Simple tests to screen for diabetic peripheral neuropathy

Abstract

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:

To determine the diagnostic accuracy of each simple test as triage to screen for diabetic peripheral neuropathy (DPN) involving limbs within different settings, or as replacement of nerve conduction studies (NCS) for the clinical diagnosis of DPN involving limbs, with NCS as the reference standard.

Background

Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, insulin action, or both. In 2000, more than 175 million people all over the world suffered from diabetes (Yach 2006), of which 5% to 10% had type 1 diabetes and 90% to 95% had type 2 diabetes (Creager 2003). It is estimated that the number of people with diabetes will reach around 360 million in 2030 (Wild 2004; Yach 2006). Diabetes can induce long‐term complications, including retinopathy, nephropathy, neuropathy and other vascular complications (American Diabetes Association 2013).

Target condition being diagnosed

Diabetic peripheral neuropathy (DPN)

DPN is one of the most common microvascular complications in both type1 and type 2 diabetes. DPN has been defined as "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes" (Boulton 1998; Soliman 2002). It is the most common component in the causal sequence to foot ulceration (Reiber 1999). DPN can be broadly separated into generalised symmetrical polyneuropathy, and asymmetrical (focal and multifocal) neuropathy (Boulton 2004; Boulton 2005a; Dyck 2011a; Thomas 1997) (Table 1). Autonomic neuropathy can be either present or absent in DPN (American Diabetes Association 1996). A staging system, which encompasses four stages, has also been developed to provide a framework for diagnosis and management for DPN (Boulton 1998) (Table 2).

Table 1.

Classification of diabetic peripheral neuropathy

Classificationa	Subgroup
Generalised symmetric polyneuropathies	Chronic sensorimotor (typical DPN)
	Acute sensory
	Autonomic
Focal and multifocal neuropathies	Cranial
	Truncal
	Focal limb
	Proximal motor (amyotrophy)
	Co‐existing CIDP

^aAccording to Boulton et al. (Boulton 2005a); DPN: diabetic peripheral neuropathy; CIDP: chronic inflammatory demyelinating polyneuropathy.

Table 2.

Stages of diabetic peripheral neuropathy

Stage of diabetic peripheral neuropathy	Characteristics
Stages 0/1: no clinical neuropathy
	No symptoms or signs
Stage 2: clinical neuropathy
Chronic painful	Positive symptomatology (increasing pain at night): burning, shooting, stabbing pains ± pins and needles
	Absent sensation to several modalities and reduced or absent reflexes
Acute painful	Less common
	Diabetes poorly controlled, weight loss
	Diffuse (trunk)
	Hyperaesthesia may occur
	May be associated with initiation of glycaemic therapy
	Minor sensory signs or even normal peripheral neurological examination
Painless with complete/partial sensory loss	No symptoms or numbness/deadness of feet; reduced thermal sensitivity; painless injury
	Signs of reduced or absent sensation with absent reflexes
Diabetic amyotrophy	Muscle weakness and wasting
	Sensory loss is slight, but pain at night common
	Subacute onset
Stage 3: late complications of clinical neuropathy
	Foot lesions, e.g. ulcers
	Neuropathic deformity, e.g. Charcot joint
	Non‐traumatic amputation

Some evidence has shown that the prevalence of DPN among people with diabetes in the UK is estimated to be 50% (Sugimoto 2000), while the World Health Organization estimate for the UK is 29% (Wild 2001). A prospective study with 7.5% participants diagnosed with DPN at baseline showed that the prevalence increased to 45% after 25 years of follow‐up (Pfeifer 1995). In a large cohort of people with DPN in the UK, 7% developed a diabetic foot after one year (Abbott 1998).

DPN is largely concerned with the feet and lower limbs, although in some severe cases the hands may also be affected (Boulton 2005a; Boulton 2005b). Typically, it is a chronic, symmetrical and length‐dependent condition, compromising multiple nerves (Dyck 2011a; Tesfaye 2010). DPN of the limbs may involve large‐fibre nerves (more related to touch, vibration, position perception and muscle control), small‐fibre nerves (more related to thermal perception, pain and autonomic function) (Vinik 2004) or both. Most patients, however, have both large‐ and small‐nerve fibre damages in DPN of the limbs (Vinik 2004).

DPN of the limbs increases with both age and duration of diabetes, and seems more common in those with suboptimal glycaemic control and obesity (Boulton 2005b; Smith 2013). It often starts at the distal ends of the longest nerves with a stocking‐glove presentation and moves proximally (Boulton 2005b). Up to 50% of patients, however, may be asymptomatic (Boulton 2005a). Frequently reported symptoms in DPN could be positive (painful) symptoms or negative (non painful) symptoms (Boulton 2005b; Davies 2006; Melton 1999).

Reference standards

Electrodiagnostic findings provide a higher level of specificity for the diagnosis of polyneuropathy and should be included as part of the work‐up. Nerve conduction studies (NCS) are the most informative part of the electrodiagnostic evaluation which commonly include both NCS and needle electromyogram (EMG) (England 2005). For NCS, small pads are taped to the skin, deliver mild electric shocks and detect electric signals. Compared to the whole EMG, for which it may be necessary to insert thin needles into the muscles, NCS alone are relatively simple, noninvasive and timesaving. Further, due to the objectivity, reliability and sensitivity in the measurement of peripheral nerve function, NCS have long been a minimal criterion or a gold standard test for confirming the diagnosis of peripheral neuropathies (Buchthal 1957; Daube 1999; Donofrio 1990; Dyck 1988; Nasseri 1998).

Routine NCS include evaluation of motor function of the median, ulnar, peroneal, and tibial nerves, and sensory function of median, ulnar, radial, and sural nerves (Albers 1995). Recommended attributes encompass amplitude, distal latency, distance, conduction velocity, F‐wave latency and other measurements. It is important to decide how many and which nerves and parameters to assess when performing NCS (American Diabetes Association 1992). As different nerves and multiple attributes can be chosen in NCS, diagnostic criteria might vary in different studies (Dyck 2011a; Dyck 2011b). Despite many previous recommendations regarding NCS criteria of the diagnosis of polyneuropathy, no formal consensus exists (England 2005). In our review, we will accept the minimal diagnostic criteria as abnormality of one or more attributes (exceeding the normal limits between the 1st and 99th percentiles, or exceeding mean ± 2.3 standard deviation; variables, such as age, height, and temperature, should be considered when developing the reference range and interpreting the results) in two or more separate nerves to correctly define DPN (Dyck 1988; Dyck 2011a; Feldman 1994).

Results of NCS are vulnerable to many factors including filter setting, type of electrodes, the location of recording, limb temperature, qualification of examiner and other aspects. All these factors require meticulous attention to detail for reliable NCS (American Diabetes Association 1992). Applicable variables such as skin temperature, age, height, sex, and weight should be measured and accounted for when reporting a NCS as normal or abnormal (AAEM 1999).

In addition, two potential disadvantages must be acknowledged when NCS are considered in clinical and research settings. First, NCS have limits on the availability for routine diagnostic evaluation of DPN. Second, NCS are insensitive for the identification of small‐fibre neuropathy (Perkins 2003), although the clinical importance of small‐fibre neuropathy is likely to be insignificant in the context of DPN in which progressive loss of all nerve fibres is observed (Giannini 1999; Perkins 2003).

Index test(s)

Nowadays various simple neurological tests have been reported to be used for screening for DPN, some of which have also been combined into composite scoring systems to enhance the accuracy in the detection of DPN (Cornblath 2004; Perkins 2003). These tests whose accuracy we will evaluate mainly refer to the assessment of large‐fibre function, involving tendon reflex, pressure/touch sensation, vibratory sensation and protective sensation.

