Diabetes mellitus (DM) is one of the most common metabolic diseases worldwide. The incidence, prevalence, and importance of DM as a chronic disease are increasing [
Early detection of DPN contributes to preventing of foot ulcers and amputations. Several methods are used to detect DPN, including quantitative sensory testing, physical examination scoring systems (e.g., the neuropathy disability score), nerve conduction studies (NCS), and electrodiagnostic tests [
Monofilament tests have been widely used in clinical practice for DPN screening owing to their availability and convenience [
We searched EMBASE (OvidSP, 1976 to April 2016), MEDLINE (OvidSP, 1946 to April 2016), the Cochrane Library (issue 4, 2016), and Web of Science (1995 to April 2016) to identify diagnostic accuracy studies of monofilament tests for detecting DPN. Our search strategy was focused on monofilament tests, diabetic peripheral neuropathy, and diagnostic accuracy. See Supplementary Material Appendices
One author screened all titles and abstracts generated by the electronic database searches for relevance and selected all potentially eligible studies for review of the full-text articles. Two reviewers independently assessed the full-text articles according to the inclusion criteria and exclusion criteria. When it was necessary, a third arbitrator resolved any disagreements that remained after discussion between the two reviewers. The inclusion criteria were as follows: (1) the study examined the diagnostic accuracy of a monofilament test for detecting DPN, (2) the article was published in English, and (3) the study provided sufficient data. The exclusion criteria were as follows: (1) the study was performed on patients without DM or (2) the study was performed on patients who had visible ulcers.
Two authors independently extracted the following data from each included study: first author, year of publication, sample size, mean age of the participants, description of the monofilament, sites and number, threshold of the monofilament test, reference standard, sensitivity, and specificity. A third arbitrator resolved any remaining disagreements that the two review authors could not resolve through discussion. If more than one threshold was published in primary studies, we reported the diagnostic accuracy under all thresholds. The present systematic review of all diagnostic accuracy studies for the monofilament was conducted irrespective of reference standard utilized, whereas the quantitative synthesis was confined to trials using NCS as the reference standard. Additional information was extracted from studies that used NCS as the reference standard to demonstrate the variation across each study.
We assessed the methodological quality of the studies using Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2;
Because of varying reference standards enrolled in studies, we selected studies that used NCS as the reference standard for meta-analyses of its validity in diagnosing DPN [
A total of 522 records were identified through the electronic searches of MEDLINE (OvidSP) (
Flowchart of the study search and selection process.
Sensitivity and specificity were retrieved or calculated from data available in the primary studies. Tables
The characteristics of the included studies using VPT, NDS, SAC, and MNSI as the reference standard.
Study (author year) | Sample size (male) | Age (years) Mean ± SD | Monofilament | Sites and number | Threshold | Reference test | Sensitivity (%) (95% CI) | Specificity (%) (95% CI) |
---|---|---|---|---|---|---|---|---|
Valk et al., 1997 [ |
68 (36) | 51.6 ± NR | (a) SWF 5.07/10 g | Three sites on both feet: first toe, medial surface, and base of the third metatarsal bone | 1 of 18 | VPT | 95.8 | 45.5 |
