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Identification of potential plantar ulceration among diabetes patients using plantar soft tissue stiffness
Journal Pre-proof Identification of potential plantar ulceration among diabetes patients using plantar soft tissue stiffness Jee Chin Teoh, Taeyong Lee PII:
S1751-6161(19)30531-4
DOI:
https://doi.org/10.1016/j.jmbbm.2019.103567
Reference:
JMBBM 103567
To appear in:
Journal of the Mechanical Behavior of Biomedical Materials
Received Date: 16 April 2019 Revised Date:
9 November 2019
Accepted Date: 29 November 2019
Please cite this article as: Teoh, J.C., Lee, T., Identification of potential plantar ulceration among diabetes patients using plantar soft tissue stiffness, Journal of the Mechanical Behavior of Biomedical Materials (2019), doi: https://doi.org/10.1016/j.jmbbm.2019.103567. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Identification of potential plantar ulceration among diabetes patients using plantar soft tissue stiffness
Jee Chin Teoh, Taeyong Lee*
Division of Mechanical and Biomedical Engineering Faculty of Engineering EwhaWomans University Korea
Corresponding address: Taeyong Lee, Ph. D. Division of Mechanical and Biomedical Engineering ELTEC College of Engineering EwhaWomans University 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760 Republic of Korea Email: [email protected] Tel: +82 2 3277 2795 Fax: +82 2 3277 2846 Disclaimers: No conflict of interest
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Abstract and key terms This study investigates the relationship between plantar tissue stiffness and selected parameters, including age, diabetes mellitus (DM) duration, body mass index (BMI), and HbA1c level. 70 diabetes patients with no foot problems were recruited. The plantar soft tissue at the 2nd sub-metatarsal head (MTH) pad was examined using the novel indentation system developed. The stiffness constant, K, was used to describe the tissue stiffness. The four factors (age, DM duration, BMI, and HbA1c level) were plotted against the plantar tissue stiffness. The scatter plots revealed that a higher plantar tissue stiffness was usually associated with (1) BMI>25kgm-2, (2) HbA1c score >10% (86mmol/mol), and (3) DM duration >10years. The three risk criteria were further evaluated using the binary classification test. The predictions were reported to be fairly accurate and reliable in detecting stiffened tissues. The study has successfully identified the strong association of BMI, HbA1c, and DM duration with the plantar tissue properties. Special attention should be given to the high risk group with BMI>25kgm-2, HbA1c score >10% (86mmol/mol), and DM duration >10 years. The high diagnostic odds ratio attained suggests its potential usefulness in helping clinicians to diagnose diabetic foot more efficiently.
Key terms Diabetic Ulcer; Plantar Tissue Stiffness; Indentation; Body Mass Index; HbA1c
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1.
Introduction Diabetes mellitus (DM) is a 21st century epidemic affecting 6.7% of the world’s adult
population. This figure is expected to rise to 10.4% by 2040, as reported in the Diabetes Atlas (Federation, 2015). Singapore has a diabetic prevalence of 10.5%, which is one of the highest in the developed countries. Despite a good team approach, below knee amputation rate in the country is about 11% among patients with diabetic foot complications (Nather et al., 2010). The profound impact of diabetes on life expectancy and quality of life warrants continuous improvement in screening modalities to allow early detection and prevention. The pathological changes among diabetics occur at a cellular level (Sharma, 2015). Chemical reactions between reducing glucose and cellular proteins generate advanced glycation end products (AGE) (Ahmed and Thornalley, 2007). These compounds attach to biological tissues throughout the body, including skin, connective tissue, and blood vessels, significantly altering the tissue behavior. Electron microscopy studies have supported this theory, showing evidence of glycation induced irregular collagen structure and arrangement (Bai et al., 1992; Grant et al., 1997). Accumulation of AGE accelerates tissue ageing that decreases tissue elasticity (Sell et al., 2005), in turn making the soft tissues stiffer and more prone to ulcers. Plantar soft tissue is a composite material composed of fatty and specific connective tissues located between the skin dermis and the bony segment of the foot (Natali et al., 2010). The adipose pad contains fibrous strands which form circular or cone shaped septa (Natali et al., 2012) that develop a honeycomb configuration. This structure has a resistance to external compressive loads, i.e. ground reaction forces during the stance phase of the gait cycle. The fatty chambers are filled with adipose tissues, reinforced by elastic transverse and diagonal fibers extended from the skin (Jahss et al., 1992). The plantar soft tissue is crucial in protecting the foot from external injuries. This cushioning ability is attributed to the tissue’s viscoelastic
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behavior. Therefore, as the tissue loses its viscoelasticity and stiffens abnormally due to the inhabitance of excessive AGE, the tissue will gradually surrender its competency to attenuate the ground impact (Gefen, 2003). The stiffened tissue is also more prone to rupture (Cheung et al., 2005) and has a higher risk of ulceration. The occurrence of plantar ulcers can result from several factors, such as aging (Teoh et al., 2014) and the presence of diabetes mellitus (DM). Clinical data suggest diabetic plantar soft tissues are significantly stiffer than agedmatched controls (Gefen et al., 2001; Sun et al., 2011; Zheng et al., 2000). These changes bring about unfavorable alterations to the stress-strain characteristics of collagen. The yield point and failure point are lowered, causing the diabetic tissue to be unreasonably brittle and more vulnerable to injuries (Verzijl et al., 2000). Several tools are available in current clinical practice for foot examination and diabetic foot risk assessment. The commonly used tools are monofilament, tuning fork, and biothesiometer. These recommended clinical appraisals evaluate the loss of protective sensation (LOPS), which is believed to be strongly associated with foot ulceration. A 10-g monofilament test is the neurological assessment generally used to diagnose sensory loss in DM patients. It is found to be useful in the screening of sensory loss and is predictive of foot ulceration (Salvotelli et al., 2015). However, a lack of consensus remains on the appropriate and reproducible threshold and standard (Dros et al., 2009) in the diagnosis. The resulting discrepancies have led to different conclusions in the foot screening procedure (McGill et al., 1999). In addition to the variation in the interpretation of diagnosis outcomes, Booth and Young pointed out the problem with monofilaments, whereby they may have different elastic moduli and performances due to environmental factors (Booth and Young, 2000). They reported that only 70% of the monofilament buckled as defined, resulting in inaccurate assessment. Consequently, the sole use of monofilament to examine diabetic foot is not recommended (Dros et al., 2009) due to the inadequate and inappropriate screening criteria
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(Booth and Young, 2000). These sensation rating assessments are still widely used to predict the tissue conditions and ulceration risks, even though they do not quantify the behavior of plantar soft tissue and the test results may not be conclusive. In fact, the loss of sensation, which is measured by neurological screening, is merely one of the more prevalent factors, but not the root cause of ulceration. Instead, the development of ulcers is caused by the failure of the tissue to withstand the repetitive high pressure (Scales et al., 1976). Naemi et al. found that inclusion of plantar soft tissue stiffness and thickness into their screening methodology improved the specificity (by 3%), the sensitivity (by 14%), the prediction accuracy (by 5%) and the prognosis strength (by 1%) of their proposed predictor model. Their finding is in accordance with the postulation of possible association between plantar tissue stiffness and the tissue health status (Chatzistergos et al., 2014; Ledoux et al., 2016; Naemi et al., 2015; Naemi et al., 2017; Wang et al., 2017). Perhaps, a direct measurement of the tissue characteristic such as stiffness may be a good simple alternative to improve the diagnosis of diabetic foot (Naemi et al., 2017; Teoh and Lee, 2016). The input from such measurement on tissue properties and the sensation evaluation will certainly provide clinicians with a more complete picture of the foot pathology. In fact, great amount of efforts have been put into the establishment of models that predict the occurrence of diabetic ulcer (Boyko et al., 2006; Naemi et al., 2017; Pham et al., 2000). However, most of these prediction models requires clinical information (such as foot sensation testing (Boyko et al., 1999), thermography (Lavery et al., 2004), and plantar pressure measurement (Veves et al., 1992)) from the clinicians to better estimate the ulceration risk. These models may not effectively alleviate the burden to the patients and the healthcare system as patients still have to visit their clinicians and undergo a series of foot screening tests.