Ankle reflex test

While reflex tests are a conventional clinical examination in neurology, it is most common to test only ankle reflexes in the assessment of DPN (Cornblath 2004). The test is performed at both ankles. With the patient sitting or lying, the examiner dorsiflexes the foot and gently strikes the Achilles tendon with the reflex hammer. In the absence of reflex, the test can be repeated with reinforcement. Reflexes are typically scored as zero (absent with reinforcement), one (present but decreased), two (normal), three (increased), or four (increased with clonus) (Smieja 1999).

Touch sensation test

Semmes‐Weinstein monofilament test (SWMT)

The SWMT is a common screening tool for assessing the sensory function and the loss of pressure sensation (light touch perception) (Appendix 1). The size of the monofilament includes 0.5 g, 2 g, 10 g, 50 g, 200 g and other various types, which indicate the magnitude of the force on the monofilament when the monofilament is just bent. A 10 g monofilament test (also referred to the 5.07 monofilament) is the most common in practice (Boulton 2004; Valk 1997).

Neuropen

The Neuropen combines an interchangeable 10 g monofilament for cutaneous pressure assessment, and a calibrated sterile Neurotip for assessing pain sensation (Paisley 2002). The operation of the 10 g monofilament in the Neuropen is similar to that of SWMT (Appendix 1).

Ipswich touch test (IpTT)

As a simple, quick, and easily taught procedure, IpTT has been developed recently to screen DPN with the initial purpose of simplifying touch sensation test from SWMT (Appendix 1). The fact that IpTT necessitates little training may facilitate care assistants and nurses to obtain immediate feedback as to which patients require protection (Rayman 2011).

von Frey's hairs for testing touch perception thresholds

von Frey's hairs are a fast, novel and easy‐to‐perform procedure (Appendix 1). They are designed based on the similar principle of SWMT; however, touch perception thresholds can be assessed by buckling the hairs with the force ranging from 0.026 g on the first hair to 110 g on the last hair (Moharić 2012).

Vibratory sensation test

128‐Hz standard tuning fork

As an easy and traditional way to test vibratory sensation, the 128‐Hz standard (non‐graduated) tuning fork is a tool of screening for DPN (Appendix 1). An abnormal response is identified when the tested patients fail to perceive the vibration sensation while the examiner can. There are two general methods: on‐off method and timing method (Perkins 2001).

Graduated tuning fork

Unlike the standard tuning fork with limited capability to determine only the presence or absence of vibration perception, the graduated 128‐Hz tuning fork (Rydel‐Seiffer tuning fork) is able to determine the ability of patients to discriminate different vibration intensities (Appendix 1) (Garrow 2006; Kästenbauer 2004; Thivolet 1990). It relies on a threshold of vibration extinction estimated by the intersect between two virtual triangles that move exponentially on a scale from 0 to 8. In general practice, most physicians would rate a tuning fork vibration perception threshold of lower than four as abnormal (Liniger 1990)

VibraTip

VibraTip is a pocket sized, wipe clean device to test vibration perception for routine screening of DPN (Appendix 1). The product can overcome the limitations of using tuning forks by using a vibrating motor which provides consistent frequency and amplitude to allow a consistent intensity of vibration without pressure, coldness and sound. When activated, it provides a stimulus of 128 Hz.. VibraTip can be applied to the toe from any angle facilitating ease of testing, and can be magnetically attached to a specially designed neck lanyard facilitating ease of access (Bowling 2012; Bracewell 2012).

Electromechanical instruments for testing vibration perception thresholds (VPT)

VPT is one type of quantitative sensory test which is an extension of the sensory portion of the neurological evaluation with the ability to determine the absolute threshold in thermal perception, light touch perception, pain perception, cutaneous current perception, as well as vibration perception (American Diabetes Association 1992).

Electromechanical instruments for VPT include Biothesiometer, Neurothesiometer, Maxivibrometer, Vibrameter, Vibratron and the CASE IV system (Garrow 2006; van Deursen 2001) used on the basis of method of limits or method of levels (also called 'forced choice') (Appendix 1) (Cornblath 2004; Hansson 2007; Shy 2003). An average of three readings is recorded commonly from a test site (for example, at the end of the great toe). VPT cut‐off scores indicative of high or low risk for long‐term complications vary by the type of equipment utilised (Garrow 2006). Because of their ability to measure lower VPTs than a tuning fork, electromechanical devices have been recommended for community screening and routine clinical use, but the their expense can be higher (Garrow 2006).

Tactile circumferential discriminator (TCD)

The TCD is a new, portable sensory testing device used for a two‐point discrimination test which can reflect large‐fibre nerve function (two‐point discrimination) (Appendix 1). The device consists of a handheld disc with eight protruding rods of increasing circumference (numbered zero through seven). Rod zero rod is 12.5 mm in diameter, and rod seven is 40 mm. Scores are denoted as the lowest number of rods a patient can discriminate from rod zero and this is the threshold value of the TCD test. A score of six or higher is significantly correlated with neuropathy (Maser 1997; Vileikyte 1997).

Steel ball‐bearing test

The steel ball‐bearing test is also a novel test, invented to exam the protective sensory (Appendix 1). Five ball‐bearings numbered 1 to 5 correspondingly designed with a diameter of 1.5, 2.0, 2.5, 3.0 and 3.5 millimetres are used in this test. The score range of the ball‐bearing test is 1 to 6, which indicates the smallest ball‐bearing that the patient can feel. A score of six indicates that the patient can not feel any of the ball‐bearings. Both feet will be examined and physicians begin with the right one. The higher result of the two feet will be recorded as the ball‐bearing score (Papanas 2006).

Clinical pathway

It is recommended that all patients should be screened for DPN at the diagnosis of type 2 diabetes and five years after the diagnosis of type 1 diabetes and should receive one or more of the following tests annually: pinprick, temperature, ankle reflex, and vibration perception (128‐Hz tuning fork) or pressure sensation (10 g monofilament test) (American Diabetes Association 2013; Boulton 1998; Boulton 2005a). Combinations of more than one test may help to detect DPN more sensitively (Boulton 2005a). In such screening, any history of neuropathic symptoms should be elicited and a careful clinical examination of the feet and lower limbs should be performed (Boulton 2005a); in fact, NCS and exclusion of other causes are rarely needed except when the diagnosis of DPN needs to be confirmed (American Diabetes Association 2013).

As recommended by the 1988 consensus statement from the San Antonio conference on diabetic neuropathy, multiple assessments, including clinical symptoms, clinical signs, electrodiagnostic studies, quantitative sensory testing and autonomic function testing, should be applied for the diagnosis and classification of DPN (American Diabetes Association 1988). The report from the American Academy of Neurology in conjunction with the American Association of Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation define distal symmetric polyneuropathy (of which DPN of limbs is a member) and suggests that patients with abnormal NCS have a relatively high likelihood of this condition (England 2005). Recently, it was proposed that an abnormality of NCS combined with symptom(s) or sign(s) is essential to confirm the diagnosis of DPN since NCS appears to be the first objective and quantitative indication. Symptoms, signs or both without abnormal NCS contribute to the diagnosis of possible clinical DPN or probable clinical DPN, while abnormal nerve conduction alone without symptoms or signs may support the diagnosis of subclinical DPN (Dyck 2011a; Tesfaye 2010). The procedure of screening and diagnosis of DPN in clinical care has been summarised in a flow chart (Figure 1).

Figure 1.

Flow chart of screening and diagnosis of DPN of limbs in clinical practice

Screening tests could be tests to identify symptoms and/or signs

Prior test(s)

Type 1 or type 2 diabetes should be confirmed by diagnostic tests for diabetes. Information on the duration of diabetes, history of foot ulcer, glycaemic control and complaints related to peripheral neuropathy should be obtained.

Role of index test(s)

Relatively traditional tests such as ankle reflex, 10 g monofilament test and 128 Hz tuning fork have been recommended as screening tests for DPN. They can be used solely or jointly as triage tests in clinical practice for physical examination to assess the signs of DPN, which may also contribute to clinical diagnosis of DPN. Their results require confirmation by more objective measures such as electrodiagnostic, quantitative sensory and autonomic function tests, which can help establish the confirmed diagnosis and classification of DPN (American Diabetes Association 1992; Boulton 2005a). However, in some population‐based epidemiological studies, these tests have been used jointly in the replacement of NCS to identify DPN.

