Scoring systems 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 scoring system 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 and 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 (WHO) 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)

Various clinical scoring systems are used for screening DPN (Table 3). Each system may involve symptom scoring, sign scoring or both (Cornblath 2004; Perkins 2003). They can enhance the diagnostic accuracy because individual examination findings from different simple screening tests are combined into a composite examination score (England 2005).

Table 3.

Summary of scoring systems with their abbreviations

Abbreviation	Full names
Scoring systems that we will include
CNE	Clinical Neurological Examination
DNE	Diabetic Neuropathy Examination
DNS	Diabetic Neuropathy Symptom Score
MNSI	Michigan Neuropathy Screening Instrument
NDS	Neuropathy Disability Score
NIS	Neuropathy Impairment Score
NIS‐LL	Neuropathy Impairment Score in the Lower Limbs
NSP	Neuropathy Symptom Profile
NSS	Neuropathy Symptom Score
TCSS	Toronto Clinical Scoring System
Scoring systems that we will exclude
MDNS	Michigan Diabetic Neuropathy Score
mTCNS	modified Toronto Clinical Neuropathy Score
NIS‐LL+4	Neuropathy Impairment Score in the Lower Limbs +4
NIS‐LL+5	Neuropathy Impairment Score in the Lower Limbs +5
NIS‐LL+7	Neuropathy Impairment Score in the Lower Limbs +7
NTSS ‐ 6	Neuropathy Total Symptom Score ‐ 6
NSC	Neuropathy Symptom Change Score
TNS	Total Neuropathy Score
TSS	Total Symptom Score

Neurological symptom score (NSS), neuropathy symptom profile (NSP) and diabetic neuropathy symptom score (DNS)

The NSS initially consists of symptoms of muscle weakness, sensory disturbances, autonomic symptoms and can be further divided into 17 items (Dyck 1980). An NSS score of ≥ 1 could be considered abnormal (Dyck 1988). Another scoring system also for assessing neurological symptoms is named NSP, which contains 34 test categories, where an abnormal score is defined as ≥ 97.5 percentile (Dyck 1986). However, both scores are developed for general neuropathy rather than specifically for DPN. However, the NSS was later shown not to reflect the progress of DPN (Dyck 1997). A more simplified scoring system, the diabetic neuropathy symptom score (DNS) (Table 4) assessing pain, numbness, tingling and ataxia, is now available. The maximum score of DNS is four points, one point or more indicates neurological abnormalities (Meijer 2002).

Table 4.

Diabetic neuropathy symptom score (DNS)

DNS items	Rate
Unsteadiness in walking	0 = absent, 1 = present
Numbness	0 = absent, 1 = present
Burning, aching pain or tenderness in legs or feet	0 = absent, 1 = present
Prickling sensations	0 = absent, 1 = present

Neuropathy disability score (NDS) and neuropathic impairment score in the lower limbs (NIS‐LL)

The NDS can be used to assess the signs of neuropathy by 35 items for both sides. The evaluation is derived from cranial nerve damage, muscle strength, reflex loss, and loss of sensation (Dyck 1980). However, some items have been found not to be essentially abnormal in DPN and therefore, the neuropathy impairment score (NIS), revised on the basis of the NDS, has been proposed (Dyck 1995).

Considering that the typical DPN is a distal symmetric sensorimotor polyneuropathy, the neuropathy impairment score in the lower limbs (NIS‐LL), as a subset of the NIS for the lower limbs, has been adopted in the evaluation of peripheral neuropathy (Dyck 1997). The performance of the NIS‐LL in the detection of DPN is almost similar to that of the NDS but the main drawback is too much emphasis on the motor nerve function. In addition, no recognised diagnostic threshold for neuropathy has been set (Singleton 2008).

Currently, another clinical scoring system, the revised NDS (Table 5), is more commonly used. It includes the ankle reflex, vibration, pin‐prick and temperature (cold tuning fork) sensation at both sides of the great toes with a maximum score of 10 points. People with an NDS of six points or more are considered to show abnormal reactions (Abbott 2002; Moreira 2005; Weintrob 2007).

Table 5.

Revised neuropathy disability score (NDS)

NDS items	Description
Vibration sensation (128 Hz tuning fork)	0 = present, 1 = reduced/absent
Temperature sensation (cold tuning fork)	0 = present, 1 = reduced/absent
Pin‐prick	0 = present, 1 = reduced/absent
Ankle reflex	0 = normal, 1 = present with reinforcement, 2 = absent per side

Diabetic neuropathy examination (DNE)

The DNE (Table 6) is an examination adapted from the NDS, in which only eight items were retained. In this examination, only the right side of the limb is examined, and the maximum score is 16 points. A score of greater than three points is considered abnormal (Meijer 2000). It is recommended for the daily use in diagnosing DPN in clinical practice (Meijer 2000; Meijer 2003).