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The objective of this study is to evaluate the relationship between plantar tissue stiffness and several easily acquired parameters, including age, DM duration (years of DM), body mass index (BMI), and HbA1c level. Understanding the associations between these factors is certainly helpful to clinicians in identifying high risk patients, so that treatment options and precautions can be more efficiently recommended. Besides, the study also attempts to deliver an easy mass screening tool which can be used by the patients as a general guide at home. Foot screening can thus be performed more effectively and reliably at a reduced cost and effort.
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Materials and Methods
2.1. Subjects Seventy diabetes patients from the National University Hospital (NUH) were recruited with approvals from the National University of Singapore (NUS) Institutional Review Board (IRB) and the National Healthcare Group (NHG) Domain Specific Review Board (DSRB). Eligible participants were men and women between the ages of 40 and 70 years, of all racial and ethnic groups who have no foot deformities and have not undergone foot surgeries. Those with heel ulcers, as well as limb and foot amputees and participants with previous foot surgeries were excluded from the analysis. The patient data (e.g. age, BMI, and DM duration) were recorded. All recruited patients underwent serum analysis for HbA1c levels.
2.2. Plantar Soft Tissue Testing The tissue indentation system (Chen et al., 2011) as shown in Fig. 1 consisted of a 5mm diameter hemispherical tipped probe driven by a stepper motor (MYCOM, Singapore). A linear actuator was incorporated to convert the rotary motion of the stepper motor into
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linear motion to execute the indentation procedure. The force response of the plantar soft tissue was measured by a miniature compression load cell (FUTEK, USA) which was placed at the lower end of the probe tip. The output signal was fed into the data acquisition module (Tokyo Sokki Kenkyujo, Japan) for visualization. The system had a foot positioning device with two acrylic plates which were connected by a hinge joint. This flexible design allowed indentation of plantar soft tissue at various metatarsophalangeal joint (MTPJ) dorsiflexion angles (Fig. 1A) to mimic the different foot conditions in stance phase. Velcro straps could also be added to stabilize the foot and to prohibit any undesirable movements of the foot during the assessment. A cylindrical hole was drilled into the forefoot plate to accommodate the indenter probe as depicted in Fig. 1B. The hole was filled entirely by the indenter probe to prevent the bulging of plantar soft tissue into the porthole during the experiment. The indenter tip was adjusted to be completely level with the surface of the forefoot plate at the beginning of the indentation procedure. At least 3 indentation cycles were induced onto the selected plantar regions during tissue assessment. Each indentation cycle comprised a loading and unloading phase. The average deformation of plantar soft tissues was about 7mm (45.7% of unloaded tissue thickness) (Cavanagh, 1999) and 10.3mm (53.9% of unloaded tissue thickness) (Wearing et al., 2009) at the sub-metatarsal head (MTH) and heel pad respectively. However, a previous study by Teoh et al. (Teoh et al., 2015) reported that a minimum indentation of 2.5mm is necessary to mimic the realistic behavior of plantar soft tissues. Hence, the maximum indentation depth of the experiment was set at 4mm. Indentation tests were conducted on the 2nd sub-MTH pad at a 0º MTPJ angle. The region selected is one of the major load transmission points with high incidence of ulceration in DM patients (Cowley et al., 2008). Loading on foot was maintained at 50% bodyweight by monitoring the load on the untested foot using a weighing scale as shown in Fig. 1C.
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Tissue preconditioning was performed by applying three cycles of indentation onto the tissue before the actual testing. Another three cycles of indentation were induced during the data acquisition. The initial state was defined as the instant when the indenter tip was barely touching the plantar tissue and there was no tissue deformation. Measurement was conducted on the left foot of all subjects. When an indentation cycle was induced onto the selected plantar region, the plantar soft tissue was subjected to deformation in the form of compression. The elastic component of the soft tissue then responded by restoring the tissue. The tissue resistance to the deformation was quantified as the stiffness constant, K. Stiffness constant, K N⁄mm =
Tissue reaction force N Tissue deformation mm
The tissue reaction force was the plantar soft tissue response to resist the compressive load exerted by the indentation probe and it could be measured by the load cell embedded in the indenter. Tissue deformation was the extent of compression experienced by the tissue which was equal to the predetermined indentation depth.
2.3. Data Analysis Scatter plots were computed with stiffness values as a function of the various parameters examined. Correlation analysis were also conducted to examine the relationship between the parameters and stiffness values. The risk criteria of stiffened tissue were determined based on the plots. The criteria were then assessed using the binary classification test. The results were modeled into a two-class prediction problem, as shown in Table 1. Evaluation was performed on the risk criteria individually and collectively. The important parameters derived were sensitivity, specificity, precision, accuracy, F1 score, and the diagnostic odds ratio (DOR). Sensitivity was used to measure the actual positives that are correctly identified. On the other hand, specificity was considered as the opposite to 8
sensitivity, and was used to measure the actual negatives that were correctly rejected. Precision was used to measure the proportion of correctly identified actual positives in the positively identified cases. Accuracy was considered as the degree to which the prediction criteria conformed to the stiffness measurement. The F1 score was another measure of accuracy, and considered both the precision and sensitivity of the test. The DOR assessed the effectiveness of a diagnostic test, which served as a convenient indicator of performance in many screening tests.
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Results The average tissue stiffness of 70 patients was 6.69 N/mm, with a standard deviation
of 3.07 N/mm. The scatter plots describe the tissue stiffness in terms of N/mm as a function of the variables examined, i.e. age, DM duration, HbA1c score and BMI. Fig. 2A correlates the stiffness values of DM patients with DM duration. The data points are observed to be concentrated at the top right and bottom left regions of the scatter plot. Higher plantar tissue stiffness is generally found in patients with longer DM record. On the other hand, lower stiffness values are often identified in patients with relative shorter DM duration. No conclusive pattern is observed between the patient’s age and tissue stiffness as shown in Fig. 2B. The tissue stiffness values are randomly scattered, implying the weak association between the two variables. There is no noticeable elevation of tissue stiffness as the age increases along the horizontal axis. The factor of age does not explicitly account for the changes in tissue stiffness among the DM patients. It is also discovered that patient’s age and DM duration has little correlation (R2 < 0.01). This counter intuitive finding suggests that older DM patients do not necessarily have a longer duration of DM.