VPT potentially offers a quick and accurate screening instrument to evaluate DPN in the clinic; however, selection of the suitable instrument may depend on the availability of resources, the number of clinicians involved in neuropathy testing and frequency of use (Garrow 2006). It has also replaced NCS to detect patients with DPN in epidemiological studies.

Although TCD and the steel ball‐bearing test are new tests for the assessment of large‐fibre function, wider use may be expected in the near future (Papanas 2011).

Alternative test(s)

Some other simple tests, which mainly assess small‐fibre function are also available to screen for DPN, including conventional tests ‐ temperature sensation test (e.g. Tip‐therm) (Viswanathan 2002) and superficial pain test (e.g. Neurotip) (Perkins 2001), and innovative tests ‐ NeuroQuick (Ziegler 2005) and Neuropad (Papanas 2005). However, there is no acknowledged 'gold standard' for the evaluation of tests in diagnosing small‐fibre neuropathy (skin biopsy seems relatively preferred) (Devigili 2008). It is still insufficient to evaluate the accuracy of these tests using NCS as a reference standard, which primarily indexes large‐fibre dysfunction, and therefore, we will not include these tests in our review.

Rationale

DPN places a large burden on healthcare budgets. Of all the complications of diabetes mellitus, lifetime expenditures on DPN ranks third after macrovascular disease and diabetic nephropathy (Caro 2002). If patients with DPN progress to diabetic foot, any foot lesion occurring as a result of diabetes and its complications (Boulton 2008), makes the costs of long‐term treatment much heavier. Curing one case of diabetic foot without requiring amputation would cost 17,500 US dollars (13,075 EUR, September 2012 conversion), while the cost of an amputation is 30,000 US dollars to 35,000 US dollars (23,075 EUR to 26,920 EUR, September 2012 conversion) (Ragnarson 2004). But if DPN could be detected in the early stage, enhanced glucose control might prevent the development of clinical neuropathy and reduce nerve conduction and vibration threshold abnormalities (Callaghan 2012).

From the perspective of clinical practice, screening for DPN in community and outpatient settings successfully predicts those at risk of ulceration (Abbott 2002; Adler 1997). Hospitalised patients with diabetes, who are likely to be older, bed bound and with more co‐morbidities, should also be screened so that foot protection can be targeted, because 3.3% of people with diabetes in hospital acquired a foot lesion (Rayman 2010). Although some tests have been recommended in related clinical guidelines for the diagnosis or screening of DPN (Boulton 2003; Boulton 2005a; Boulton 2005b; Vijan 1997), the development of these recommendations was based more on expert consensus than sound evidence. So far, there is no agreement which standardised screening tool should be applied in clinical practice.

As for epidemiological research, index tests used for the assessment of the prevalence of DPN varied in different studies and thus, the studies resulted in different estimates ranging from 17% to 60% (Adler 1997; Davies 2006; Gregg 2004; Liu 2010; Tesfaye 1996; Won 2012; Young 1993). Not only were the varied estimates attributed to different populations but also to the different screening tools (Davies 2006).

There are three related systematic reviews published: two focus on the SWMT while another involves SWMT, tuning fork, NSS, NDS and MNSI (Dros 2009; Feng 2009; Kanji 2010). They all prefer to use NCS as the reference standard. In the two studies that are only relevant to SWMT, variation in both of the diagnostic values and the accuracy was found (Dros 2009; Feng 2009). However, both reviews solely evaluated the accuracy of SWMT, failing to provide the whole spectrum of tests in this field. Another review found that abnormal results on monofilament testing and vibratory perception (alone or in combination with the appearance of the feet, ulceration, and ankle reflexes) are the most helpful signs (Kanji 2010). However, this review limited the setting to the bedside, where the accuracy of tests may differ from that in community due to possibly different disease spectra. In the Kanji 2010 review, only two databases were searched and the language of studies was restricted to English. Further, the authors only provided limited rather than integral detailed information on the methodological quality for each included study.

With reference to the problems mentioned above, this review will therefore further assess the accuracy of all potential simple tests for screening DPN to supply more comprehensive evidence.

Objectives

To determine the diagnostic accuracy of each simple test as triage to screen for diabetic peripheral neuropathy (DPN) involving limbs within different settings, or as replacement of nerve conduction studies (NCS) for the clinical diagnosis of DPN involving limbs, with NCS as the reference standard.

Secondary objectives

To estimate the relative accuracy of simple tests for screening DPN involving limbs, with NCS as the reference standard.

To assess the impact of potential sources of heterogeneity on the performance of simple tests for DPN involving limbs: (1) related to the study population (spectrum of the disease: with versus without other vascular complications; symptoms of DPN: people with no neurological symptoms versus neurological symptoms (if available, positive versus negative neurological symptoms); duration of diabetes; level of glycosylated haemoglobin A1c (HbA1c) in adults: < 7% versus ≥ 7%; body mass index (BMI) in adults: < 25 versus ≥ 25 kg/m²; types of diabetes: type 1 versus type 2 diabetes mellitus; age: < 18 years old versus ≥ 18 years old); (2) related to the simple tests (different thresholds; body sites tested; numbers of body sites tested; types of instrument; examiner's expertise: specialists in diabetes or neurology versus other healthcare professionals); (3) related to the reference standard (numbers of body sites tested with NCS; examiner's expertise: specialists in electrodiagnosis versus other healthcare professionals); (4) related to the healthcare setting (community versus outpatient setting versus inpatient setting); (5) related to the methodology based on the QUADAS‐2 items (risk of bias for patient selection, index test, reference standard, and flow and timing; concerns regarding applicability of patient selection, index test, and reference standard).

Methods

Criteria for considering studies for this review

Types of studies

Prospective and retrospective single‐gate studies (that is 'cohort type accuracy studies') (Deeks 2009; Rutjes 2005) and studies with fully paired or randomised comparison design (Bossuyt 2008) will be eligible, regardless of language of publication.

Participants

People with type 1 or type 2 diabetes, who are being screened for neuropathy, regardless of age and gender. We will exclude those who already have overt neuropathy with foot ulcers and other related manifestations.

Index tests

Any of the following (but not limited to) simple tests including ankle reflex test, light touch sensation tests (SWMT, Neuropen, IpTT, von Frey's hairs), vibratory sensation tests (128‐Hz standard tuning fork, graduated tuning fork, VibraTip, electromechanical instruments for VPT), TCD and steel ball‐bearing test.

Target conditions

We will focus on DPN that involves limbs. Any stage of DPN will be dichotomised as ’no DPN’ versus ’DPN of any stage’, which may include mild, moderate and severe DPN. Where different classifications were used in primary studies, we will require and convert the data according to our stage dichotomous classification.

Reference standards

We will include studies in which nerve conduction studies (NCS) have been applied solely as the reference standard. We will specify and critically consider the possible differences of reference standards among all the eligible studies in our review.

Search methods for identification of studies

Electronic searches

We will use the following sources from inception to present time for the identification of studies.

• The Cochrane Library

• MEDLINE (Ovid)

• EMBASE (Ovid)

• MEDION

• ARIF

• Web of Science: Science Citation Index Expanded

• Trials registers:

  • The metaRegister of Controlled Trials (www.controlled‐trials.com/mrct/)

  • The EU Clinical Trials register (www.clinicaltrialsregister.eu/)

  • The US National Institutes of Health trials register ClinicalTrials.gov (www.clinicaltrials.gov)

  • The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au)

  • The WHO International Clinical Trials Registry Platform Search Portal (apps.who.int/trialsearch/)

• Grey literature:

  • The Grey Literature Report (www.greylit.org/)

  • OpenGrey (www.opengrey.eu/)

  • OAISTER (www.oaister.org/)

For detailed search strategies please see Appendix 2. We will use Web of Science for forward citation tracking of early key publications. We will continuously apply PubMed's 'My NCBI' (National Center for Biotechnology Information) email alert service for identification of newly published studies using a basic search strategy (see Appendix 2). Four weeks before we submit the final review draft to the Cochrane Metabolic and Endocrine Disorders Group (CMED) for editorial approval, we will perform a complete update search on all specified databases. Should we detect new studies for inclusion, we will evaluate these and incorporate findings in our review before submission of the final review draft.