Table 6.

Diabetic neuropathy examination (DNE)

DNE items		Description
Muscle strength	Quadriceps femoris: extension of the knee	Score for each item: 0 = normal 1 = Medical Research Council scale 3–4 2 = Medical Research Council scale 0–2
	Tibialis anterior: dorsiflexion of the foot
Reflex	Triceps surae	0 = normal 1 = mild/moderate deficit: decreased but present 2 = absent
Sensation: index finger	Sensitivity to pinpricks	Score for each item: 0 = normal 1 = decreased but present 2 = absent
Sensation: big toe	Sensitivity to pinpricks
	Sensitivity to touch
	Vibration perception
	Sensitivity to joint position

Clinical neurological examination (CNE)

The CNE is a composite scoring system for measurement of sensory signs and reflexes in the lower limb (Table 7). It involves clinical testing of sensory dysfunction (pinprick, light touch, vibration, and position sense) of the feet, the anatomic level below which light touch sensation is impaired, muscle strength of the feet and ankle reflexes (Valk 1992; Valk 1997).

Table 7.

Clinical neurological examination (CNE)

CNE items		Description
Sensory dysfunction of the feet	Pinprick	Score for each item: 0 = normal 2 = impaired in comparison with proximal sensation (for position sense, comparison between the first toe and the first finger) 4 = absent
	Light touch
	Vibration
	Position sense
Anatomic level below which light touch sensation is impaired		0 = normal 1 = toe 2 = mid‐foot 3 = ankle 4 = mid‐calf 5 = knee
Muscle strength	Extensor hallucis longus	Score for each item: 0 = normal 2 = impaired 4 = absent
	Gastrocnemius muscles
Ankle reflexes		0 = normal 2 = impaired in comparison with the other reflexes 4 = absent

Two versions of CNE are available. In the older one, the maximal score of the CNE is 33 points. A total score of zero can be graded as no polyneuropathy, one to nine as mild, 10 to 18 as moderate, and 19 to 33 as severe polyneuropathy (Valk 1992). The other version, with a maximal score of 37 points is quantified on the basis of the older one, but the diagnostic criteria have not been presented in detail (Valk 1997).

Michigan neuropathy screening instrument (MNSI)

The MNSI is an instrument including two parts, a questionnaire with 15 questions and a foot examination (Feldman 1994). The questionnaire inquires about positive (pain, temperature sensation, tingling) and negative (numbness) sensory symptoms, cramps and muscle weakness, foots ulcers or cracks and amputation. Neuropathy can be defined as seven or more positive responses on the MNSI questionnaire (Feldman 1994). Compared with the questionnaire, the foot examination is more frequently used. It encompasses foot appearance and foot ulcers, ankle reflex and the 128‐Hz tuning fork test (Table 8). The maximum score of the foot examination is eight points and bilateral limbs are independently scored. A MNSI examination score of equal to or greater than two is positive for DPN (Feldman 1994). MNSI has been used in combination with the Semmes‐Weinstein monofilament test (SWMT) to evaluate the prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with type 2 diabetes in Korea (Won 2012).

Table 8.

Michigan neuropathy screening instrument (MNSI)

MNSI items	Description
Appearance of feet	0 = normal, 1 = abnormal
Ulceration	0 = normal, 1 = abnormal
Ankle reflexes	0 = present, 0.5 = present with reinforcement, 1 = absent
Vibration perception	0 = present, 0.5 = reduced, 1 = absent

Toronto clinical scoring system (TCSS)

Also called the Toronto clinical neuropathy score (TCNS), the system was first adopted by a research group in Toronto for the screening of DPN. The TCSS (Table 9) consists of three parts: symptom scores, reflex scores and sensory test scores. The maximum score is 19 points (Bril 2002; Perkins 2003). The criteria of classification for DPN have also been proposed according to the TCSS score: zero to five points, without DPN; six to eight points, mild DPN; nine to 11 points, moderate DPN; and 12 to 19 points, severe DPN (Perkins 2003). The TCSS has been employed in people with type 2 diabetes to assess the prevalence of painful DPN (Davies 2006).

Table 9.