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Fig. 2C compares plantar tissue stiffness with HbA1c score. Data points are observed to be aggregated at the top right and bottom left of the figure. Based on the results, it is deduced that DM patients with HbA1c scores higher than 10% (86mmol/mol) often have higher stiffness values. Meanwhile majority of DM patients with HbA1c scores less than 10% have lower tissue stiffness. In reference to Fig. 2D, BMI is found to be a strong contributing factor to the stiffening of plantar soft tissue. The tissue stiffness increases as BMI increases. The scattering of data points follows the same pattern as depicted in Fig. 2A and 2C. A BMI of 25kgm-2 is perceived to be the cut-off. Patients are more likely to have higher tissue stiffness if the BMI exceeds 25kgm-2 and lower stiffness if the BMI remains below 25kgm-2. From the correlation analysis, the parameters and the tissue stiffness values are only weakly associated (R2 < 0.1). Nonetheless, certain regions of the plots are observed to have higher number of data points whereas some other regions are scarce. From Fig. 2, it can be concluded that several risk criteria generally contribute to higher plantar tissue stiffness in patients. Among the factors examined, HbA1c scores, BMI, and DM duration are the factors positively associated with the change of tissue stiffness. Meanwhile, the age of patients does not have a significant influence in altering the tissue condition. In order to better understand the results, the plots are divided into four quadrants. Horizontal reference lines in Fig. 2 denote the average tissue stiffness value computed. A tissue stiffness above the average score (i.e. 6.69 N/mm) of the 70 patients recruited means the patient has stiffened tissue. Otherwise, the tissue is considered to be healthy tissue. Vertical reference lines represent the threshold risk criteria of the respective parameters. The vertical reference line is fixed at the point such that there are maximum number of data points in the first and third quadrant of the scatter plot. The derived risk criteria of stiffened tissue are as follows:
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1) BMI>25kgm-2 2) HbA1cscore >10% (86mmol/mol) 3) DM duration >10 years The results are modelled into a two-class prediction problem. The test outcomes are the predictions using the three risk criteria stated above. The outcome can be positive (predicting the tissue is stiffened) and negative (predicting the tissue is healthy). The prediction test outcome may or may not match the patient’s actual measurement results. The four possible outcomes are as shown in Table 1. The statistical measures of the performance of prediction by the risk criteria are given in Table 2. True positive and true negative cases are represented by the first and third quadrants of the scatter plots (Fig. 2) respectively; while false positive and false negative are corresponding to the second and fourth quadrants. The performance of prediction using a single criterion is generally not satisfactory with very low DOR, except for BMI criterion which has a DOR slightly more than 10. BMI criterion also achieves relatively higher scores in sensitivity, accuracy and F1 score as compared to the other two criteria. However, the DOR which measures the effectiveness of diagnostic test still remains low. For the multiple criteria evaluation, in the first case of “any 2 criteria”, the prediction test outcome is positive if the patient meets any two of the three criteria stated, while the outcome is negative if the patient meets only one criterion or none. The accuracy and DOR obtained are still below satisfaction, at 0.700 and 5.816 respectively. Meanwhile in the case of “all 3 criteria”, the outcome is assigned as positive only if all three criteria are met. In this multivariate evaluation, the performance of prediction improves. The highest score in accuracy is achieved at 0.743, with DOR reaches 37.647, suggesting the feasibility in speculating the stiffness of plantar soft tissue in DM patients. The
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case of “all 3 criteria” is found to be a better screening method than the cases of single criteria and “any 2 criteria”. In other words, the patients who meet the three listed risk criteria are tending to have higher than average tissue stiffness and those who do not are more likely to have healthier plantar soft tissues.
4.
Discussion This paper is designed to study the relationship between plantar tissue stiffness and
four easily acquired parameters, including age, DM duration, BMI, and HbA1c level. Apart from examining these risk factors, the paper aims to come out with a user-friendly gauge tool to enable self-evaluation of one’s foot health. The ultimate goal is to provide a straightforward mass screening method in the form of an idiot-proof index, e.g. BMI which is commonly used to predict the risk of a number of chronic diseases, that is applicable to all DM patients to estimate their foot health and ulceration risk. The self-identified at-risk patients can then proceed to consult clinicians for further and detailed assessment. Overall increased understanding on the tissue behavior and ulceration risk, coupled with the following sensation examination can considerably improve the judgments in diagnosing diabetic foot. From the results, it can be deduced that the HbA1c score has an influential role in altering the tissue stiffness. HbA1c is the glycated form of hemoglobin, which can be used to assess the average plasma glucose concentration over prolonged periods of time. A high HbA1c score of above 9.0% (75mmol/mol) indicates poor control of blood sugar in diabetic patients. Fig. 2C demonstrates that patients with a tissue stiffness above the average (i.e. 6.69N/mm) are usually those with a HbA1c score greater than 10% (86mmol/mol). Prolonged exposure to high blood glucose incurs pathological changes by enhancing the reactions between reducing glucose and cellular protein that increases the formation of AGE (Ahmed
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and Thornalley, 2007). Accumulation of these compounds decreases the elasticity of tissue due to the excessive intermolecular cross linking and adversely modified side-chains (Bailey, 2001). A large cohort of data has shown glycated collagen to be consistent with the HbA1c level (Monnier et al., 1999). Based on the results, BMI is also a key indicator of tissue stiffness. BMI is an established measure of the relative size of an individual based on their weight and height. It is widely used as the preliminary diagnosis of obesity. According to the World Health Organization (WHO), a BMI of less than 18.5kgm-2 is considered as underweight, while a BMI of more than 25kgm-2 is regarded as overweight and above 30 is designated as obese. It can be inferred from Fig. 2D that patients with a BMI greater than 25 are often those who have been diagnosed with high tissue stiffness. This may be explained by the strong relationship between high BMI and DM (Colditz et al., 1990; Edelstein et al., 1997; Knowler et al., 1981). It is also postulated that a loss in weight and BMI effectively improve glycemic control (Heilbronn et al., 1999). In other words, high BMI may cause the increase in HbA1c which may undesirably stiffen the tissue through the process of accelerated tissue glycation. DM duration above 10 years is another common characteristic among the patients with stiffened tissue. Various studies have suggested a strong relationship between duration of DM and the presence of peripheral neuropathy. Peripheral neuropathy is the most extensively studied risk factor of DM foot ulcers (Akanji et al., 1989; Jones et al., 1992; Walters et al., 1992). The loss of protective pain sensation results in abnormal stress concentration and uneven pressure distribution over the plantar regions of the foot (Okuyama et al., 1983), which lead to impaired tissue properties and eventually the breakdown of tissue. In fact, Oguejiofor et al. reported that 100% of the DM patients recruited with DM duration of more than 15 years suffer from peripheral neuropathy (Oguejiofor et al., 2010). This may
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explain the association of DM duration of >10 years (69.0 % with DM duration > 15 years) with high tissue stiffness values as shown in Fig. 2A. On the other hand, the age of the patient does not significantly affect the tissue response. Even in young patients with a short duration of diabetes, the tissue stiffness may still be adversely increased, depending on the other factors. The effect of BMI, HbA1c, and DM duration may have priority over the effect of aging. The performance of the prediction method proposed is compared to the 5.07/10g Semmes-Weinstein monofilament test, which is widely used by the medical practitioners for the screening of diabetic peripheral neuropathy (DPN). The sensitivity, specificity and DOR of monofilaments for detecting DPN are reported within the range of 0.06 – 0.59, 0.68 – 0.98 and 1.92 – 13.99 respectively (Baraz et al., 2014; Pambianco et al., 2011; Pourhamidi et al., 2014). The performance of the proposed prediction method in identifying stiffened tissue is found to be as good as or better than the monofilaments in diagnosing DPN. In fact, DOR of 10.00 is considered a very good test by current clinical standard (ter Riet et al., 2001). The introduction of stiffness measurement into the screening matrix has been reported to enhance the identification of plantar tissue at risk and to improve the prediction of diabetic foot ulcer (Naemi et al., 2017). The use of indentation methodology to acquire tissue status by mechanical means is more direct than the inferential palpation tests, which can be prejudiced by the subjective judgements of patients. This study uses load cell to quantify tissue response against the controlled tissue deformation. The approach is slightly different from the elastography studies with the aid of ultrasonic and OCT modules, that examine tissue deformation against external indentation force. Our instrumented indentation system with real time force feedback enables the tissue measurement to be conducted under load bearing condition, a tissue state whereby diabetic ulceration is more likely to occur. The tissue deformation rate of tissue can also be
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manipulated to mimic realistic loading condition. In this study, the rate is fixed at 12.3mm/s. The value is still distinctly lower than the actual loading rate of mild physical activity such as walking, nevertheless, it is one of the highest rate achieved among the plantar tissue studies (Chao et al., 2010; Chatzistergos et al., 2014; Klaesner et al., 2001; Kwan et al., 2010; Parker et al., 2015; Pathak et al., 1998; Sun et al., 2011; Zheng et al., 2000). Unfortunately, the comparison of plantar stiffness values obtained between the two major approaches (i.e. elastography and force feedback) is difficult due to the different measurement mechanisms. In addition, there is still a lack of consensus on the indentation parameters, even among those studies with the same acquisition technique. This makes the sharing and comparison of the tissue stiffness values, which depend greatly on the experimental condition and subjects’ physical attributes, a very challenging task. In brief, the results suggest that patients with BMI higher than 25kgm-2 or HbA1c score >10% (86mmol/mol) or DM duration >10 years are likely to have stiffened plantar tissue that require special attention to prevent the occurrence of foot ulcers. The study has generated useful results in the diagnosis of foot complications. However, several limitations need to be acknowledged. The sample size is rather small and may not be representative of a wider diabetes population. More subjects from diverse backgrounds and from all walks of life, e.g. various ethnicity, lifestyles and diet preferences, need to be recruited in the future study in order to derive more persuasive and useful conclusions. In addition, another source of error is the negligence of other potential risk factors such as diet and physical activity level, which may eventually be significant contributors to the stiffening of plantar soft tissues. Research that is more extensive and that encompasses more causes of tissue stiffening should be performed to further expand the scope of the study. The findings are considered to provide useful insights that can be utilized to enhance the efficiency of the current clinical assessment.