If we detect additional relevant key words during any of the electronic or other searches we will modify the electronic search strategies to incorporate these terms and document the changes. We will place no restrictions on the language of publication when searching the electronic databases or reviewing reference lists in identified studies.

We will send results of electronic searches to Cochrane Metabolic and Endocrine Disorders Group for databases that are not available at the editorial office.

Searching other resources

We will try to identify other potentially eligible studies or ancillary publications by searching the reference lists of retrieved included studies, (systematic) reviews, meta‐analyses, and health‐technology assessment reports.

We will try to contact manufacturers of related index tests to identify studies.

Data collection and analysis

Selection of studies

To determine the studies to be assessed further, two review authors (ZY, YZ) will independently scan the abstract, titles or both sections of every record retrieved. All potentially relevant articles will be investigated as full text. Differences will be resolved by a third party (YH). If resolving disagreement is not possible, the article will be added to those 'awaiting assessment' and authors will be contacted for clarification. An adapted PRISMA (preferred reporting items for systematic reviews and meta‐analyses) flow‐chart of study selection (Figure 2) will be attached (Liberati 2009; Moher 2009).

Figure 2.

Flow chart of study inclusion

Data extraction and management

Two review authors (ZY, YH) will independently extract data concerning details of study design, study population, comparator test(s), index test(s) and their performance using standard data extraction templates (Table 3; Appendix 3; Appendix 4; Appendix 5; Appendix 6) with any disagreements to be resolved by discussion, or if required by a third party (LJ).

Table 3.

Overview of study populations

Characteristic Study ID	Eligible [N]	Recruited into the study [N]	Received index test [N]	Received reference standard [N]	Included in the analysis [N]	Lost to follow‐up [N]
Study 1
Study 2
Study 3
Study 4
Total	...	...			...	...

"‐" denotes not reported.

The following items will be included.

General information: published/unpublished, title, authors, country, language of publication, year of publication, sponsoring, setting, prevalence in study centre(s).

Participants: sampling (consecutive/convenience), inclusion criteria, exclusion criteria, total number and number in comparison groups, sex, age, ethnicity, BMI, type of diabetes mellitus, duration of diabetes mellitus, glycaemic control, antihyperglycaemic treatment, symptoms, severity of target condition.

Index test: type of test, type of device, diagnostic criteria, sites investigated, additional sources of clinical material, qualification of assessor.

Reference test: type of test, type of device, diagnostic criteria, sites investigated, additional sources of clinical material, qualification of assessor.

Results: number of true positives, false positives, true negatives, false negatives, adverse events.

We will send an email request to contact persons of included studies to enquire whether authors are willing to answer questions regarding their studies. The results of this survey will be published in Appendix 7. Thereafter, we will seek relevant missing information on the study from the study author(s) of the article, if required. For example, when we find studies with a limb rather than a patient as the unit of analysis, we will email the authors to ask whether they have summary data on the individual, as the unit of analysis in our review is the whole person.

Dealing with duplicate publications and companion papers

In the case of duplicate publications and companion papers of a primary study, we will try to maximise the yield of information by simultaneous evaluation of all available data but we will not include the same group of patients more than once in any given analysis.

Assessment of methodological quality

In the QUADAS‐2 (quality assessment of diagnostic accuracy studies) instrument, quality is defined as both the risk of bias and applicability of a study, i.e. "1) the degree to which estimates of diagnostic accuracy avoided risk of bias, and 2) the extent to which primary studies are applicable to the review's research question" (Whiting 2011). We will complete the assessment in four phases with QUADAS‐2 as required (Whiting 2011).

We will assess the applicability of a study and risk of bias. Two review authors (ZY, RC) will independently rate each of the four key domains (patient selection, index test(s), reference standard, flow and timing) using signalling questions (Appendix 8). Possible disagreement will be resolved by consensus, or with consultation of a third author (SZ) in case of disagreement.

We have followed the process for tailoring QUADAS‐2 to our systematic review as described in the publication (Whiting 2011) by omitting a signalling question in the domain of patient selection and adding one signalling question respectively in the domain of index test, and flow and timing. We have also developed preliminary review‐specific guidance on how to assess each signalling question to judge risk of bias. We will pilot the tool and apply criteria in a small number of studies by at least two authors (ZY, RC). If agreement is not good, we will add further refinement to the tool. We will use our guidelines to judge risk of bias as 'low', 'high' or 'unclear'.

We will primarily analyse studies at low risk of bias, low concern regarding applicability or both for all or specified domains. We will explore the influence of individual criteria in a sensitivity analysis.

We will present a 'Risk of bias and applicability concerns' figure and a 'Risk of bias and applicability concerns summary' figure.

Statistical analysis and data synthesis

The unit of analysis is a patient rather than a limb or a part of limb. Data for the true positive, true negative, false positive and false negative values for each study will be tabulated. Test results will be treated as positive or negative for the cut‐off values of the index tests as described above. Forest plots showing pairs of sensitivity and specificity, with 95% confidence intervals (CI) will be constructed for each study. The sensitivity and specificity pairs will be visualised in the receiver operator characteristic (ROC) space for each test.

Our primary analyses will compare each simple test with the reference standard. As we expect that, for each simple test, the number of investigated sites may vary and thus various thresholds will have been used across studies, we will consider using the hierarchical summary receiver operating characteristics (HSROC) model (Rutter 2001) to estimate a summary ROC curve. In case of multiple thresholds in an individual study, we will report accuracy estimates for all the thresholds. For the HSROC model, we will give priority to the pre‐specified threshold, while in the absence of the pre‐specified threshold we will then choose the most common one across the studies. We will use SAS software to fit the HSROC model. Results from the hierarchical models will be input into Review Manager 5.2 to provide plots of the estimated curve(s), or summary point(s) and confidence region(s).

Secondly, we will focus on the comparative accuracy of the simple tests with the reference standard. We will use the HSROC model within SAS software to conduct indirect and direct comparisons separately (Rutter 2001), in which case from each included study we will also choose the same threshold as is used in our primary analyses. We will assess the fit of model by likelihood ratio tests comparing models with and without the covariates for shape and accuracy parameters successively (Macaskill 2010). All studies will be included in each pair‐wise indirect comparison. Only those studies that make a direct fully paired or randomised comparison will be included in the direct comparisons.

Investigations of heterogeneity

We will investigate heterogeneity by visual inspection of forest plots and ROC curves. Given adequate amount of data (10 or more studies for one index test), we will investigate heterogeneity within SAS environment by adding the covariates specified under Secondary objectives as potential determinants or sources of heterogeneity to the HSROC model to identify statistically significant covariates.

For individual patients' characteristics such as age, metabolic control, effect of treatment, and duration of diabetes, we will first extract and analyse stratified accuracy results (for example, results separately of the subgroup of less than 18 years old versus the subgroup 18 years and older), if available within a study. However, if not available, we will convert the covariates age, effect of treatment to percentages and the covariate duration of diabetes to mean and then add the converted numerical covariates to the model.

Sensitivity analyses

We will perform sensitivity analyses to explore the impact of study quality on the meta‐analytic results.

• Restricting the analyses to the studies with either low risk of bias or low concerns regarding applicability in each domain of the QUADAS‐2 instrument.

• Restricting the analysis to the studies with prospective design.

• Restricting the analysis taking account of three individual quality items: blinding of reference standard results, blinding of index test results and interval of less than two months between index tests and reference test.

• Restricting the analysis on the data sources (published versus unpublished).