Toronto clinical scoring system (TCSS)

TCSS items		Description
Symptoms score	Pain	0 = absent, 1 = present
	Numbness	0 = absent, 1 = present
	Tingling	0 = absent, 1 = present
	Weakness	0 = absent, 1 = present
	Ataxia	0 = absent, 1 = present
	Upper‐limb symptoms	0 = absent, 1 = present
Reflex score	Knee reflexes	Score for each side: 0 = normal, 1 = reduced, 2 = absent
	Ankle reflexes	Score for each side: 0 = normal, 1 = reduced, 2 = absent
Sensory test score	Pinprick	0 = normal, 1 = abnormal
	Temperature	0 = normal, 1 = abnormal
	Light touch	0 = normal, 1 = abnormal
	Vibration sense	0 = normal, 1 = abnormal
	Position sense	0 = normal, 1 = abnormal

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); 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 appear to be the first objective and quantitative indication. Symptoms and/or signs 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)

Scoring systems combining some simple screening tests can be used to assess symptoms, signs or both of DPN. Scoring systems may serve as triage tests for screening in clinical practice. 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). In the replacement of nerve conduction studies, they can be also used as diagnostic tests in epidemiological studies to determine DPN independently.

Alternative test(s)

Some scoring systems are also available to diagnose DPN, such as the Michigan diabetic neuropathy score (MDNS) (paired with NCS) (Feldman 1994), the NIS‐LL+4/+5/+7 (Dyck 1997) and the total neuropathy score (TNS) (Cornblath 1999). As they combine the results of NCS scoring, it is relatively difficult to use them to screen DPN in the community or clinic. Therefore, we will not evaluate their accuracy in our review (Table 3).

Other types of composite scoring systems, for example, the neuropathy symptom change score (NSC) (Dyck 1997), the total symptom score (TSS) (Ziegler 1995), the neuropathy total symptom score ‐ 6 (NTSS ‐ 6) (Bastyr 2005) and the modified Toronto clinical neuropathy score (mTCNS) (Bril 2009), which are primarily developed for the evaluation of therapeutical efficacy or the longitudinal assessment of polyneuropathy, will be excluded in our review as well (Table 3).

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) were 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 scoring systems for screening DPN to supply more comprehensive evidence.

Objectives

To determine the diagnostic accuracy of each scoring system 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 scoring systems for screening DPN involving limbs, with NCS as the reference standard.

To assess the impact of potential sources of heterogeneity on the performance of scoring systems 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 scoring systems (different thresholds; 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) scoring systems including NSS, NSP, DNS, NDS, NIS, NIS‐LL, DNE, CNE, MNSI, TCSS.

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 or combined with other tests in a parallel and/or serial way as reference standard. We will specify and critically consider the 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 1. 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 1). 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, YH) 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 (YZ). 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, YZ) will independently extract data concerning details of study design, study population, reference test, index test(s) and their performance using standard data extraction templates (Table 10; Appendix 2; Appendix 3; Appendix 4; Appendix 5) with any disagreements to be resolved by discussion, or if required by a third party (TH).

Table 10.

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, clinical presentation, severity of target condition.

Index test: type of scoring system, diagnostic criteria, 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 study authors are willing to answer questions regarding their studies. The results of this survey will be published in Appendix 6. 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 7). Possible disagreement will be resolved by consensus, or with consultation of a third review 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 in the domain of index test. 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 review 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 (Sensitivity analyses).

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 scoring system with the reference standard. For each scoring system, the same common threshold (as described in the section of Index test(s) for each scoring system) will be used according to the description in the manuals or the original empirical studies. We will use bivariate random‐effects model to conduct meta‐analyses of pairs of sensitivity and specificity (Reitsma 2005). Where different thresholds have been applied, we will report accuracy estimates for all the thresholds, use the bivariate model to calculate the summary sensitivity and specificity at each specific threshold respectively, and use the hierarchical summary receiver operating characteristics (HSROC) model (Rutter 2001) to estimate a summary ROC curve. For HSROC model, we will give priority to the common threshold as described in the section of Index test(s). Where the common threshold is not available, we will select the one that is closest to the common threshold. We will use SAS software to fit the bivariate and HSROC model. Results from these 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 scoring systems with the reference standard. We will compare the accuracy within SAS software by adding covariate terms for test type to the parameters of the models. We will use the bivariate model (Reitsma 2005) at specific thresholds to conduct indirect and direct comparisons separately. We will use likelihood ratio tests comparing models with and without the covariate terms in the bivariate model to assess the statistical significant difference in sensitivity or specificity between tests (Macaskill 2010). When the studies report several different thresholds, the HSROC model will be used (Rutter 2001), in which case we will also choose the 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 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 bivariate model or 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 resources (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. 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

