Deep Learning for Predicting Progression of Patellofemoral Osteoarthritis Based on Lateral Knee Radiographs, Demographic Data, and Symptomatic Assessments

Abstract

Objective In this study, we propose a novel framework that utilizes deep learning and attention mechanisms to predict the radiographic progression of patellofemoral osteoarthritis (PFOA) over a period of 7 years.

Material and Methods This study included subjects (1,832 subjects, 3,276 knees) from the baseline of the Multicenter Osteoarthritis Study (MOST). Patellofemoral joint regions of interest were identified using an automated landmark detection tool (BoneFinder) on lateral knee X-rays. An end-to-end deep learning method was developed for predicting PFOA progression based on imaging data in a five-fold cross-validation setting. To evaluate the performance of the models, a set of baselines based on known risk factors were developed and analyzed using gradient boosting machine (GBM). Risk factors included age, sex, body mass index, and Western Ontario and McMaster Universities Arthritis Index score, and the radiographic osteoarthritis stage of the tibiofemoral joint (Kellgren and Lawrence [KL] score). Finally, to increase predictive power, we trained an ensemble model using both imaging and clinical data.

Results Among the individual models, the performance of our deep convolutional neural network attention model achieved the best performance with an area under the receiver operating characteristic curve (AUC) of 0.856 and average precision (AP) of 0.431, slightly outperforming the deep learning approach without attention (AUC = 0.832, AP = 0.4) and the best performing reference GBM model (AUC = 0.767, AP = 0.334). The inclusion of imaging data and clinical variables in an ensemble model allowed statistically more powerful prediction of PFOA progression (AUC = 0.865, AP = 0.447), although the clinical significance of this minor performance gain remains unknown. The spatial attention module improved the predictive performance of the backbone model, and the visual interpretation of attention maps focused on the joint space and the regions where osteophytes typically occur.

Conclusion This study demonstrated the potential of machine learning models to predict the progression of PFOA using imaging and clinical variables. These models could be used to identify patients who are at high risk of progression and prioritize them for new treatments. However, even though the accuracy of the models were excellent in this study using the MOST dataset, they should be still validated using external patient cohorts in the future.

Keywords

patellofemoral osteoarthritis - deep learning - prediction of osteoarthritis progression - knee

Introduction

Knee osteoarthritis (OA) is the most prevalent chronic joint disorder that involves degeneration and loss of articular cartilage along with bony changes. High age and body mass index (BMI) are strong risk factors for knee OA.[1] Structural knee OA often leads to significant pain, stiffness, disability, and reduced quality of life for affected individuals.[2] Current understanding of OA disease process is inadequate and, consequently, there is a lack of disease-modifying medical treatments. As a result, knee OA continues to impose a significant burden on individuals and society.[3]

Although the patellofemoral (PF) joint is an important source of symptoms in knee OA, the majority of the research on knee OA has focused on tibiofemoral (TF) joint of the knee.[4] [5] Patellofemoral OA (PFOA) can be caused by a number of factors, including previous injury to the knee, inflammation, biomechanical abnormalities, overuse of joint, obesity, and genetic predisposition.[3] [6] Symptoms often include anterior knee pain, especially when kneeling and squatting, as well as swelling and a grinding or popping sensation when moving the knee (crepitus).[7] As the importance of the PF joint in OA is increasingly acknowledged, the number of studies into it has been increasing.[3] [8] [9] Still, more research is needed.[3]

Noninvasive imaging techniques play a crucial role in diagnosing and monitoring PFOA. Without imaging, a confident diagnosis will seldom be possible for PFOA.[10] X-ray imaging is one of the primary diagnostic tools because of its low cost and wide availability. Although radiography does not allow to visualize soft tissues, changes in the joint space and bone structure can be well depicted from X-rays. Several imaging biomarkers such as the narrowing of the joint space, bony spurs, malalignment of the patella, bone sclerosis, and cysts are associated with PFOA ([Fig. 1]).[9] [11]

Fig. 1 Example of PFOA progression/development. Figure on the left demonstrates an exemplar patellofemoral joint ROI imaged at the first visit in the MOST study. At the baseline, PFOA is not present. Right figure presents the same particpant's PF joint 7 years after the baseline visit. The knee has developed PFOA where joint space narrowing and osteophytes—characteristic features of OA—are clearly seen. Best viewed on screen. MOST, Multicenter Osteoarthritis Study; OA, osteoarthritis; PF, patellofemoral; PFOA, patellofemoral osteoarthritis; ROI, region of interest.