Assessment of reporting bias

We will not undertake any formal assessment of reporting bias in our review due to current uncertainty about how to assess reporting bias in diagnostic test accuracy reviews, especially in the presence of heterogeneity (Macaskill 2010).

Appendices

Appendix 1. Description of test procedures

Touch sensation test

Semmes‐Weinstein monofilament test (SWMT) During the monofilament examination, patients should close their eyes, and then the examiner will select the appropriate locations (1st, 3rd, and 5th metatarsal heads and plantar surface of distal hallux recommended; areas of callus avoided), use the required force, and ask patients to answer "yes" or "no" to indicate whether they feel the monofilament and to report the correct sites as well. The answer "no" suggests anaphia of the site in this strength. The examiner can also apply a rapid threshold test to grade the anaphia (Bell‐Krotoski 1995; Birke 1998). Neuropen To assess pressure perception, the Neuropen monofilament should be pressed against the skin surface until it is buckled. The monofilament can be performed twice in random order on the plantar surface of each hallux and also the 1st, 2nd, 3rd and 5th metatarsal heads which are areas that most frequently ulcerate in diabetic patients as a result of high pressure loading. The monofilament should be held in place for two seconds and then be removed. The patient is requested to affirm when a stimulus is felt (Paisley 2002). Ipswich touch test (IpTT) The IpTT involves lightly touching/resting the tip of the index finger for one to two seconds on the tips of the 1st, 3rd, and 5th toes and the dorsum of the hallux in both feet. Diabetic peripheral neuropathy (DPN) can be defined as ≥ 2 insensate of the eight sites. The other procedure is to test only the 1st, 3rd, and 5th toes and neuropathy can be defined as ≥ 2 insensate of the six sites. Examiners should not push, prod, tap, or poke because this may elicit a sensation other than light touch. With eyes closed, patients indicate whenever they feel the touch (Rayman 2011). von Frey's hairs for testing touch perception thresholds Patients are requested to close their eyes after the site of testing had been shown. Measurements are performed at four sites: on the great toe's interphalangeal (IF) joint, 1st metatarsal, lateral malleolus and lateral part of the leg on the dominant lower limb. Each site is tested five times; hairs are applied perpendicular to skin surface and with just enough pressure to buckle the hair. They are applied in order of increasing stiffness (i.e., from the tiniest to the thickest) until a positive threshold is reached or a negative threshold is recorded with the thickest hair. A positive threshold is detected when the patient could positively feel the hair at least three times out of five. Touch thresholds at each site are scored as either 0 (normal) or 1 (abnormal) (Moharić 2012).

Vibratory sensation test

128 Hz standard tuning fork In the on‐off method the 128‐Hz tuning fork is bilaterally applied to the bony prominence situated at the dorsum of the first toe proximal to the nail bed. The test is conducted twice on each toe and the patients are asked to report the perception of both the start and the cessation of the vibration. The vibration testing threshold is defined as the total number of times the application of the vibrating tuning fork and the dampening of vibration is not felt, with scores varying between zero and eight (Olaleye 2001; Perkins 2001). The operation of timing method is similar to that with the on‐off method, but patients examined are asked to report the time at which vibration diminished beyond perception. The tuning fork is also applied to the dorsal aspect of the distal phalanx of the examiner’s thumb. The time (in seconds) at which vibration sensation diminished beyond both patients' and examiner's perception is then recorded. DPN could be defined according to the difference between the time indicated by the patient and the examiner (Perkins 2001). Graduated tuning fork The difference of the graduated tuning fork from the standard one is that the vibration extinction threshold can be estimated as the intersection of two virtual triangles that moves on a scale from zero to eight which represents different vibration intensities from the strong to the weak. This intersection point moves from zero to eight in an exponential way. The graduated tuning fork is applied bilaterally to the test site (for example, the distal phalange of the big toes). Patients are requested to respond when they can no longer feel the vibration. At this time, the vibration threshold is determined on the nine‐point grading scale (0/8–8/8) of the tuning fork (Kästenbauer 2004; Thivolet 1990). VibraTip The device should be held firmly to the hallux and placed very gently against the patient's skin twice, each time for half to a second, explaining that 'this is touch one' and 'this is touch two'. VibraTip is randomly activated on either the first or second touch and the patients with their eyes closed are asked to indicate which of the touches is associated with vibration (Bowling 2012; Bracewell 2012). Electromechanical instruments for testing vibration perception threshold (VPT) To test the sensory threshold, algorithms have been developed and generally can be described as methods of limits and methods of levels. As to the former, the patient should indicate when first feeling an increasing stimulus or no longer feeling a decreasing stimulus. With the latter method, also known as the 'forced choice' algorithm, the participants should report whether the stimulus with a specific level is perceived. For most tests, cut‐offs have been determined for the discrimination between normal and abnormal perception (Cornblath 2004; Hansson 2007; Shy 2003). VPT is usually performed with the Biothesiometer, Neurothesiometer, Maxivibrometer and Vibrameter using the method of limits, while the Vibratron and CASE IV System are used in 'forced choice' protocol (Bril 1997; van Deursen 2001). As the Biothesiometer is quick, portable and relatively inexpensive, it is beneficial for clinical screening of DPN (van Deursen 2001)). The biothesiometer probe can vibrate at an amplitude proportional to the square of the applied voltage. After patients are initially familiarised with the sensation by holding the probe against the distal palmar surface of hand, the probe is applied perpendicular to the distal plantar surface of great toe of both the legs. The voltage slowly increases at the rate of 1 mV/sec and the VPT value can be defined as the voltage level when the patient indicates that he or she first feels the vibration sense (Davis 1997). The mean of three records is taken and neuropathy can be diagnosed if the VPT is ≥ 25 mV (Young 1994)

Tactile circumferential discriminator (TCD)

The tactile discrimination threshold is assessed with the TCD. The tested site can be the plantar aspect of the great toe. Stimuli with different circumference are presented and participants are asked to discriminate them. According to the standard procedure, first the smallest rod (0) is presented followed by the largest (7), with a standard contact time of two seconds. Then an ascending and descending method of stimulus presentation and a two‐alternative forced‐choice response procedure will be used to determine the ability to discern the smallest difference. Scores are denoted as the lowest number of rods a patient can discriminate from rod (0) and this is the threshold value of the TCD test. For example, if the patient can only discern rods (5), (6), and (7) from (0), a score of five will be denoted. A score of six or higher is significantly correlated with neuropathy (Maser 1997; Vileikyte 1997).

Steel ball‐bearing test

Examination can be performed on the plantar area over the second metatarsal head of each foot. Participants are asked to walk barefoot with the plaster attaching ball‐bearings on flat ground. At the same time, an empty control plaster is applied on the contralateral foot. The examination will begin with the smallest diameter ball‐bearing and increase until the patient can feel the ball‐bearing while walking (Papanas 2006).

Appendix 2. Search strategies

Search terms and databases

Unless otherwise stated, search terms are free text terms. '$': stands for any character; '?': substitutes one or no character; adj: adjacent (i.e. number of words within range of search term); exp: exploded MeSH; MeSH: medical subject heading (MEDLINE medical index term); pt: publication type; sh: MeSH; tw: text word; ot: original title.