(b) SWF 4.17/1 g | ||||||||
(c) SWF 6.10/75 g | ||||||||
McGill et al., 1999 [ |
132 (NR) | 57 (47.5–65.8) | MF 5.07/10 g | Five sites on the right foot: great toe, dorsum between the first and second metatarsals, the plantar aspect of the first metatarsal, the plantar aspect of the fifth metatarsal, the plantar aspect of the arch | (a) 5 of 5 | VPT | (a) 31 | (a) 100 |
(b) 3 of 5 | (b) 37 | (b) 98 | ||||||
(c) 1 of 5 | (c) 39 | (c) 83 | ||||||
Nagai et al., 2001 [ |
65 (NR) | 61.0 ± 1.3 | (a) SWF 5.07/10 g | Three sites on the foot: great toe, the plantar aspect of the first metatarsal, the plantar aspect of the fifth metatarsal | NR | Numbness in the toes and loss of ankle jerk and VPT | (a) 88 | (a) 68 |
(b) 85 | (b) 73 | |||||||
(b) SWF 4.56/4 g | (c) 48 | (c) 86 | ||||||
(c) SWF 4.31/2 g | ||||||||
Paisley et al., 2002 [ |
124 (84) | 55.4 ± 13.7 | MF 5.07/10 g | Twice on the plantar surface of each hallux and also the 1st, 2nd, 3rd, and 5th metatarsal heads | 3 of 10 | (a) NDS | (a) 87.8 | (a) 57.3 |
(b) VPT | (b) 70 | (b) 63.8 | ||||||
Kamei et al., 2005 [ |
82 (44) | 61.6 ± 11.0 | (a) SWF 5.07/10 g | The great toe, the plantar aspect of the first metatarsal, and site 3, the plantar aspect of the fifth metatarsal for each foot | NR | VPT | (a) 15–30 | (a) 92.9 |
(b) SWF 4.31/2 g | (b) 47.5–60 | (b) 71.4–76.2 | ||||||
Jayaprakash et al., 2011 [ |
1044 (532) | 53.3 ± 11.8 | SWF 5.07/10 g | The plantar surface of great toe and base of first, third, and fifth metatarsals of both feet | 1 of 8 | VPT | 63 | 93 |
Rayman et al., 2011 [ |
265 | 65 ± NR | MF 5.07/10 g | (a) 3 points in each foot: tips of the first, third, and fifth toes and dorsum of hallux of both feet | (a) 2 of 8 | VPT | (a) 85 | (a) 88 |
(b) 4 points in each foot: tips of the first, third, and fifth toes | (b) 5 of 8 | (b) 81 | (b) 91 | |||||
Bedi and Mittal, 2012 [ |
106 (48) | 54.99 ± 11.08 | SWF 5.07/10 g | The plantar surface of great toe and base of the first, third, and fifth metatarsals of both feet | 1 of 8 | VPT | 48.9 | 48 |
Bracewell et al., 2012 [ |
141 (76) | 56.9 ± 14.7 | MF 5.07/10 g | Five sites: the 1st, 3rd, and 5th metatarsal heads on the plantar surface, the hallux pulp, the dorsal surface of the hallux proximal to the nail fold | NR | VPT | 84 | 83 |
Najafi et al., 2014 [ |
107 (35) | 57.6 ± 10.2 | MF 5.07/10 g | The dorsum of the great toe midway between the nail fold and the DIP joint | 3 of 10 | MNSI | 16.7 | 87 |
NR: not reported in the paper; MF: monofilament; SWF: Semmes-Weinstein monofilaments; VPT: vibration perception threshold; VDT: vibration detection thresholds; NDS: neuropathy disability score; MNSI: Michigan neuropathy screening instrument; SAC: San Antonio Consensus for DPN diagnosis: “1 of 6”: minimum of 6 points, 1 point reported as a positive result; DIP: distal interphalangeal joint.
The characteristics of the included studies using NCS as the reference standard.
Study (Author Year) | Sample size (male) | Age (years) |
Monofilament | Prevalence of DPN | Sites and number | Threshold | Reference test | Sensitivity % (95% CI) | Specificity % (95% CI) |
---|---|---|---|---|---|---|---|---|---|
Olaleye et al., 2001 [ |
132 (84) | 52.92 ± 11.4 | SWF 5.07/10 g | 59.8% | Noncallused site on the dorsum of the first toe just proximal to the nail bed and repeated four times on both feet | (a) 2 of 8 | NCS | (a) 62 | (a) 84 |
(b) 3 of 8 | (b) 58 | (b) 92 | |||||||
(c) 4 of 8 | (c) 35 | (c) 97 | |||||||
(d) 5 of 8 | (d) 30 | (d) 97 | |||||||
Perkins et al., 2001 [ |
478 (319) | 54 (NR) | SWF 5.07/10 g | 72.2% | Noncallused site on the dorsum of the first toe just proximal to the nail bed and repeated four times on both feet | (a) 1 of 8 | NCS | (a) 77 | (a) 67.6 |
(b) 40.8 | (b) 96 | ||||||||
(b) 5 of 8 | |||||||||