In recent years, machine learning (ML) techniques have emerged as promising tools to aid in the diagnosis of PFOA from X-ray images.[12] [13] Both early diagnosis and prediction of disease progression might be critical in the management and intervention of PFOA. However, accurate and timely identification of PFOA progression based on X-ray images can be challenging due to the complexity of the disease and the variability of knee imaging. To date, there are no published studies using ML-based models for prediction of PFOA development or progression in the future from imaging data.

In this study, we introduced a deep learning-based framework to predict radiographic progression of PFOA over a 7-year-period from lateral radiographs, demographic data, and symptom assessments (clinical data). We leveraged attention mechanism in our deep learning framework and proposed an end-to-end solution via a trainable attention module. The results of this study have the potential to improve the early diagnosis and treatment of PFOA, ultimately leading to improved patient outcomes and quality of life.

Materials and Methods

[Fig. 2] shows the overall pipeline of our study. We first located patellar landmarks using BoneFinder software[14] ([Fig. 3]). Those anatomical landmarks were then used to align patellar bone constantly across the knees eliminating rotation variance.

Fig. 2 (A) Illustration of the workflow of our approach. The localization and alignment of patellofemoral (PF) joint in lateral knee X-rays were performed based on the anatomical landmarks of patellar bone (BoneFinder). Intensity normalization was then applied. Finally, each lateral knee was rotated in order to have an aligned patella. After localizing PF joint ROI, a deep convolutional neural network (CNN) model was used for predicting the progression of patellofemoral osteoarthritis (PFOA). (B) For comparison, a separate machine learning model (gradient boosting machine [GBM]) was trained based on clinical variables including age, sex, body mass index (BMI), the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, and Kellgren and Lawrence (KL) score of the tibiofemoral joint. We used a stratified subject-wise five-fold cross validation setting to measure the performance of all the models. (C) In addition to these individual models, we fused the predictions from these models in a second layer GBM model to improve the overall prediction performance. ROI, region of interest.

Fig. 3 Illustration of automated ROI localization. First, patellar height (h) was determined using landmarks. Subsequently, a small margin (Δ) is padded around the patellar region. On the femur side, ROI is located such that the width equals to the height of the ROI. Best viewed on screen. ROI, region of interest.

The image preprocessing step involved normalizing intensity using global contrast normalization and truncating the histogram between the 5th and 99th percentiles. Subsequently, we used patellar landmarks to locate the patellofemoral joint regions of interest (PFJROI) in lateral knee radiographs. To ensure a similar view with left knee images, the right knee regions of interest (ROI) images were horizontally flipped. We then utilized a deep convolutional neural network (CNN) to predict PFOA progression within 7 years. Additionally, we trained an ML model (GBM[15]) on clinical features as a reference method for comparison with the proposed approach. Finally, to increase predictive power, we trained an ensemble model using both imaging and clinical data.

Data

We used the data from the Multicenter Osteoarthritis Study public use datasets (MOST, http://most.ucsf.edu). MOST is a longitudinal observational study that aims to identify factors affecting the occurrence and progression of OA. The study enrolled 3,026 participants aged 50 to 79 years, who either had radiographic knee OA or were at high risk for developing the disease. The participants were followed up for 84 months where clinical assessments were conducted and radiological data were collected. In the study, semiflexed lateral view radiographs were acquired according to a standardized protocol. Knee radiographs were evaluated from the baseline to 15-, 30-, 60-, and 84-month follow-up visits. In this study, we employed lateral radiographs acquired at the baseline visit from both left and right legs that included 3,276 knees (1,832 subjects) which did not have PFOA at the time of first examination. The number of progressed knees that developed PFOA was 403 (12%) and the number of knees which did not develop PFOA was 2,873 (88%). Selected knees must have had PFOA assessments from lateral radiographs and KL grades from posteroanterior radiographs, all performed at the baseline. Among these, we selected knees only whose PFOA status within the following 7 years can be assessed (progressor vs. nonprogressor). For example, participants who dropped out from the study before the last follow-up timepoint and had not developed PFOA at the previous time points were excluded. See [Fig. 4] and [Table 1] for subject flow diagram and demographics.