The Cochrane Library (CENTRAL)

#1 MeSH descriptor Diabetes mellitus explode all trees #2 diabet* in All Text #3 (#1 or #2) #4 MeSH descriptor peripheral nervous system diseases explode all trees #5 MeSH descriptor Polyneuropathies explode all trees #6 ((peripheral in All Text and (nervous in All Text near/6 diseas* in All Text)) or (peripheral in All Text and (nervous in All Text near/6 disorder* in All Text))) #7 polyneuropath* in All Text #8 (#4 or #5 or #6 or #7) #9 (#3 and #8) #10 MeSH descriptor Diabetic neuropathies explode all trees #11 ((diabet* in All Text near/6 neuropath* in All Text) or (diabet* in All Text near/6 polyneuropath* in All Text)) #12 (#10 or #11) #13 (#9 or #12) #14 (tactile in All Text and circumferential in All Text and discriminator in All Text) #15 (biothesiometer in All Text or neurothesiometer in All Text or maxivibrometer in All Text or vibrameter in All Text or vibratron in All Text or (Case in All Text and IV in All Text and system in All Text)) #16 ((light in All Text and (touch in All Text near/3 perception* in All Text)) or (vibration in All Text near/3 perception* in All Text)) #17 ((nerve in All Text and (conduction in All Text near/3 test* in All Text)) or (nerve in All Text and (conduction in All Text near/3 examination* in All Text)) or (nerve in All Text and (conduction in All Text near/3 stud* in All Text))) #18 (tuning in All Text and fork* in All Text) #19 (quantitative in All Text and (sensory in All Text near/6 test* in All Text)) #20 ((vibration* in All Text near/6 threshold in All Text) or (perception* in All Text near/6 threshold in All Text)) #21 (simple in All Text and test* in All Text) #22 (monofilament* in All Text or (vibration in All Text and perception* in All Text) or (ankle in All Text and reflex* in All Text)) #23 (nerve in All Text and conduction in All Text and velocit* in All Text) #24 (vibration in All Text near/6 test* in All Text) #25 (SWMT in All Text or VPT in All Text or QST in All Text or TCD in All Text) #26 ((latency in All Text near/3 diagnos* in All Text) or (velocity in All Text near/3 diagnos* in All Text) or (amplitude in All Text near/3 diagnos* in All Text)) #27 ((large in All Text and (fiber in All Text near/6 function* in All Text)) or (large in All Text and (fiber in All Text near/6 disfunction* in All Text)) or (large in All Text and (fiber in All Text near/6 dysfunction* in All Text)) or (large in All Text and (fiber in All Text near/6 impairment* in All Text))) #28 ((large in All Text and (fibre in All Text near/6 function* in All Text)) or (large in All Text and (fibre in All Text near/6 disfunction* in All Text)) or (large in All Text and (fibre in All Text near/6 dysfunction* in All Text)) or (large in All Text and (fibre in All Text near/6 impairment in All Text))) #29 ((Semmes‐Weinstein in All Text and (monofilament in All Text near/6 test* in All Text)) or (steel in All Text and (ball‐bearing in All Text near/6 test* in All Text)) or (steel in All Text and ball in All Text and (bearing in All Text near/6 test* in All Text))) #30 ((sensor* in All Text near/6 test* in All Text) or (sensor* in All Text near/6 devic* in All Text)) #31 ((neuro in All Text near/3 test* in All Text) or (neuro* in All Text near/3 devic* in All Text)) #32 (vibration* in All Text near/3 sensation* in All Text) #33 (vibratory in All Text near/3 perception* in All Text) #34 vibratometry in All Text #35 (vibrotactile in All Text near/3 measurement* in All Text) #36 (nylon in All Text near/3 filament* in All Text) #37 (Frey* in All Text or neuropen in All Text or (ipswich in All Text and touch in All Text and test* in All Text) or IpTT in All Text) #38 ((tactile in All Text near/3 perception* in All Text and (threshold in All Text) or (tactile in All Text near/3 sensation* in All Text)) #39 ((pressure in All Text near/3 sensation* in All Text) or (pressure in All Text near/3 perception* in All Text)) #40 (tendon in All Text near/3 reflex* in All Text) #41 ((ankle in All Text and jerk in All Text) or (Achilles in All Text and tendon in All Text and reflex* in All Text)) #42 (#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25) #43 (#26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41) #44 (#42 or #43) #45 (#13 and #44)

MEDLINE

1 exp Diabetes Mellitus/ 2 diabet*.tw,ot. 3 1 or 2 4 exp Peripheral Nervous System Diseases/ 5 (peripheral nervous adj6 (diseas* or disorder*)).tw,ot. 6 exp Polyneuropathies/ 7 polyneuropath*.tw,ot. 8 or/4‐7 9 3 and 8 10 exp Diabetic Neuropathies/ 11 (diabet* adj6 (neuropath* or polyneuropath*)).tw,ot. 12 10 or 11 13 9 or 12 14 (quantitative sensory test* or tactile circumferential discriminator).tw,ot. 15 (biothesiometer or neurothesiometer or maxivibrometer or vibrameter or vibratron or Case IV system).tw,ot. 16 ((light touch or vibration) adj3 perception*).tw,ot. 17 (nerve conduction adj3 (test* or examination* or stud*)).tw,ot. 18 tuning fork*.tw,ot. 19 (quantitative sensory adj6 test*).tw,ot. 20 ((vibration* or perception*) adj6 threshold*).tw,ot. 21 simple test*.tw,ot. 22 (monofilament* or vibration perception* or ankle reflex*).tw,ot. 23 nerve conduction velocit*.tw,ot. 24 (vibration adj6 test*).tw,ot. 25 (SWMT or VPT or QST or TCD).tw,ot. 26 ((latency or velocity or amplitude) adj3 diagnos*).tw,ot. 27 ((large fiber or large fibre) adj6 (function* or disfunction* or dysfunction* or impairment*)).tw,ot. 28 ((Semmes‐Weinstein monofilament or steel ball‐bearing or two‐point discriminator) adj6 test*).tw,ot. 29 (steel adj6 (ball‐bearing or ball bearing)).tw,ot. 30 ((sensor* or neuro*) adj3 (test* or devic*)).tw,ot. 31 (vibration* adj3 sensation*).tw,ot. 32 (vibratory adj3 perception*).tw,ot. 33 vibratometry.tw,ot. 34 (vibrotactile adj3 measurement*).tw,ot. 35 (nylon adj3 filament*).tw,ot. 36 (Frey* or neuropen or ipswich touch test* or IpTT).tw,ot. 37 (tactile adj3 (perception threshold* or sensation*)).tw,ot. 38 (pressure adj3 (sensation* or perception*)).tw,ot. 39 (tendon adj3 reflex*).tw,ot. 40 (ankle jerk or Achilles tendon reflex*).tw,ot. 41 or/14‐40 42 exp ankle/ or exp achilles tendon/ 43 exp reflex/ 44 42 and 43 45 41 or 44 46 13 and 45 47 limit 46 to humans

EMBASE

1 exp Diabetes Mellitus/ 2 diabet*.tw,ot. 3 1 or 2 4 exp Peripheral Nervous System Diseases/ 5 (peripheral nervous adj6 (diseas* or disorder*)).tw,ot. 6 exp Polyneuropathies/ 7 polyneuropath*.tw,ot. 8 or/4‐7 9 3 and 8 10 exp Diabetic Neuropathies/ 11 (diabet* adj6 (neuropath* or polyneuropath*)).tw,ot. 12 10 or 11 13 9 or 12 14 (quantitative sensory test* or tactile circumferential discriminator).tw,ot. 15 (biothesiometer or neurothesiometer or maxivibrometer or vibrameter or vibratron or Case IV system).tw,ot. 16 ((light touch or vibration) adj3 perception*).tw,ot. 17 (nerve conduction adj3 (test* or examination* or stud*)).tw,ot. 18 tuning fork*.tw,ot. 19 (quantitative sensory adj6 test*).tw,ot. 20 ((vibration* or perception*) adj6 threshold*).tw,ot. 21 simple test*.tw,ot. 22 (monofilament* or vibration perception* or ankle reflex*).tw,ot. 23 nerve conduction velocit*.tw,ot. 24 (vibration adj6 test*).tw,ot. 25 (SWMT or VPT or QST or TCD).tw,ot. 26 ((latency or velocity or amplitude) adj3 diagnos*).tw,ot. 27 ((large fiber or large fibre) adj6 (function* or disfunction* or dysfunction* or impairment*)).tw,ot. 28 ((Semmes‐Weinstein monofilament or steel ball‐bearing or two‐point discriminator) adj6 test*).tw,ot. 29 (steel adj6 (ball‐bearing or ball bearing)).tw,ot. 30 ((sensor* or neuro*) adj3 (test* or devic*)).tw,ot. 31 (vibration* adj3 sensation*).tw,ot. 32 (vibratory adj3 perception*).tw,ot. 33 vibratometry.tw,ot. 34 (vibrotactile adj3 measurement*).tw,ot. 35 (nylon adj3 filament*).tw,ot. 36 (Frey* or neuropen or ipswich touch test* or IpTT).tw,ot. 37 (tactile adj3 (perception threshold* or sensation*)).tw,ot. 38 (pressure adj3 (sensation* or perception*)).tw,ot. 39 (tendon adj3 reflex*).tw,ot. 40 (ankle jerk or Achilles tendon reflex*).tw,ot. 41 or/14‐40 42 exp ankle/ or exp achilles tendon/ 43 exp reflex/ 44 42 and 43 45 41 or 44 46 13 and 45 47 limit 46 to humans