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The association of BMI with the health of plantar soft tissue was successfully observed. On the other hand, the influence of HbA1c and DM durations are not insignificant. Additional study with larger sample size and stricter selection criteria has to be conducted to further verify the effects of these factors on plantar tissue behaviour. Special consideration should be given to the high risk group of BMI > 25 kgm-2, HbA1c >10% (86mmol/mol), and DM duration >10 years. The high accuracy and DOR of predicting the tissue stiffness measurement by considering all three criteria suggests the feasibility of this prediction method in assessing a patient’s foot health. It can be a simple yet effective screening tool to identify patients with a potential foot problem. Advice can be then given to these patients to undergo a more detailed assessment.
Acknowledgements The authors acknowledge Dr Kenjin Tan and Dr Khoo Chee Meng, National University Hospital, Singapore, for their devoted contribution in the experiment. The study was supported by National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. NRF-2019R1F1A1058182).
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Figure Legend Figure 1. Schematic diagram (A) and experimental setup (B) of indentation system. Subject was instructed to stand on the platform during indentation procedure (C)(Teoh et al., 2015).
Figure 2. Scatter plots of tissue stiffness as a function of DM duration (A), age (B), HbA1c(C) and BMI (D). Horizontal reference lines denote the average tissue stiffness value computed (i.e. 6.69 N/mm). Vertical reference lines represent the threshold risk criteria of the respective parameters.
Table Legend
Table 1. Four possible outcomes formulated in a 2 X 2 contingency table
Table 2. Diagnostic testing on the proposed criteria
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Naemi, R., Chatzistergos, P., Suresh, S., Sundar, L., Chockalingam, N., Ramachandran, A., 2017. Can plantar soft tissue mechanics enhance prognosis of diabetic foot ulcer? Diabetes Research and Clinical Practice 126, 182-191. Natali, A.N., Fontanella, C.G., Carniel, E.L., 2010. Constitutive formulation and analysis of heel pad tissues mechanics. Med Eng Phys 32, 516-522. Natali, A.N., Fontanella, C.G., Carniel, E.L., 2012. A numerical model for investigating the mechanics of calcaneal fat pad region. Journal of the mechanical behavior of biomedical materials 5, 216-223. Nather, A., Siok Bee, C., Keng Lin, W., Xin-Bei Valerie, C., Liang, S., Tambyah, P.A., Jorgensen, A., Nambiar, A., 2010. Value of team approach combined with clinical pathway for diabetic foot problems: a clinical evaluation. Diabetic foot & ankle 1. Oguejiofor, O.C., Odenigbo, C.U., Oguejiofor, C.B., 2010. Evaluation of the effect of duration of diabetes mellitus on peripheral neuropathy using the United Kingdom screening test scoring system, bio-thesiometry and aesthesiometry. Nigerian journal of clinical practice 13, 240-247. Okuyama, M., Nagai, K., Miyazaki, S., Kosaka, J., Kamikubo, K., Miura, K., Matsumoto, K., Inada, K., 1983. Diabetic gangrene in Japan: analysis of 487 cases. The Tohoku journal of experimental medicine 141 Suppl, 583-586. Pambianco, G., Costacou, T., Strotmeyer, E., Orchard, T.J., 2011. The assessment of clinical distal symmetric polyneuropathy in type 1 diabetes: a comparison of methodologies from the Pittsburgh Epidemiology of Diabetes Complications Cohort. Diabetes research and clinical practice 92, 280-287. Parker, D., Cooper, G., Pearson, S., Crofts, G., Howard, D., Busby, P., Nester, C., 2015. A device for characterising the mechanical properties of the plantar soft tissue of the foot. Medical Engineering and Physics 37, 1098-1104. Pathak, A.P., Silver-Thorn, M.B., Thierfelder, C.A., Prieto, T.E., 1998. A rate-controlled indentor for in vivo analysis of residual limb tissues. IEEE Transactions on Rehabilitation Engineering 6, 12-20. Pham, H., Armstrong, D.G., Harvey, C., Harkless, L.B., Giurini, J.M., Veves, A., 2000. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 23, 606-611. Pourhamidi, K., Dahlin, L.B., Englund, E., Rolandsson, O., 2014. Evaluation of clinical tools and their diagnostic use in distal symmetric polyneuropathy. Primary care diabetes 8, 7784. Salvotelli, L., Stoico, V., Perrone, F., Cacciatori, V., Negri, C., Brangani, C., Pichiri, I., Targher, G., Bonora, E., Zoppini, G., 2015. Prevalence of neuropathy in type 2 diabetic patients and its association with other diabetes complications: The Verona Diabetic Foot Screening Program. Journal of diabetes and its complications 29, 1066-1070. Scales, J.T., Kenedi, R.M., Cowden, J.M., 1976. Bedsore biomechanics : proceedings of a seminar on tissue viability and clinical applications. Sell, D.R., Biemel, K.M., Reihl, O., Lederer, M.O., Strauch, C.M., Monnier, V.M., 2005. Glucosepane is a major protein cross-link of the senescent human extracellular matrix. Relationship with diabetes. The Journal of biological chemistry 280, 12310-12315. Sharma, K., 2015. Mitochondrial hormesis and diabetic complications. Diabetes 64, 663-672. Sun, J.H., Cheng, B.K., Zheng, Y.P., Huang, Y.P., Leung, J.Y., Cheing, G.L., 2011. Changes in the thickness and stiffness of plantar soft tissues in people with diabetic peripheral neuropathy. Archives of physical medicine and rehabilitation 92, 1484-1489. Teoh, J.C., Lee, T., 2016. Prediction of plantar soft tissue stiffness based on sex, age, bodyweight, height and body mass index. Journal of the mechanical behavior of biomedical materials 54, 219-222. 20
Teoh, J.C., Lim, B.Y., Lee, T., 2015. Minimum indentation depth for characterization of 2nd sub-metatarsal head and heel pad tissue properties. J Biomech 48, 2096-2101. Teoh, J.C., Shim, V.P., Lee, T., 2014. Quantification of plantar soft tissue changes due to aging in various metatarsophalangeal joint angles with realistic tissue deformation. J Biomech 47, 3043-3049. ter Riet, G., Kessels, A.G., Bachmann, L.M., 2001. Systematic reviews of evaluations of diagnostic and screening tests. Two issues were simplified. BMJ (Clinical research ed.) 323, 1188. Verzijl, N., DeGroot, J., Oldehinkel, E., Bank, R.A., Thorpe, S.R., Baynes, J.W., Bayliss, M.T., Bijlsma, J.W., Lafeber, F.P., Tekoppele, J.M., 2000. Age-related accumulation of Maillard reaction products in human articular cartilage collagen. The Biochemical journal 350 Pt 2, 381-387. Veves, A., Murray, H.J., Young, M.J., Boulton, A.J.M., 1992. The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia 35, 660-663. Walters, D.P., Gatling, W., Mullee, M.A., Hill, R.D., 1992. The prevalence of diabetic distal sensory neuropathy in an English community. Diabetic medicine : a journal of the British Diabetic Association 9, 349-353. Wang, Y.-N., Lee, K., Shofer, J.B., Ledoux, W.R., 2017. Histomorphological and Biochemical Properties of Plantar Soft Tissue in Diabetes. Foot, The 33, 1-6. Wearing, S.C., Smeathers, J.E., Yates, B., Urry, S.R., Dubois, P., 2009. Bulk compressive properties of the heel fat pad during walking: a pilot investigation in plantar heel pain. Clinical biomechanics (Bristol, Avon) 24, 397-402. Zheng, Y.P., Choi, Y.K., Wong, K., Chan, S., Mak, A.F., 2000. Biomechanical assessment of plantar foot tissue in diabetic patients using an ultrasound indentation system. Ultrasound in medicine & biology 26, 451-456.