Fig. 4 Chart shows the selection of knees from the MOST study used in this work. MOST, Multicenter Osteoarthritis Study; PFOA, patellofemoral osteoarthritis.

Table 1 Demographics of the data used in this study (subset of Multicenter Osteoarthritis Study)

			Age		BMI		WOMAC		KL
PFOA	Number of females	Number of males	Mean	Std	Mean	Std	Mean	Std	Mean	Std
Nonprogressor	1,665 (58%)	1,208 (42%)	61.2	7.7	29.6	5.2	14.6	14.8	0.7	1.0
Progressor	281 (70%)	122 (30%)	61.1	7.6	32.8	6.3	24.1	17.1	1.7	1.3

Abbreviations: BMI, body mass index; KL, Kellgren and Lawrence; PFOA, patellofemoral osteoarthritis; WOMAC, Western Ontario and McMaster Universities Arthritis Index.

In the MOST public use datasets, radiographic PFOA is defined from lateral view radiographs as follows: osteophyte score ≥2 or the joint space narrowing (JSN) score is ≥1 plus any osteophyte, sclerosis or cysts ≥1 in the PF joint (grade 0–3; 0 = normal, 1 = mild, 2 = moderate, 3 = severe). Unlike TF joint OA assessment (KL grading ranging from 0 to 4), in the PF joint, OA was described as either present or absent lacking a severity grading. In this study, the term “progression” refers to both progression of existing OA and development of OA in previously nonaffected PF joints (incidence). For example, knees which showed minor signs of PFOA (e.g., osteophyte score = 1) at the baseline, which are still considered non-PFOA cases, might experience worsening of an existing abnormality in the following years and diagnosed with PFOA (progression). Similarly, knees that did not show any signs of PFOA at the baseline might develop the disease for the first time during the the following 7 years (incidence). In MOST, individual radiographic features were graded by two independent expert readers and when there was a disagreement in film readings, a panel of three adjudicators resolved the discrepancies.[16]

Selection of Regions of Interest

We placed a PFJROI automatically using landmarks ([Fig. 3]). The height of the patellar bone (h) was used to locate a square-shaped image ROI. Once the patellar bone margins were determined using landmarks, a 20-pixel (Δ/2) region is padded around the bone. On the femur side, the ROI is extended to capture the part of the femur facing the patellar bone such that the width of the ROI equals to its height (height = width = h + Δ). Finally, the size of the ROI becomes proportional to the size of the patellar bone.

Predicting Progression of Patellofemoral Osteoarthritis Using Deep Convolutional Neural Network

We adopted the deep CNN architecture proposed by Yan et al[17] to predict PFOA development based on the baseline imaging data. It uses VGG-16[18] backbone with two additional attention layers and one penultimate global feature vector (obtained via global average pooling; [Fig. 2]). PFJROI data were preprocessed by resizing it to 256 × 256 pixels and then applying a random crop of size 224 × 224 pixels. The backbone network VGG-16 was initialized with its pretrained version on ImageNet. The attention modules were initialized using He et al's initialization.[19] We employed Focal loss,[20] a variant of the cross-entropy, which has shown to be effective when facing the class imbalance problem by selectively downweighting well-classified examples. We used a batch size of 32 and trained the network end-to-end for 45 epochs using stochastic gradient descent with momentum. The initial learning rate was 0.001 and it was decayed by 10, every 10 epochs.

To examine the impact of the attention mechanism on the model's performance, a separate training was conducted with the original VGG-16 network without the attention modules. The network parameters were initialized with ImageNet pretraining, and the last layer was modified for binary classification. To ensure a fair comparison, we maintained consistency in the other network parameters and hyperparameters between the attention model and the model without attention.

Attention Module

Previous deep learning works that employ post hoc analysis for visual explanations such as Grad-CAM[21] require extra computation based on a fully trained classification network and relies on gradient information passed to the last convolutional layer combined with the forward activation maps. However, those feature maps, that are often used to produce explanations, are not necessarily related to the target class and they do not affect the network parameters at all. In this study, we employed a trainable spatial attention mechanism to produce insights into the model decisions. Attention mechanisms are widely used in the field of natural language processing (NLP) as a way to improve the performances of models by emphasizing the important parts of the information.[22] In case of image classification, the idea of trainable attention is to focus on the most informative parts of an image while ignoring less relevant or noisy parts. During training, the network learns to weight different regions of the input image based on the classification performance. See [Supplementary Material S1] (available in the online version) for more details of the attention module used in our architecture.

