see that adding context provides nearly identical performance to training a model with no extra-sentential context at all, with differences rarely exceeding one standard deviation of F1 score.
However, we see increased variability in “Positive Combination F1” performance when extrasentential context is used.
To explain this, recall from §2.1 that determining the efﬁcacy of a drug combination often requires paragraph-level context for annotators, while identifying any combination usually requires no context.
From qualitative analysis of attention maps, we observed that our models are not able to consistently identify the salient parts of paragraph-level context, potentially causing instability with larger inputs.
[Figure]
Metric (for Positive Combination RE)
M e t r i c
V a l u e
BinaryRelations N -aryRelations( N ≥ 3 )
[Figure]
[Figure]
M e t r i c
V a l u e
CombinationsSeeninTrainingCombinationsUnseeninTraining
These results suggest ample room for improvement in extracting document-level evidence.
This makes our dataset a potentially useful benchmark for document-level language understanding
Binary vs. higher-arity relations
Given that our dataset is the ﬁrst relation extraction dataset with variable-arity relations, do higherorder relations pose a particular challenge for our models?
To answer this, we separate all predicted and ground truth relations for the test set into binary relations and higher-arity relations.
We then report precision among each subset of predicted relations and recall among each subset of ground truth relations.
We perform this experiment across four different model seeds, and report results in aggregate using a paired multi-bootstrap procedure.
In the results in Figure 4, we see no consistent signiﬁcant differences between models of different arities, suggesting that our technique of computing relation representations by averaging entity representations scales well to higher-order relations.
4.3. Generalizing to new drug combinations
How well can relation extraction models classify drug combinations not seen during training?
Similar to the setup in §4.3.2, we divide all predicted and ground truth relations for the test set into the set of drug combinations which are also annotated in our training set, and the set that have not been.
In our dataset, over 80% of annotated test set relations are not found in the training set.
In Figure 5, performance is consistently better for relations observed in the training set than for unseen relations, by a margin of 10-15 points.
Recall, in particular, is signiﬁcantly worse for relations unseen during training (at 95% conﬁdence), and precision is potentially also worse.
Considering that unseen drug combinations are practically more valuable than already-known combinations, improving generalization to new combinations is a critical area of improvement for this task.
Related Work
The DDI dataset (Herrero-Zazo et al., 2013) is the only work to our knowledge that annotates drug interactions for text mining.
However, it fundamentally differs from our dataset in the type of annotations provided: the DDI annotates the type of discourse context in which a drug combination is mentioned, without providing explicit information about combination efﬁcacy.
In contrast, our dataset is focused on semantically classifying the efﬁcacy of drug combinations as stated in text.
Other RE datasets exist in the biomedical ﬁeld (Peng et al., 2017;
Li et al., 2016; Wu et al., 2019;
Krallinger et al., 2017), but do not focus on drug combinations.
Similarly, several RE datasets tackle the N -arity problem in the scientiﬁc domain (Peng et al., 2017; Jain et al., 2020; Kardas et al., 2020;
Hou et al., 2019), and in the non-scientiﬁc domain (Akimoto et al., 2019; Nguyen et al., 2016), however, all of them consider a ﬁxed choice of N .
Conclusions
We present a new resource for drug combination and efﬁcacy identiﬁcation.
We establish baseline models that achieve promising results but reveal clear areas for improvement.
Beyond the immediate, application-ready value of this task, this task poses unique relation extraction challenges as the ﬁrst dataset containing variablearity relations.
We also highlight challenges with document-level representation learning and incorporating domain knowledge.
We encourage others to participate in this task, and our dataset and modeling code are all available to the public at https://github.com/allenai/ drug-combo-extraction .
Acknowledgements
This project has received funding in part from the
European Research Council (ERC) under the European Union’s Horizon2020 research and innovation programme, grant agreement 802774 (iEXTRACT), and in part from the NSF Convergence
Accelerator Award #2132318.
We would also like to thank our annotators from the Shamay lab at the
Faculty of Biomedical Engineering, Technion, including Shaked Launer-Wachs, Yuval Harris, Maytal Avrashami, Hagit Sason-Bauer and Yakir Amrusi
A. Evaluation Metric Discussion
For measuring the agreement, we chose to use our adaptation of F1 score and not other common metrics such as Cohen’s Kappa (Cohen, 1960) or one of its variations (e.g. Feliss’s Kappa (Fleiss, 1971) and
Krippendorf’s Alpha (Hayes and Krippendorff, 2007)).
These metrics expect a setup where the relation candidates are already marked and the task is only to label them – a labeling task and not an extraction task.
This causes two problems, one is that they inherently do not need to handle a partial match.
So if for example there are three drugs in a sentence, the ﬁrst annotator annotated a relation between drugs
A and B, while a second annotator annotated the same relation between drugs A, B and C.
So we will either underestimate or overestimate their agreement score if we considered this a mismatch or a match respectively.
Moreover, their calculations depend on the hypothetical agreement by chance normalization factor, but this will not reﬂect the difﬁculty of random choosing in our setup as they ignore the size of the combinatorial set of relation candidates we can possibly have.
A. Trigger List
[Equation]
Trigger words
P e r ce n t a g e o f
C on t a i n i ng
A b s t r ac t s
In Figure 7 we show the triggers that we used in the Spike queries.
We show the percentage of abstracts that included each trigger (others under 1%: conjunction, two-drug, ﬁrst choice, additivity, combinational, synergetic, simultaneously with, supra-additive, ﬁve-drug, combinatory, over-additive, timed-sequential, co-blister, super-additive, synergisms, synergic, synergistical, less-than-additive, greater-than-additive, additivesynergistic, supraadditive, superadditive, overadditive, subadditive, ﬁrst-choice, 2-drug, subadditive, more-than-additive, 3-drug ).