Lee et al., 2003 [ |
37 (20) | 57.0 ± 9.3 | SWF 5.07/10 g | 78.4% | The dorsal surface of the foot between the base of the first and second toes, the first, third, and fifth toes, the first, third, and fifth metatarsal heads, the medial and lateral midfoot, and the heel in random order | 5 of 10 | NCS | 93.1 | 100 |
Mythili et al., 2010 [ |
100 (48) | 52.9 (30–80) | SWF 5.07/10 g | 71% | Both feet on the plantar surface of the hallux and centrally at the heel six times at each point | 1 of 6 | NCS | 98.5 | 55 |
Perkins et al., 2010 [ |
175 (118) | 57 ± 8 | SWF 5.07/10 g | 28.6% | Noncallused site on the dorsum of the great toe just proximal to the nail bed four times at each foot | 5 of 8 | NCS | 72 | 64 |
Pambianco et al., 2011 [ |
195 (NR) | 46.2 ± 7.2 (170) |
MF 5.07/10 g | 12.8% | The dorsum of the great toe ten times for each foot | 3 of 10 | NCS | 20 | 98 |
Pourhamidi et al., 2014 [ |
110 (61) | 60 ± 1 | SWF 5.07/10 g | 44.5% | Three standard points (plantar surface of distal hallux and 1st and 5th metatarsal heads) bilaterally on the sole of the foot | 1 of 6 | NDS & NCS | 6 | 97 |
Baraz et al., 2014 [ |
150 (47) | 55.71 ± 8.95 | SWF 5.07/10 g | 38% | (a) Three points in each foot: the great toe, the plantar aspect of the first, and the fifth metatarsal head | (a1) 1 of 6 | NCS | (a1) 53.8 | (a1) 73.9 |
(a2) 2 of 6 | (a2) 43.6 | (a2) 79.3 | |||||||
(a3) 3 of 6 | (a3) 35.9 | (a3) 84.7 | |||||||
(b) Four points in each foot: the plantar surface of hallux, and the first, third, and fifth metatarsal heads | (b1) 1 of 8 | (b1) 51.3 | (b1) 73 | ||||||
(b2) 2 of 8 | (b2) 46.2 | (b2) 74.8 | |||||||
(b3) 4 of 8 | (b3) 38.5 | (b3) 87.4 | |||||||
(c) Eight points in each foot: the dorsal aspect of the first, second, third, fourth, and fifth digits; the dorsal aspect of the medial, central, and lateral aspect of mid foot | (c1) 1 of 16 | (c1) 61.5 | (c1) 77.5 | ||||||
(c2) 2 of 16 | (c2) 59 | (c2) 79.3 | |||||||
(c3) 8 of 16 | (c3) 38.5 | (c3) 95.5 | |||||||
(d) 10 points in each foot: nine plantar sites (distal great toe, third toe, and fifth toe; first, third, and fifth metatarsal heads; medial foot, lateral foot, and heal) and one dorsal site | (d1) 1 of 20 | (d1) 64.1 | (d1) 64 | ||||||
(d2) 2 of 20 | (d2) 61.5 | (d2) 64 | |||||||
(d3) 10 of 20 | (d3) 30.8 | (d3) 89.2 | |||||||
Ruhdorfer et al., 2015 [ |
55 (28) | 64.3 ± 12.6 | SWF 5.07/10 g | 70% | The big toe, the fifth toe, the heel, the arch of the foot, and on the dorsum of the foot | 1 of 1 | (a) SRS | (a) 76 | (a) 79 |
(b) NCS | (b) 67 | (b) 67 |
NR: not reported in the paper; MF: monofilament; SWF: Semmes-Weinstein monofilaments; NCS: nerve conduction study; SRS: self-reported symptoms; “1 of 6”: minimum of 6 points, 1 point reported as a positive result.
Moderator variables.
Study (author year) | Diabetes duration (years) |
Type of the diabetes |
Techniques | Geography |
---|---|---|---|---|
Olaleye et al., 2001 [ |
11.5 ± NR | Type 1 (17.4%) | Yes-no | Canada |
Perkins et al., 2001 [ |
12.53 ± 11.47 | Type 1 (17.4%) | Yes-no | Canada |
Type 2 (69.7%) | ||||
NGT (12.9%) | ||||
Lee et al., 2003 [ |
14.8 ± 6.7 | Type 2 | Yes-no | Korea |
Mythili et al., 2010 [ |
6.9 ± NR | Type 2 | Yes-no | India |
Perkins et al., 2010 [ |
13 ± 9 | Type 2 (84%) | Forced choice (0, 0.5, 1) | Canada |
Pambianco et al., 2011 [ |
33.6 ± 5.2( |
Type 1 | Yes-no | USA |
38.3 ± 7.2( |
||||
Pourhamidi et al., 2014 [ |
7.2 ± 0.9 | NGT (33%) | Unknown | Sweden |
IGT (24%) | ||||
Type 2 (43%) | ||||
Baraz et al., 2014 [ |
6.1 ± 7.7 | Type 2 | Yes-no & point the site | Iran |
Ruhdorfer et al., 2015 [ |
12.2 ± 10.3 | Type 1 (7.3%) | Yes-no | Austria |
Type 2 (92.7%) |
NGT: normal glucose tolerance; IGT: impaired glucose tolerance; NR: not reported in the paper.