Reference Models

We employed GBM to predict the development of PFOA from demographic data and self-reported symptom assessments. GBM is a popular and powerful ML algorithm used for regression and classification based on ensembles of decision trees.[15] It works iteratively by adding decision trees to the model where each new tree attempts to correct the errors made by the previous trees. In this study, we used an efficient implementation of GBM called LightGBM.[23]

We built three GBM classifiers based on the clinical data and risk factors. These include age, sex, BMI, the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, and the KL grade of the TF joint (Model1, Model2, and Model3 in [Table 2]). The WOMAC score is a widely used questionnaire-based assessment tool designed to evaluate the severity of pain, stiffness, and physical disability in patients with OA of the knee and hip.

Table 2 Comparison of the developed models

	Input	Method	AUC (95% CI)	AP (95% CI)	Brier score
Model1	Age, sex, BMI	GBM	0.655 (0.624, 0.684)	0.232 (0.205, 0.268)	0.103	Clinical model
Model2	Age, sex, BMI, WOMAC	GBM	0.707 (0.678, 0.732)	0.265 (0.231, 0.299)	0.100	Clinical model
Model3	Age, sex, BMI, WOMAC, KL	GBM	0.767 (0.74, 0.789)	0.334 (0.293, 0.377)	0.095	Clinical model
Model4	VGG-16	CNN	0.832 (0.812, 0.851)	0.4 (0.359, 0.444)	0.262	CNN model
Model5	VGG-16-Attn	CNN	0.856 (0.838, 0.872)	0.431 (0.387, 0.475)	0.165	CNN model
Model6	Predictions from Model3 and Model5	GBM	0.865 (0.849, 0.88)	0.447 (0.404, 0.491)	0.084	Stacked model

Abbreviation: AP, average precision; AUC, area under the receiver operating characteristic curve; BMI, body mass index; CNN, convolutional neural network; GBM, gradient boosting machine; KL, Kellgren and Lawrence; PFOA, patellofemoral osteoarthritis; WOMAC, Western Ontario and McMaster Universities Arthritis Index.

AUC and AP indicate the area under the receiver operating characteristics curve and the area under the Precision–Recall curves, respectively. The 95% confidence intervals in parentheses were given based on a five-fold cross-validation setting.

For all of our models, we utilized subject-wise stratified five-fold cross-validation. This involves dividing the dataset into five folds, each containing data from different subjects, and stratifying the data within each fold so that the proportion of progressors versus nonprogressors is similar to the overall dataset. This helps to eliminate subject-dependent bias between the training and validation sets.

K-fold cross-validation involves iteratively selecting one fold as the testing set and the remaining folds as the training set. The model is trained on the training set and evaluated on the testing set. This process is repeated for each fold, with each fold serving as the testing set exactly once.

To ensure fair comparisons, we used the same folds for all of the models. All of the models were trained separately and the reported performances were derived from these separate models.

Statistical Methods

The performance of the models was compared using receiver operating characteristics (ROC) curves, precision–recall (PR) curves, and Brier score.[24] ROC curves plot the true positive rate (TPR) against the false positive rate at various classification thresholds. The area under the ROC curve (AUC-ROC) is often used as a summary metric for model performance, with a value of 1 indicating perfect classification and 0.5 indicating random classification. On the other hand, PR curves plot the precision (positive predictive value) against the recall (TPR) at various classification thresholds. The area under the PR curve (average precision, AP) is another commonly used summary metric for model performance, with a value of 1 indicating perfect classification and 0 indicating random classification. ROC curves are often used when the number of negative instances is much larger than the number of positive instances while PR curves are more suitable when the number of positive instances is relatively small. In general, a good classifier should have high values for both AUC-ROC and AUC-PR. Brier score equals to the mean squared error of the prediction. In order to compare the differences between model AUCs, we applied DeLong et al's test.[25]

Results

[Table 2] and [Fig. 5] show the performance of different models in predicting PFOA progression. Our proposed VGG-16-Attn model achieved the highest AUC of 0.856 (0.838, 0.872) and AP of 0.431 (0.387, 0.475) among all the considered models (Model1 to Model5). We compared the performance of VGG-16-Attn with the original VGG-16 model to assess the contribution of attention modules. Our results show that the addition of attention modules has a positive impact on the performance of the model, with a statistically significant difference between the AUC values of the two models (DeLong's p-value =0.00018).