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Table 1. The four possible outcomes formulated in a 2X2 contingency table
Actual Condition (stiffness measurement) Positive (stiffness > average) True Positive correctly identified
Positive (identified) Test Outcome (prediction by the criteria)
Stiffened tissue is correctly predicted as stiffened tissue
False Negative Negative (rejected)
incorrectly rejected Stiffened tissue predicted as healthy tissue
Negative (stiffness < average) False Positive incorrectly identified Healthy tissue predicted as stiffened tissue
True Negative Correctly rejected Healthy tissue is correctly predicted as healthy tissue
Table 2. Diagnostic testing on the proposed criteria Descriptions True positive (TP) True negative (TN) False positive (FP) False negative (FN) True positive rate (TPR) or sensitivity True negative rate (TNR) or specificity Positive predictive value (PPV) or precision Negative predictive value (NPV) False positive rate (FPR) or fall-out rate False discovery rate (FDR) False negative rate (FNR) or miss rate Accuracy (ACC) F1 score Diagnostic odd ratio (DOR)
Single criteria DM duration > 10 yrs HbA1c> 10 29 24 15 26 18 7 8 13
BMI > 25kgm 34 16 17 3
-2
Multiple criteria Any 2 criteria All 3 criteria 30 20 19 32 14 1 7 17
0.784
0.649
0.919
0.811
0.541
0.455
0.788
0.485
0.576
0.97
0.617
0.774
0.667
0.682
0.952
0.652
0.667
0.842
0.731
0.653
0.545
0.212
0.515
0.424
0.030
0.383
0.226
0.333
0.318
0.048
0.216
0.351
0.081
0.189
0.459
0.629 0.690
0.714 0.706
0.714 0.773
0.700 0.741
0.743 0.690
3.021
6.857
10.667
5.816
37.647
April 15, 2019
Prof. Markus Buehler, Ph.D. Editor-in-Chief Journal of the Mechanical Behavior of Biomedical Materials Laboratory for Atomistic and Molecular Mechanics (LAMM) Department of Civil and Environmental Engineering (CEE) Massachusetts Institute of Technology Cambridge, Massachusetts U.S.A.
Conflict of Interest
Disclosure of potential conflict of interest: The authors declared that no conflict of interest exists.
Regards,
Taeyong Lee, Ph. D. Division of Mechanical and Biomedical Engineering Ewha Womans University 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760 Korea Email: [email protected] Tel: +82 2 3277 2795 Fax: +82 2 3277 2846
S1751-6161(19)30531-4
DOI:
https://doi.org/10.1016/j.jmbbm.2019.103567
Reference:
JMBBM 103567
To appear in:
Journal of the Mechanical Behavior of Biomedical Materials
Received Date: 16 April 2019 Revised Date:
9 November 2019
Accepted Date: 29 November 2019
Please cite this article as: Teoh, J.C., Lee, T., Identification of potential plantar ulceration among diabetes patients using plantar soft tissue stiffness, Journal of the Mechanical Behavior of Biomedical Materials (2019), doi: https://doi.org/10.1016/j.jmbbm.2019.103567. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.
Identification of potential plantar ulceration among diabetes patients using plantar soft tissue stiffness
Jee Chin Teoh, Taeyong Lee*
Division of Mechanical and Biomedical Engineering Faculty of Engineering EwhaWomans University Korea
Corresponding address: Taeyong Lee, Ph. D. Division of Mechanical and Biomedical Engineering ELTEC College of Engineering EwhaWomans University 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760 Republic of Korea Email: [email protected] Tel: +82 2 3277 2795 Fax: +82 2 3277 2846 Disclaimers: No conflict of interest
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Abstract and key terms This study investigates the relationship between plantar tissue stiffness and selected parameters, including age, diabetes mellitus (DM) duration, body mass index (BMI), and HbA1c level. 70 diabetes patients with no foot problems were recruited. The plantar soft tissue at the 2nd sub-metatarsal head (MTH) pad was examined using the novel indentation system developed. The stiffness constant, K, was used to describe the tissue stiffness. The four factors (age, DM duration, BMI, and HbA1c level) were plotted against the plantar tissue stiffness. The scatter plots revealed that a higher plantar tissue stiffness was usually associated with (1) BMI>25kgm-2, (2) HbA1c score >10% (86mmol/mol), and (3) DM duration >10years. The three risk criteria were further evaluated using the binary classification test. The predictions were reported to be fairly accurate and reliable in detecting stiffened tissues. The study has successfully identified the strong association of BMI, HbA1c, and DM duration with the plantar tissue properties. Special attention should be given to the high risk group with BMI>25kgm-2, HbA1c score >10% (86mmol/mol), and DM duration >10 years. The high diagnostic odds ratio attained suggests its potential usefulness in helping clinicians to diagnose diabetic foot more efficiently.
Key terms Diabetic Ulcer; Plantar Tissue Stiffness; Indentation; Body Mass Index; HbA1c
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1.