We assessed the methodological quality of the studies using QUADAS-2. The risk of bias and applicability concerns were analyzed using RevMan 5.3. Figures
Risk of bias and applicability concerns: reviewers’ judgments about each domain presented as percentages across included studies.
Risk of bias and applicability concerns: reviewers’ judgments about each domain for each included study.
Only five studies (Baraz et al. [
Studies using NCS as the reference standard were included in the quantitative synthesis; however, one study (Ruhdorfer et al. [
The sROC analysis for the studies yielded an overall weighted area under the curve of 0.8158 (0.0364); the index Q∗ value was 0.7498 (0.035), which is a strong indicator (0.7 < ROC = 0.8158< 0.9). A visual inspection of the forest plots shows large deviations, which indicate possible heterogeneity. Statistical tests such as chi-square, Cochran-Q, and the inconsistency index (
Forest plot of the sensitivity and specificity (red diamond) and its 95% CI (blue horizontal line).
Meta-analysis of diagnostic accuracy under the HSROC model.
Pooled value | SE | 95% CI | ||
---|---|---|---|---|
Sensitivity | 0.53 | 0.12 | 0.32 | 0.74 |
Specificity | 0.88 | 0.04 | 0.78 | 0.94 |
DOR | 8.62 | 2.68 | 4.69 | 15.84 |
LR+ | 4.56 | 1.03 | 2.93 | 7.10 |
LR− | 0.53 | 0.11 | 0.35 | 0.81 |
SE: standard error; CI: confidence interval.
Forest plot of the summary LR+ and LR−.
Forest plot of the diagnostic odds ratio.
SROC with a 95% confidence interval for monofilament tests in the diagnosis of DPN.
HSROC of the monofilament test for detecting DPN.
Figures
Regular sensory examinations for people with DM are recommended by clinical guidelines [
A previous review [
Our findings are based on studies with low methodological quality (as identified by QUADAS-2); hence, many factors were labeled as being unclear. In practice, the monofilament test should directly follow or precede the reference standard test, with examiners blinded to the results. However, most of included studies did not report this information. An appropriate interval between the monofilament test and the reference standard is necessary because misclassification may occur due to recovery or deterioration of the targeted condition.
As part of a reliable clinical tool to assess changes in the protective sensation of the feet, the 5.07/10 g monofilament is the most commonly employed filament nowadays [
At present, monofilament tests have been already widely used and advocated for in many clinical guidelines. However, there is no consensus on the optimal location, number of sites, and threshold values for DPN diagnosis. Therefore, further research is needed to standardize the method for clinical practice. As indicated by our meta-analysis, heterogeneity exists among studies. Two main causes are indicated: (1) there were different clinical protocols for the application of monofilaments in DM and (2) the subjects may differ in age, severity of DM, or other confounding factors. Semmes-Weinstein 5.07/10 g monofilaments (manufactured by North Coast Medical) were used in 13 of the 19 studies included in our review. The commercial manufacturing source was frequently identified in studies; however, the durability of monofilaments should be considered. Longevity and recovery testing suggest that each monofilament can be used with approximately 10 patients, with a period of 24 hours required between uses [
The present review has three main limitations. Firstly, our meta-analysis was performed based on a small number of studies with obvious heterogeneity. Although we used a HSROC model in our analysis, our conclusion should be interpreted with caution. Secondly, the protocol for using monofilament tests in DPN screening varied from study to study, which made it difficult to draw a firm conclusion at this stage. Thirdly, restricting the search to English-language publications may result in missing some relevant literature. Last but not least, we did not search grey literature sources and it can be acknowledged as a potential source of publication bias.
In summary, our study found that the 5.07/10 g Semmes-Weinstein monofilament seemed to be a screen with limited sensitivity for DPN in primary care settings based on currently available evidence. Available studies with regard to the application of monofilament testing for DPN diagnosis varied greatly, and an optimal protocol for conducting monofilament tests in patients with DM is under exploration. Higher-quality studies on Semmes-Weinstein monofilament examination detecting DPN are needed.
No author of this study has a commercial/financial interest in or other relationship with manufacturers of pharmaceuticals, laboratory supplies, and/or medical devices or with commercial providers of medically related services.
The authors thank Fengjie Wang, who provided literature knowledge and useful information for this paper.