Fig. 5 (A) ROC and (B) PR curves demonstrating the performance of the models. Area under the curves and 95% confidence intervals in parentheses were given based on a five-fold cross-validation setting. Dashed lines in ROC indicate the performance of a random classifier, and in case of PR it indicates the distributions of the labels of the dataset (progressor vs. nonprogressor). AUC, area under the receiver operating characteristic curve; BMI, body mass index; KL, Kellgren and Lawrence; PR, precision–recall; ROC, receiver operating characteristics; WOMAC, Western Ontario and McMaster Universities Arthritis Index.

To assess the value of imaging biomarkers in predicting PFOA progression, we conducted a thorough evaluation of various risk factors, including age, sex, BMI, WOMAC, and TFOA KL scores ([Fig. 5]) as reference models. Using GBM models, we trained the models to predict the probability of developing PFOA based on different combinations of these risk factors. Our results showed that the best-performing reference model (Model3) incorporated age, sex, BMI, WOMAC, and TFOA KL scores, achieving an AUC of 0.767 (0.74, 0.789) and an AP of 0.334 (0.293, 0.377; [Fig. 5]). We also measured the impact of each feature on the model's output by looking at the contribution of that feature to the predicted outcome compared to what the predicted outcome would be if the feature was not included in the model (SHapley Additive exPlanations[26] [[Supplementary Figs. S1] and [S2], available in the online version]). High BMI, WOMAC, and KL scores increase the predicted PFOA progression risk and low BMI, WOMAC, and KL scores reduce the risk.

Subsequently, we compared the performance of our deep CNN attention model (VGG-16-Attn, Model5) to the best-performing reference method (Model3). Our results showed a statistically significant difference between the AUC values of the two models (DeLong's p-value <1e − 10).

To further improve predictive accuracy, we used a second-layer GBM model that fused the predictions of the VGG-16-Attn CNN model (Model5) and the strongest reference model (Model3) with imaging features and clinical assessments ([Figs. 2C] and [6]). This stacked model (Model6) achieved the best AUC of 0.865 (0.838, 0.872), an AP of 0.447 (0.404, 0.491), and a Brier score of 0.084, outperforming both individual models. While the increase in AUC between the stacked model (Model6) and the VGG-16-Attn CNN model (Model5) was statistically significant (DeLong's p-value =0.0085), it was not highly significant.

Fig. 6 (A) ROC and (B) PR curves demonstrating the performance of the attention model (VGG-16-Attn), best clinical model (Model3), and stacked model (Model6). Area under the curves and 95% confidence intervals in parentheses were given based on a five-fold cross-validation setting. Dashed lines in ROC indicate the performance of a random classifier and in case of PR it indicates the distributions of the labels of the dataset (PFOA vs. non-PFOA). AUC, area under the receiver operating characteristic curve; BMI, body mass index; KL, Kellgren and Lawrence; PFOA, patellofemoral osteoarthritis; PR, precision–recall; ROC, receiver operating characteristics; WOMAC, Western Ontario and McMaster Universities Arthritis Index.

Examples of spatial attention maps are presented in [Fig. 7]. The shallower attention map which is applied after conv3 layer, focuses on more general and diffused areas. Therefore, we present here only the deeper attention map (after the conv4 layer in [Fig. 2]). In various cases, the model paid attention to the PF joint space width and the inferior and posterior regions of patellar bone. Additional examples of such attention maps are presented in the [Supplementary Figs. S3] and [S4] (available in the online version).

Fig. 7 Examples of attention maps of the two progressor knees from the dataset. First column shows the baseline radiographs in which the knee does not have PFOA yet. Middle column illustrates the attention maps and finally last column presents the final follow-up radiographs. PFOA, patellofemoral osteoarthritis.