Introduction Diabetes mellitus (DM) is a 21st century epidemic affecting 6.7% of the world’s adult
population. This figure is expected to rise to 10.4% by 2040, as reported in the Diabetes Atlas (Federation, 2015). Singapore has a diabetic prevalence of 10.5%, which is one of the highest in the developed countries. Despite a good team approach, below knee amputation rate in the country is about 11% among patients with diabetic foot complications (Nather et al., 2010). The profound impact of diabetes on life expectancy and quality of life warrants continuous improvement in screening modalities to allow early detection and prevention. The pathological changes among diabetics occur at a cellular level (Sharma, 2015). Chemical reactions between reducing glucose and cellular proteins generate advanced glycation end products (AGE) (Ahmed and Thornalley, 2007). These compounds attach to biological tissues throughout the body, including skin, connective tissue, and blood vessels, significantly altering the tissue behavior. Electron microscopy studies have supported this theory, showing evidence of glycation induced irregular collagen structure and arrangement (Bai et al., 1992; Grant et al., 1997). Accumulation of AGE accelerates tissue ageing that decreases tissue elasticity (Sell et al., 2005), in turn making the soft tissues stiffer and more prone to ulcers. Plantar soft tissue is a composite material composed of fatty and specific connective tissues located between the skin dermis and the bony segment of the foot (Natali et al., 2010). The adipose pad contains fibrous strands which form circular or cone shaped septa (Natali et al., 2012) that develop a honeycomb configuration. This structure has a resistance to external compressive loads, i.e. ground reaction forces during the stance phase of the gait cycle. The fatty chambers are filled with adipose tissues, reinforced by elastic transverse and diagonal fibers extended from the skin (Jahss et al., 1992). The plantar soft tissue is crucial in protecting the foot from external injuries. This cushioning ability is attributed to the tissue’s viscoelastic
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behavior. Therefore, as the tissue loses its viscoelasticity and stiffens abnormally due to the inhabitance of excessive AGE, the tissue will gradually surrender its competency to attenuate the ground impact (Gefen, 2003). The stiffened tissue is also more prone to rupture (Cheung et al., 2005) and has a higher risk of ulceration. The occurrence of plantar ulcers can result from several factors, such as aging (Teoh et al., 2014) and the presence of diabetes mellitus (DM). Clinical data suggest diabetic plantar soft tissues are significantly stiffer than agedmatched controls (Gefen et al., 2001; Sun et al., 2011; Zheng et al., 2000). These changes bring about unfavorable alterations to the stress-strain characteristics of collagen. The yield point and failure point are lowered, causing the diabetic tissue to be unreasonably brittle and more vulnerable to injuries (Verzijl et al., 2000). Several tools are available in current clinical practice for foot examination and diabetic foot risk assessment. The commonly used tools are monofilament, tuning fork, and biothesiometer. These recommended clinical appraisals evaluate the loss of protective sensation (LOPS), which is believed to be strongly associated with foot ulceration. A 10-g monofilament test is the neurological assessment generally used to diagnose sensory loss in DM patients. It is found to be useful in the screening of sensory loss and is predictive of foot ulceration (Salvotelli et al., 2015). However, a lack of consensus remains on the appropriate and reproducible threshold and standard (Dros et al., 2009) in the diagnosis. The resulting discrepancies have led to different conclusions in the foot screening procedure (McGill et al., 1999). In addition to the variation in the interpretation of diagnosis outcomes, Booth and Young pointed out the problem with monofilaments, whereby they may have different elastic moduli and performances due to environmental factors (Booth and Young, 2000). They reported that only 70% of the monofilament buckled as defined, resulting in inaccurate assessment. Consequently, the sole use of monofilament to examine diabetic foot is not recommended (Dros et al., 2009) due to the inadequate and inappropriate screening criteria
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(Booth and Young, 2000). These sensation rating assessments are still widely used to predict the tissue conditions and ulceration risks, even though they do not quantify the behavior of plantar soft tissue and the test results may not be conclusive. In fact, the loss of sensation, which is measured by neurological screening, is merely one of the more prevalent factors, but not the root cause of ulceration. Instead, the development of ulcers is caused by the failure of the tissue to withstand the repetitive high pressure (Scales et al., 1976). Naemi et al. found that inclusion of plantar soft tissue stiffness and thickness into their screening methodology improved the specificity (by 3%), the sensitivity (by 14%), the prediction accuracy (by 5%) and the prognosis strength (by 1%) of their proposed predictor model. Their finding is in accordance with the postulation of possible association between plantar tissue stiffness and the tissue health status (Chatzistergos et al., 2014; Ledoux et al., 2016; Naemi et al., 2015; Naemi et al., 2017; Wang et al., 2017). Perhaps, a direct measurement of the tissue characteristic such as stiffness may be a good simple alternative to improve the diagnosis of diabetic foot (Naemi et al., 2017; Teoh and Lee, 2016). The input from such measurement on tissue properties and the sensation evaluation will certainly provide clinicians with a more complete picture of the foot pathology. In fact, great amount of efforts have been put into the establishment of models that predict the occurrence of diabetic ulcer (Boyko et al., 2006; Naemi et al., 2017; Pham et al., 2000). However, most of these prediction models requires clinical information (such as foot sensation testing (Boyko et al., 1999), thermography (Lavery et al., 2004), and plantar pressure measurement (Veves et al., 1992)) from the clinicians to better estimate the ulceration risk. These models may not effectively alleviate the burden to the patients and the healthcare system as patients still have to visit their clinicians and undergo a series of foot screening tests.
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The objective of this study is to evaluate the relationship between plantar tissue stiffness and several easily acquired parameters, including age, DM duration (years of DM), body mass index (BMI), and HbA1c level. Understanding the associations between these factors is certainly helpful to clinicians in identifying high risk patients, so that treatment options and precautions can be more efficiently recommended. Besides, the study also attempts to deliver an easy mass screening tool which can be used by the patients as a general guide at home. Foot screening can thus be performed more effectively and reliably at a reduced cost and effort.
2.
Materials and Methods
2.1. Subjects Seventy diabetes patients from the National University Hospital (NUH) were recruited with approvals from the National University of Singapore (NUS) Institutional Review Board (IRB) and the National Healthcare Group (NHG) Domain Specific Review Board (DSRB). Eligible participants were men and women between the ages of 40 and 70 years, of all racial and ethnic groups who have no foot deformities and have not undergone foot surgeries. Those with heel ulcers, as well as limb and foot amputees and participants with previous foot surgeries were excluded from the analysis. The patient data (e.g. age, BMI, and DM duration) were recorded. All recruited patients underwent serum analysis for HbA1c levels.
2.2. Plantar Soft Tissue Testing The tissue indentation system (Chen et al., 2011) as shown in Fig. 1 consisted of a 5mm diameter hemispherical tipped probe driven by a stepper motor (MYCOM, Singapore). A linear actuator was incorporated to convert the rotary motion of the stepper motor into
6
linear motion to execute the indentation procedure. The force response of the plantar soft tissue was measured by a miniature compression load cell (FUTEK, USA) which was placed at the lower end of the probe tip. The output signal was fed into the data acquisition module (Tokyo Sokki Kenkyujo, Japan) for visualization. The system had a foot positioning device with two acrylic plates which were connected by a hinge joint. This flexible design allowed indentation of plantar soft tissue at various metatarsophalangeal joint (MTPJ) dorsiflexion angles (Fig. 1A) to mimic the different foot conditions in stance phase. Velcro straps could also be added to stabilize the foot and to prohibit any undesirable movements of the foot during the assessment. A cylindrical hole was drilled into the forefoot plate to accommodate the indenter probe as depicted in Fig. 1B. The hole was filled entirely by the indenter probe to prevent the bulging of plantar soft tissue into the porthole during the experiment. The indenter tip was adjusted to be completely level with the surface of the forefoot plate at the beginning of the indentation procedure. At least 3 indentation cycles were induced onto the selected plantar regions during tissue assessment. Each indentation cycle comprised a loading and unloading phase. The average deformation of plantar soft tissues was about 7mm (45.7% of unloaded tissue thickness) (Cavanagh, 1999) and 10.3mm (53.9% of unloaded tissue thickness) (Wearing et al., 2009) at the sub-metatarsal head (MTH) and heel pad respectively. However, a previous study by Teoh et al. (Teoh et al., 2015) reported that a minimum indentation of 2.5mm is necessary to mimic the realistic behavior of plantar soft tissues. Hence, the maximum indentation depth of the experiment was set at 4mm. Indentation tests were conducted on the 2nd sub-MTH pad at a 0º MTPJ angle. The region selected is one of the major load transmission points with high incidence of ulceration in DM patients (Cowley et al., 2008). Loading on foot was maintained at 50% bodyweight by monitoring the load on the untested foot using a weighing scale as shown in Fig. 1C.
7
Tissue preconditioning was performed by applying three cycles of indentation onto the tissue before the actual testing. Another three cycles of indentation were induced during the data acquisition. The initial state was defined as the instant when the indenter tip was barely touching the plantar tissue and there was no tissue deformation. Measurement was conducted on the left foot of all subjects. When an indentation cycle was induced onto the selected plantar region, the plantar soft tissue was subjected to deformation in the form of compression. The elastic component of the soft tissue then responded by restoring the tissue. The tissue resistance to the deformation was quantified as the stiffness constant, K. Stiffness constant, K N⁄mm =
Tissue reaction force N Tissue deformation mm
The tissue reaction force was the plantar soft tissue response to resist the compressive load exerted by the indentation probe and it could be measured by the load cell embedded in the indenter. Tissue deformation was the extent of compression experienced by the tissue which was equal to the predetermined indentation depth.
2.3. Data Analysis Scatter plots were computed with stiffness values as a function of the various parameters examined. Correlation analysis were also conducted to examine the relationship between the parameters and stiffness values. The risk criteria of stiffened tissue were determined based on the plots. The criteria were then assessed using the binary classification test. The results were modeled into a two-class prediction problem, as shown in Table 1. Evaluation was performed on the risk criteria individually and collectively. The important parameters derived were sensitivity, specificity, precision, accuracy, F1 score, and the diagnostic odds ratio (DOR). Sensitivity was used to measure the actual positives that are correctly identified. On the other hand, specificity was considered as the opposite to 8
sensitivity, and was used to measure the actual negatives that were correctly rejected. Precision was used to measure the proportion of correctly identified actual positives in the positively identified cases. Accuracy was considered as the degree to which the prediction criteria conformed to the stiffness measurement. The F1 score was another measure of accuracy, and considered both the precision and sensitivity of the test. The DOR assessed the effectiveness of a diagnostic test, which served as a convenient indicator of performance in many screening tests.