Web of Science: Science Citation Index Expanded

# 1 Topic=(peripheral nervous diseas*) OR Topic=(peripheral nervous disorder*) OR Topic=(polyneuropath*) OR Topic=(neuropath*) # 2 Topic=(diabet*) # 3 #2 AND #1 # 4 Topic=(quantitative sensory test*) OR Topic=(tactile circumferential discriminator) # 5 Topic=(biothesiometer) OR Topic=(neurothesiometer) OR Topic=(maxivibrometer) OR Topic=(vibrameter) OR Topic=(vibratron) OR Topic=(case IV system) # 6 Topic=(light touch perception*) OR Topic=(vibration perception*) # 7 Topic=(nerve conduction test*) OR Topic=(nerve conduction examination*) OR Topic=(nerve conduction stud*) # 8 Topic=(tuning fork*) # 9 Topic=(quantitative sensory test*) # 10 Topic=(vibration* threshold*) OR Topic=(perception* threshold*) # 11 Topic=(simple test*) # 12 Topic=(monofilament*) OR Topic=(vibration perception*) OR Topic=(ankle reflex*) # 13 Topic=(nerve conduction velocit*) OR Topic=(vibration test*) OR Topic=(SWMT) OR Topic=(VPT) OR Topic=(QST) OR Topic=(TCD) # 14 Topic=(latency diagnos*) OR Topic=(velocity diagnos*) OR Topic=(amplitude diagnos*) # 15 Topic=(large fiber function*) OR Topic=(large fiber disfunction*) OR Topic=(large fiber dysfunction*) OR Topic=(large fiber impairment*) # 16 Topic=(large fibre function*) OR Topic=(large fibre disfunction*) OR Topic=(large fibre dysfunction*) OR Topic=(large fibre impairment*) # 17 Topic=(Semmes‐Weinstein monofilament) OR Topic=(steel ball‐bearing) OR Topic=(two‐point discriminator test*) # 18 Topic=(vibration* sensation*) OR Topic=(vibratory perception*) OR Topic=(vibratometry) OR Topic=(vibrotactile measurement*) OR Topic=(nylon filament*) # 19 Topic=(Frey*) OR Topic=(neuropen) OR Topic=(ipswich touch test*) OR Topic=(IpTT) # 20 Topic=(tactile perception threshold*) OR Topic=(tactile sensation*) # 21 Topic=(pressure sensation*) OR Topic=(pressure perception*) # 22 Topic=(ankle reflex*) OR Topic=(tendon reflex*) # 23 Topic=(ankle jerk) OR Topic=(Achilles tendon reflex*) # 24 Topic=(sensor test*) OR Topic=(neuro test*) OR Topic=(sensor device*) OR Topic=(neuro device*) # 25 #24 OR #23 OR #22 OR #21 OR #20 OR #19 OR #18 OR #17 OR #16 OR #15 OR #14 OR #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 # 26 #25 AND #3 # 27 Topic=(animal*) # 28 #26 NOT #27

MEDION

ICPCcode: "Neurological" or "Endocrine metabolic and nutritional" Filter: Systematic Reviews of Diagnostic Studies

ARIF

neuropath*

Trial registers

The metaRegister of Controlled Trials: diabetes and neuropathy The EU Clinical Trials register: neuropath* The US National Institutes of Health trials register ClinicalTrials.gov: "Diabetic Neuropathies"(by topics) The Australian New Zealand Clinical Trials Registry: neuropathy The WHO International Clinical Trials Registry Platform Search Portal: diabetes and neuropathy

Grey literature

neuropath*

'My NCBI' alert service

("diabetic neuropathies"[MeSH Terms] OR ("diabetic"[All Fields] AND "neuropathies"[All Fields]) OR "diabetic neuropathies"[All Fields] OR ("diabetic"[All Fields] AND "neuropathy"[All Fields]) OR "diabetic neuropathy"[All Fields]) AND ("diagnosis"[Subheading] OR "diagnosis"[All Fields] OR "screening"[All Fields] OR "mass screening"[MeSH Terms] OR ("mass"[All Fields] AND "screening"[All Fields]) OR ("early"[All Fields] AND "detection"[All Fields]))

Appendix 3. Outline of index test

Characteristic Study ID	Order of test execution	Type of test	Type of device	Diagnostic criteria	Sites investigated	Average time to complete the simple test per person	Additional sources of clinical material	Qualification of assessor
Study 1
Study 2
Study 3
Study 4
"‐" denotes not reported.

Appendix 4. Outline of reference test

Characteristic Study ID	Time interval between simple test to NCS	Minimum follow‐up to assess if target condition is presenta	Type of device	Diagnostic criteria	Sites investigated	Additional sources of clinical material	Qualification of assessor
Study 1
Study 2
Study 3
Study 4
"‐" denotes not reported aFor reference standards involving follow‐up; NCS: nerve conduction studies.

Appendix 5. Baseline characteristics (I)

Characteristic Study ID	Study design/sampling	Study period [year to year]	Target condition	Country	Setting	Sex [female %]	Age [mean years (SD)/range]	Ethnic groups [%]	BMI [kg/m2]	Type 2 diabetes [%]
Study 1
Study 2
Study 3
Study 4
"‐" denotes not reported BMI: body mass index; SD: standard deviation.

Appendix 6. Baseline characteristics (II)

Characteristic Study ID	Duration of diabetes [mean years (SD)/range]	Severity of target condition	Symptoms (spectrum of DPN)	Prevalence in study centre	Follow‐up	Glycaemic control	Antihyperglycaemic treatment	Co‐morbidities	Co‐medications / Co‐interventions
Study 1
Study 2
Study 3
Study 4
"‐" denotes not reported DPN: diabetic peripheral neuropathy; SD: standard deviation.

Appendix 7. Survey of authors providing information on included trials

Characteristic	Study author contacted [DD/MM/YY]	Study author replied [DD/MM/YY]	Study author asked for additional information [short summary]	Study author provided data [short summary]
Study 1	Yes, date:	Yes, date: / No
Study 2	Yes, date:	Yes, date: / No
Study 3	Yes, date:	Yes, date: / No
Study 4	Yes, date:	Yes, date: / No
N/A: not applicable.