Discussion

This study presents a novel deep learning-based approach for predicting progression of PFOA, utilizing both clinical variables and imaging data. The results demonstrate the potential of ML techniques, especially deep learning, in predicting PFOA progression, which could provide valuable information for clinicians in patient care.

In general, ML-based models can handle heterogeneous data and they can identify patterns that may not be apparent to human experts. We highlighted this by the inclusion of both clinical variables and imaging data into the stacked model. This combination model achieved the highest accuracy in predicting PFOA progression, indicating its ability to differentiate between patients who are likely to experience PFOA and those who are not. However, it should be still noted that the performance gain with the stacked model (AUC = 0.865, AP = 0.447), compared to the imaging-based model (AUC = 0.856, AP = 0.431), was only minor and, although statistically significant, probably the clinical gain might be insignificant. Consequently, this suggests that clinical variables have only minor contribution to the prediction performance on top of the X-ray image alone. Similarly, as in the case of knee OA progression prediction,[27] it looks like that a knee lateral X-ray image already includes indirectly a lot of clinical information, such as age and BMI.

Our study confirmed that high BMI, high WOMAC score, female sex, and OA in the TF joint (KL score) are all risk factors for PFOA development ([Supplementary Figs. S1] and [S2] [available in the online version] and [Table 1]). Out of the three main demographical variables age, sex, and BMI in isolation (Model1), the strongest predictive capability was high BMI.

It has been earlier reported that the use of attention mechanism increases the performance of NLP models.[22] [28] Here, we also observed the increased performance in this kind of image classification task (AUC = 0.856 vs. 0.832, AP = 0.431 vs. 0.400). Besides the increase in overall model performance, generated attention maps highlighted the joint space and the regions where osteophytes typically occur. These regions are known to be affected in PFOA, and they reflect manual imaging biomarkers of OA, including JSN and morphological and structural changes in bone.

The present study is unique as it investigated the potential of ML approaches based on imaging data to accurately predict PFOA progression for the first time. However, there are also some limitations of this study. First and foremost, the model was trained on data from a single population, and further research is necessary to validate the model's generalizability to other populations and settings. Additionally, the study did not consider other potential predictors of PFOA progression, such as biomechanical or genetic factors. Incorporating longitudinal data and other types of imaging data, such as MRI, could further improve the model.

In conclusion, our study demonstrates the potential of ML models to predict PFOA progression using imaging and clinical variables. These models could assist in identifying patients at high risk of PFOA progression, enabling clinicians to intervene with personalized treatment plans and potentially prevent or delay disease progression.

Summary

• We present the first study for predicting PFOA progression based on a multimodal ML method using lateral X-ray images and clinical data.

• We leveraged trainable attention mechanism to highlight regions in lateral X-rays which highly contributed to the decision of the model.

• We compared the performances of deep CNN-based models and GBM-based models using clinical variables including age, sex, BMI, the total WOMAC score, and KL score of the TF joint.

• Finally, we proposed a stacked model where both deep CNN predictions and predictions from clinical model are combined with a second-level ML model—GBM.

• Our results demonstrated that imaging biomarkers contain useful information for predicting PFOA progression within 7 years. Moreover, addition of clinical data slightly improves the prediction power of the imaging-based model, although the clinical significance of this performance gain is unknown.

• Predicting PFOA progression/development has the potential to improve the early diagnosis, management, and treatment of PFOA.

Conflict of Interest

I.K.H. received consulting fees from Novartis, GSK, and Grünenthal. He also received honorarium from Abbvie. M.E. is a president of OARSI (Osteoarthritis Research Society International). S.S. is an Associate Editor of Associate Editor for Osteoarthritis and Cartilage Open journal. All other authors have nothing to declare.

Acknowledgment

We gratefully acknowledge Claudia Lindner for providing the BoneFinder® tool and lateral knee active shape model; Aleksei Tiulpin for providing an interface to BoneFinder to fully leverage multiple processors; and the support of NVIDIA Corporation for the donation of the Quadro P6000 GPU used in this research.

Authors' Contribution

N.B. originated the idea of the study, and performed the experiments and took major part in writing of the manuscript. S.S. supervised the project. All authors participated in producing the final manuscript draft and approved the final submitted version.

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Publication History

Received: 12 August 2023

Accepted: 29 March 2024

Accepted Manuscript online:
11 April 2024

Article published online:
14 May 2024