3.
Results The average tissue stiffness of 70 patients was 6.69 N/mm, with a standard deviation
of 3.07 N/mm. The scatter plots describe the tissue stiffness in terms of N/mm as a function of the variables examined, i.e. age, DM duration, HbA1c score and BMI. Fig. 2A correlates the stiffness values of DM patients with DM duration. The data points are observed to be concentrated at the top right and bottom left regions of the scatter plot. Higher plantar tissue stiffness is generally found in patients with longer DM record. On the other hand, lower stiffness values are often identified in patients with relative shorter DM duration. No conclusive pattern is observed between the patient’s age and tissue stiffness as shown in Fig. 2B. The tissue stiffness values are randomly scattered, implying the weak association between the two variables. There is no noticeable elevation of tissue stiffness as the age increases along the horizontal axis. The factor of age does not explicitly account for the changes in tissue stiffness among the DM patients. It is also discovered that patient’s age and DM duration has little correlation (R2 < 0.01). This counter intuitive finding suggests that older DM patients do not necessarily have a longer duration of DM.
9
Fig. 2C compares plantar tissue stiffness with HbA1c score. Data points are observed to be aggregated at the top right and bottom left of the figure. Based on the results, it is deduced that DM patients with HbA1c scores higher than 10% (86mmol/mol) often have higher stiffness values. Meanwhile majority of DM patients with HbA1c scores less than 10% have lower tissue stiffness. In reference to Fig. 2D, BMI is found to be a strong contributing factor to the stiffening of plantar soft tissue. The tissue stiffness increases as BMI increases. The scattering of data points follows the same pattern as depicted in Fig. 2A and 2C. A BMI of 25kgm-2 is perceived to be the cut-off. Patients are more likely to have higher tissue stiffness if the BMI exceeds 25kgm-2 and lower stiffness if the BMI remains below 25kgm-2. From the correlation analysis, the parameters and the tissue stiffness values are only weakly associated (R2 < 0.1). Nonetheless, certain regions of the plots are observed to have higher number of data points whereas some other regions are scarce. From Fig. 2, it can be concluded that several risk criteria generally contribute to higher plantar tissue stiffness in patients. Among the factors examined, HbA1c scores, BMI, and DM duration are the factors positively associated with the change of tissue stiffness. Meanwhile, the age of patients does not have a significant influence in altering the tissue condition. In order to better understand the results, the plots are divided into four quadrants. Horizontal reference lines in Fig. 2 denote the average tissue stiffness value computed. A tissue stiffness above the average score (i.e. 6.69 N/mm) of the 70 patients recruited means the patient has stiffened tissue. Otherwise, the tissue is considered to be healthy tissue. Vertical reference lines represent the threshold risk criteria of the respective parameters. The vertical reference line is fixed at the point such that there are maximum number of data points in the first and third quadrant of the scatter plot. The derived risk criteria of stiffened tissue are as follows:
10
1) BMI>25kgm-2 2) HbA1cscore >10% (86mmol/mol) 3) DM duration >10 years The results are modelled into a two-class prediction problem. The test outcomes are the predictions using the three risk criteria stated above. The outcome can be positive (predicting the tissue is stiffened) and negative (predicting the tissue is healthy). The prediction test outcome may or may not match the patient’s actual measurement results. The four possible outcomes are as shown in Table 1. The statistical measures of the performance of prediction by the risk criteria are given in Table 2. True positive and true negative cases are represented by the first and third quadrants of the scatter plots (Fig. 2) respectively; while false positive and false negative are corresponding to the second and fourth quadrants. The performance of prediction using a single criterion is generally not satisfactory with very low DOR, except for BMI criterion which has a DOR slightly more than 10. BMI criterion also achieves relatively higher scores in sensitivity, accuracy and F1 score as compared to the other two criteria. However, the DOR which measures the effectiveness of diagnostic test still remains low. For the multiple criteria evaluation, in the first case of “any 2 criteria”, the prediction test outcome is positive if the patient meets any two of the three criteria stated, while the outcome is negative if the patient meets only one criterion or none. The accuracy and DOR obtained are still below satisfaction, at 0.700 and 5.816 respectively. Meanwhile in the case of “all 3 criteria”, the outcome is assigned as positive only if all three criteria are met. In this multivariate evaluation, the performance of prediction improves. The highest score in accuracy is achieved at 0.743, with DOR reaches 37.647, suggesting the feasibility in speculating the stiffness of plantar soft tissue in DM patients. The
11
case of “all 3 criteria” is found to be a better screening method than the cases of single criteria and “any 2 criteria”. In other words, the patients who meet the three listed risk criteria are tending to have higher than average tissue stiffness and those who do not are more likely to have healthier plantar soft tissues.
4.
Discussion This paper is designed to study the relationship between plantar tissue stiffness and
four easily acquired parameters, including age, DM duration, BMI, and HbA1c level. Apart from examining these risk factors, the paper aims to come out with a user-friendly gauge tool to enable self-evaluation of one’s foot health. The ultimate goal is to provide a straightforward mass screening method in the form of an idiot-proof index, e.g. BMI which is commonly used to predict the risk of a number of chronic diseases, that is applicable to all DM patients to estimate their foot health and ulceration risk. The self-identified at-risk patients can then proceed to consult clinicians for further and detailed assessment. Overall increased understanding on the tissue behavior and ulceration risk, coupled with the following sensation examination can considerably improve the judgments in diagnosing diabetic foot. From the results, it can be deduced that the HbA1c score has an influential role in altering the tissue stiffness. HbA1c is the glycated form of hemoglobin, which can be used to assess the average plasma glucose concentration over prolonged periods of time. A high HbA1c score of above 9.0% (75mmol/mol) indicates poor control of blood sugar in diabetic patients. Fig. 2C demonstrates that patients with a tissue stiffness above the average (i.e. 6.69N/mm) are usually those with a HbA1c score greater than 10% (86mmol/mol). Prolonged exposure to high blood glucose incurs pathological changes by enhancing the reactions between reducing glucose and cellular protein that increases the formation of AGE (Ahmed
12
and Thornalley, 2007). Accumulation of these compounds decreases the elasticity of tissue due to the excessive intermolecular cross linking and adversely modified side-chains (Bailey, 2001). A large cohort of data has shown glycated collagen to be consistent with the HbA1c level (Monnier et al., 1999). Based on the results, BMI is also a key indicator of tissue stiffness. BMI is an established measure of the relative size of an individual based on their weight and height. It is widely used as the preliminary diagnosis of obesity. According to the World Health Organization (WHO), a BMI of less than 18.5kgm-2 is considered as underweight, while a BMI of more than 25kgm-2 is regarded as overweight and above 30 is designated as obese. It can be inferred from Fig. 2D that patients with a BMI greater than 25 are often those who have been diagnosed with high tissue stiffness. This may be explained by the strong relationship between high BMI and DM (Colditz et al., 1990; Edelstein et al., 1997; Knowler et al., 1981). It is also postulated that a loss in weight and BMI effectively improve glycemic control (Heilbronn et al., 1999). In other words, high BMI may cause the increase in HbA1c which may undesirably stiffen the tissue through the process of accelerated tissue glycation. DM duration above 10 years is another common characteristic among the patients with stiffened tissue. Various studies have suggested a strong relationship between duration of DM and the presence of peripheral neuropathy. Peripheral neuropathy is the most extensively studied risk factor of DM foot ulcers (Akanji et al., 1989; Jones et al., 1992; Walters et al., 1992). The loss of protective pain sensation results in abnormal stress concentration and uneven pressure distribution over the plantar regions of the foot (Okuyama et al., 1983), which lead to impaired tissue properties and eventually the breakdown of tissue. In fact, Oguejiofor et al. reported that 100% of the DM patients recruited with DM duration of more than 15 years suffer from peripheral neuropathy (Oguejiofor et al., 2010). This may