Appendix 8. QUADAS‐2 tool

Domain	Yes	No	Unclear
Patient selection (describe methods of patient selection):
1. Was a consecutive or random sample enrolled?	The enrolment was consecutive or random.	The enrolment was not consecutive or random.	Insufficient information is available to answer ‘yes’ or ‘no’.
2. Was a case‐control design avoided?	This question is irrelevant because studies with case‐control design are excluded from the review.
3. Did the study avoid inappropriate exclusions?	All diabetic patients (type 1 and 2) with suspicious DPN were recruited regardless of any other characteristic. But exclusion of those with no diabetes and established diagnosis of DPN is common and will be accepted.	Diabetic patients (type 1 and 2) with some characteristics which may modify the performance of index tests were excluded, for example, those who were asymptomatic.	Insufficient information is available to answer ‘yes’ or ‘no’.
Risk of bias:	Low	High	Unclear
Could the selection of patients have introduced bias?	Both signalling question 1 and 3 are answered ‘yes’.	Either signalling question 1 or 3 is answered ‘no’.	Both signalling question 1 and 3 can not be answered ‘yes’ or ‘no’ because of insufficient information.
Concerns regarding applicability (describe included patients (prior testing, presentation, intended use of index test and setting)
Is there concern that the included patients do not match the review questions?	The study population represents an unselected sample of diabetics with suspected DPN in community or outpatient setting or inpatient setting, regardless of gender, presentation and severity.	The study population is selected by gender, presentation or severity. Or the study includes those with the established diagnosis of DPN or with treatment of DPN.	Insufficient information is available to answer ‘low’ or ‘high’.
Index test (describe the index test and how it was conducted and interpreted):
1. Were the index test results interpreted without knowledge of the results of reference standard?	The outcome assessors for the simple test(s) were not aware of the results of NCS.	The outcome assessors for the simple test(s) were aware of the results of NCS.	Insufficient information is available to answer ‘yes’ or ‘no’.
2. Where multiple index tests were compared in the study or had been repeatedly used before the study, were the results of the index test interpreted without knowledge of other index test results or the previous test results?	Simple test results were interpreted without any knowledge of other simple test results or the previous test results.	Simple test results were interpreted with knowledge of other simple test results or the previous test results .	Insufficient information is available to answer ‘yes’ or ‘no’.
3. If a threshold was used, was it pre‐specified?	The threshold used to define DPN is pre‐specified.	The threshold used to define DPN is derived from the results of the study, for example, the optimal threshold in ROC.	Insufficient information is available to answer ‘yes’ or ‘no’.
Risk of bias:	Low	High	Unclear
Could the conduct or interpretation of the index test have introduced bias?	When signalling 2 is applicable, all the signalling question are answered ‘yes’. When signalling 2 is not applicable, both question 1 and 3 are answered ‘yes’.	Any one of the signalling questions is answered ‘no’.	All the signalling questions can not be answered ‘yes’ or ‘no’ because of insufficient information.
Concerns regarding applicability
Are there concerns that the index test, its conduct, or interpretation differ from the review question?	The study met both of the following items: 1. Sufficient details are correctly described about the examination procedures of simple test(s) (thresholds, investigated sites, etc.) to permit its replication. 2. Simple tests were performed by qualified physicians in diabetes or neuropathy or other trained professionals.	The study did not meet either of the following items: 1. Sufficient details are correctly described about the examination procedures of simple test(s) (thresholds, investigated sites, etc.) to permit its replication. 2. Simple tests were performed by qualified physicians in diabetes or neuropathy or other trained professionals.	Insufficient information is available to answer ‘low’ or ‘high’.
Reference standard (describe the reference standard and how it was conducted and interpreted):
1. Was the reference standard likely to correctly classify the target condition?	The study met all of the following items: 1. Diagnostic criteria were up to the minimal diagnostic criteria of NCS we have pre‐defined. 2. Applicable variables, such as age, height and temperature, for NCS were considered. 3. NCS were performed by qualified physicians in diabetes or neuropathy or other trained professionals.	The study did not meet any one of the following items: 1. Diagnostic criteria were up to the minimal diagnostic criteria of NCS we have pre‐defined. 2. Applicable variables, like age, height and temperature, for NCS were considered. 3. NCS were performed by qualified physicians in diabetes or neuropathy or other trained professionals.	Insufficient information is available to answer ‘yes’ or ‘no’.
2. Were the reference standard results interpreted without knowledge of the results of the index test?	The outcome assessors for NCS were not aware of the results of the simple test(s).	The outcome assessors for NCS were aware of the results of the simple test(s).	Insufficient information is available to answer ‘yes’ or ‘no’.
Risk of bias:	Low	High	Unclear
Could the reference standard, its conduct, or its interpretation have introduced bias?	All the signalling question are answered ‘yes’.	Any one of the signalling questions is answered ‘no’.	All the signalling questions can not be answered ‘yes’ or ‘no’ because of insufficient information.
Concerns regarding applicability
Are there concerns that the target condition as defined by the reference standard does not match the review question?	The study met both of the following items: 1. Sufficient details are correctly described about the examination procedures of the NCS (thresholds, investigated sites, etc.) to permit its replication. 2. NCS was performed by qualified physicians in diabetes or neuropathy or other trained professionals.	The study did not meet either of the following items: 1. Sufficient details are correctly described about the examination procedures of the NCS (thresholds, investigated sites, etc.) to permit its replication. 2. NCS was performed by qualified physicians in diabetes or neuropathy or other trained professionals.	Insufficient information is available to answer ‘low’ or ‘high’.
Flow and timing (describe any patients who did not receive the index test(s) and/or reference standard or who were excluded from the 2 x 2 table (refer to flow diagram); describe the time interval and any interventions between index test(s) and reference standard:
1. Was there an appropriate interval between index test(s) and reference standard?	The time period was two months or less.	The time period was more than two months.	Insufficient information is available to answer ‘yes’ or ‘no’.
2. Did all patients receive a reference standard?	All patients receiving simple test(s) underwent NCS.	Not all patients receiving simple tests underwent NCS, including the case in which a random sample of those who were tested negative by simple test(s) underwent NCS and then analyses for sensitivity and specificity were adjusted or not.	Insufficient information is available to answer ‘yes’ or ‘no’.
3. Did patients receive the same reference standard?	The same NCS procedure was performed for the patients.	Different reference standards or different NCS procedure were performed for the patients.	Insufficient information is available to answer ‘yes’ or ‘no’.
4. Were index tests and reference standard tested in the same limbs	Simple tests and NCS were tested in the same limbs.	Body sites tested by simple tests and NCS had some differences.	Insufficient information is available to answer ‘yes’ or ‘no’.
5. Were all patients included in the analysis?	All patients recruited into the study were included in the analysis.	Not all the patients recruited into the study were included in the analysis.	Insufficient information is available to answer ‘yes’ or ‘no’.
Risk of bias:	Low	High	Unclear
Could the patient flow have introduced bias?	All signalling questions are answered ‘yes’.	Any signalling question is answered ‘no’.	All the signalling questions can not be answered ‘yes’ or ‘no’ because of insufficient information.
DPN: diabetic peripheral neuropathy; NCS: nerve conduction studies; ROC: receiver operator characteristic.

What's new

Date	Event	Description
26 July 2018	Amended	This review was withdrawn by the Editorial Office of the Cochrane Metabolic and Endocrine Disorders Group because finishing the project within adequate deadlines could not be achieved.

Contributions of authors

Zhirong Yang (ZY): conception of study, protocol draft, search strategy development, study selection, data extraction, quality assessment, data analysis, data interpretation, review draft and update draft.

Yuan Zhang (YZ): protocol draft, acquirement of study copies, study selection, review draft and update draft.

Ru Chen (RC): protocol draft, quality assessment, data interpretation, review draft and update draft.

Yuansheng Huang (YH): study selection, data interpretation, review draft and update draft.

Linong Ji (LJ): protocol draft, data extraction, data interpretation, review draft and update draft.

Feng Sun (FS): data analysis, data interpretation, review draft and update draft.

Tianpei Hong (TH): protocol draft, data interpretation, review draft and update draft.

Siyan Zhan (SZ): conception of study, protocol draft, quality assessment, data analysis, data interpretation, review draft and update draft.

Sources of support

Internal sources

• Peking University, China.

External sources

• Specialized Research Fund for the Doctoral Program of Higher Education (20120001110015), China.

Declarations of interest

ZY: none known.

YZ: none known.

RC: none known.

YH: none known.

LJ: none known.

FS: none known.

TH: none known.

SZ: none known.

Notes

This review was withdrawn by the Editorial Office of the Cochrane Metabolic and Endocrine Disorders Group because finishing the project within adequate deadlines could not be achieved.

Withdrawn from publication for reasons stated in the review