13
explain the association of DM duration of >10 years (69.0 % with DM duration > 15 years) with high tissue stiffness values as shown in Fig. 2A. On the other hand, the age of the patient does not significantly affect the tissue response. Even in young patients with a short duration of diabetes, the tissue stiffness may still be adversely increased, depending on the other factors. The effect of BMI, HbA1c, and DM duration may have priority over the effect of aging. The performance of the prediction method proposed is compared to the 5.07/10g Semmes-Weinstein monofilament test, which is widely used by the medical practitioners for the screening of diabetic peripheral neuropathy (DPN). The sensitivity, specificity and DOR of monofilaments for detecting DPN are reported within the range of 0.06 – 0.59, 0.68 – 0.98 and 1.92 – 13.99 respectively (Baraz et al., 2014; Pambianco et al., 2011; Pourhamidi et al., 2014). The performance of the proposed prediction method in identifying stiffened tissue is found to be as good as or better than the monofilaments in diagnosing DPN. In fact, DOR of 10.00 is considered a very good test by current clinical standard (ter Riet et al., 2001). The introduction of stiffness measurement into the screening matrix has been reported to enhance the identification of plantar tissue at risk and to improve the prediction of diabetic foot ulcer (Naemi et al., 2017). The use of indentation methodology to acquire tissue status by mechanical means is more direct than the inferential palpation tests, which can be prejudiced by the subjective judgements of patients. This study uses load cell to quantify tissue response against the controlled tissue deformation. The approach is slightly different from the elastography studies with the aid of ultrasonic and OCT modules, that examine tissue deformation against external indentation force. Our instrumented indentation system with real time force feedback enables the tissue measurement to be conducted under load bearing condition, a tissue state whereby diabetic ulceration is more likely to occur. The tissue deformation rate of tissue can also be
14
manipulated to mimic realistic loading condition. In this study, the rate is fixed at 12.3mm/s. The value is still distinctly lower than the actual loading rate of mild physical activity such as walking, nevertheless, it is one of the highest rate achieved among the plantar tissue studies (Chao et al., 2010; Chatzistergos et al., 2014; Klaesner et al., 2001; Kwan et al., 2010; Parker et al., 2015; Pathak et al., 1998; Sun et al., 2011; Zheng et al., 2000). Unfortunately, the comparison of plantar stiffness values obtained between the two major approaches (i.e. elastography and force feedback) is difficult due to the different measurement mechanisms. In addition, there is still a lack of consensus on the indentation parameters, even among those studies with the same acquisition technique. This makes the sharing and comparison of the tissue stiffness values, which depend greatly on the experimental condition and subjects’ physical attributes, a very challenging task. In brief, the results suggest that patients with BMI higher than 25kgm-2 or HbA1c score >10% (86mmol/mol) or DM duration >10 years are likely to have stiffened plantar tissue that require special attention to prevent the occurrence of foot ulcers. The study has generated useful results in the diagnosis of foot complications. However, several limitations need to be acknowledged. The sample size is rather small and may not be representative of a wider diabetes population. More subjects from diverse backgrounds and from all walks of life, e.g. various ethnicity, lifestyles and diet preferences, need to be recruited in the future study in order to derive more persuasive and useful conclusions. In addition, another source of error is the negligence of other potential risk factors such as diet and physical activity level, which may eventually be significant contributors to the stiffening of plantar soft tissues. Research that is more extensive and that encompasses more causes of tissue stiffening should be performed to further expand the scope of the study. The findings are considered to provide useful insights that can be utilized to enhance the efficiency of the current clinical assessment.
15
The association of BMI with the health of plantar soft tissue was successfully observed. On the other hand, the influence of HbA1c and DM durations are not insignificant. Additional study with larger sample size and stricter selection criteria has to be conducted to further verify the effects of these factors on plantar tissue behaviour. Special consideration should be given to the high risk group of BMI > 25 kgm-2, HbA1c >10% (86mmol/mol), and DM duration >10 years. The high accuracy and DOR of predicting the tissue stiffness measurement by considering all three criteria suggests the feasibility of this prediction method in assessing a patient’s foot health. It can be a simple yet effective screening tool to identify patients with a potential foot problem. Advice can be then given to these patients to undergo a more detailed assessment.
Acknowledgements The authors acknowledge Dr Kenjin Tan and Dr Khoo Chee Meng, National University Hospital, Singapore, for their devoted contribution in the experiment. The study was supported by National Research Foundation of Korea grant funded by the Korea government (MSIT) (No. NRF-2019R1F1A1058182).
16
Figure Legend Figure 1. Schematic diagram (A) and experimental setup (B) of indentation system. Subject was instructed to stand on the platform during indentation procedure (C)(Teoh et al., 2015).
Figure 2. Scatter plots of tissue stiffness as a function of DM duration (A), age (B), HbA1c(C) and BMI (D). Horizontal reference lines denote the average tissue stiffness value computed (i.e. 6.69 N/mm). Vertical reference lines represent the threshold risk criteria of the respective parameters.
Table Legend
Table 1. Four possible outcomes formulated in a 2 X 2 contingency table
Table 2. Diagnostic testing on the proposed criteria
17
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21
Table 1. The four possible outcomes formulated in a 2X2 contingency table
Actual Condition (stiffness measurement) Positive (stiffness > average) True Positive correctly identified
Positive (identified) Test Outcome (prediction by the criteria)
Stiffened tissue is correctly predicted as stiffened tissue
False Negative Negative (rejected)
incorrectly rejected Stiffened tissue predicted as healthy tissue
Negative (stiffness < average) False Positive incorrectly identified Healthy tissue predicted as stiffened tissue
True Negative Correctly rejected Healthy tissue is correctly predicted as healthy tissue
Table 2. Diagnostic testing on the proposed criteria Descriptions True positive (TP) True negative (TN) False positive (FP) False negative (FN) True positive rate (TPR) or sensitivity True negative rate (TNR) or specificity Positive predictive value (PPV) or precision Negative predictive value (NPV) False positive rate (FPR) or fall-out rate False discovery rate (FDR) False negative rate (FNR) or miss rate Accuracy (ACC) F1 score Diagnostic odd ratio (DOR)
Single criteria DM duration > 10 yrs HbA1c> 10 29 24 15 26 18 7 8 13
BMI > 25kgm 34 16 17 3
-2
Multiple criteria Any 2 criteria All 3 criteria 30 20 19 32 14 1 7 17
0.784
0.649
0.919
0.811
0.541
0.455
0.788
0.485
0.576
0.97
0.617
0.774
0.667
0.682
0.952
0.652
0.667
0.842
0.731
0.653
0.545
0.212
0.515
0.424
0.030
0.383
0.226
0.333
0.318
0.048
0.216
0.351
0.081
0.189
0.459
0.629 0.690
0.714 0.706
0.714 0.773
0.700 0.741
0.743 0.690
3.021
6.857
10.667
5.816
37.647
April 15, 2019
Prof. Markus Buehler, Ph.D. Editor-in-Chief Journal of the Mechanical Behavior of Biomedical Materials Laboratory for Atomistic and Molecular Mechanics (LAMM) Department of Civil and Environmental Engineering (CEE) Massachusetts Institute of Technology Cambridge, Massachusetts U.S.A.
Conflict of Interest
Disclosure of potential conflict of interest: The authors declared that no conflict of interest exists.
Regards,
Taeyong Lee, Ph. D. Division of Mechanical and Biomedical Engineering Ewha Womans University 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760 Korea Email: [email protected] Tel: +82 2 3277 2795 Fax: +82 2 3277 2846