#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 ((neurological in All Text and (symptom* in All Text near/6 scor* in All Text)) or (diabetic in All Text and (neuropathy in All Text and (symptom* in All Text near/6 scor* in All Text))) #15 (composite in All Text and scor* in All Text and system* in All Text) #16 ((scor* in All Text near/3 test* in All Text) or (scor* in All Text near/3 examination* in All Text) or (scor* in All Text near/3 instrument* in All Text) or (scor* in All Text near/3 system* in All Text) or (scor* in All Text near/3 symptom* in All Text)) #17 (scor* in All Text near/3 sign* in All Text) #18 ((diabetic in All Text and (neuropathy in All Text near/6 examination* in All Text)) or (clinical in All Text and (neurological in All Text near/6 examination* in All Text))) #19 ((neurologic* in All Text near/6 scor* in All Text) or (neuropath* in All Text near/6 scor* in All Text) or (diagnos* in All Text near/6 scor* in All Text)) #20 ((disability in All Text near/6 scor* in All Text) or (impairment in All Text near/6 scor* in All Text)) #21 ((Toronto in All Text near/6 scor* in All Text) or (Michigan in All Text near/6 scor* in All Text) or (Utah in All Text near/6 scor* in All Text) or (United in All Text and (Kingdom in All Text near/6 scor* in All Text))) #22 ((Toronto in All Text near/6 test* in All Text) or (Michigan in All Text near/6 test* in All Text) or (Utah in All Text near/6 test* in All Text) or (United in All Text and (Kingdom in All Text near/6 test* in All Text))) #23 ((Toronto in All Text near/6 examination* in All Text) or (Michigan in All Text near/6 examination* in All Text) or (Utah in All Text near/6 examination* in All Text) or (United in All Text and (Kingdom in All Text near/6 examination* in All Text))) #24 ((Toronto in All Text near/6 instrument* in All Text) or (Michigan in All Text near/6 instrument* in All Text) or (Utah in All Text near/6 instrument* in All Text) or (United in All Text and (Kingdom in All Text near/6 instrument* in All Text))) #25 ((Toronto in All Text near/6 method* in All Text) or (Michigan in All Text near/6 method* in All Text) or (Utah in All Text near/6 method* in All Text) or (United in All Text and (Kingdom in All Text near/6 method* in All Text))) #26 ((Toronto in All Text near/6 model* in All Text) or (Michigan in All Text near/6 model* in All Text) or (Utah in All Text near/6 model* in All Text) or (United in All Text and (Kingdom in All Text near/6 model* in All Text))) #27 (neuropathy in All Text and symptom in All Text and profile* in All Text) #28 ((scal* in All Text near/6 diagnos* in All Text) or (scal* in All Text near/6 screen* in All Text) or (scal* in All Text near/6 scor* in All Text)) #29 ((questionnaire* in All Text near/6 diagnos* in All Text) or (questionnaire* in All Text near/6 screen* in All Text) or (questionnaire* in All Text near/6 scor* in All Text)) #30 (MNSI in All Text or TCSS in All Text) #31 (#14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30) #32 (#13 and #31)

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 ((neurological symptom* or diabetic neuropathy symptom*) adj6 scor*).tw,ot. 15 composite scor* system*.tw,ot. 16 (scor* adj3 (test* or examination* or instrument* or system* or symptom* or sign*)).tw,ot. 17 ((diabetic neuropathy or clinical neurological) adj6 examination*).tw,ot. 18 ((neuro* or diagnos* or clinical) adj6 scor*).tw,ot. 19 ((disability or impairment or utility) adj6 scor*).tw,ot. 20 ((Toronto or Michigan or Utah or United Kingdom) adj6 (scor* or test* or examination* or instrument* or method* or model*)).tw,ot. 21 neuropathy symptom profile*.tw,ot. 22 ((scale* or questionnaire* or instrument* or tool* or checklist* or index or indices or inventor*) adj6 (diagnos* or screen*)).tw,ot. 23 (MNSI or TCSS).tw,ot. 24 or/14‐23 25 13 and 24 26 limit 25 to humans

EMBASE

1 exp diabetes mellitus/ 2 diabet*.tw,ot. 3 1 or 2 4 exp peripheral neuropathy/ 5 exp polyneuropathy/ 6 polyneuropath*.tw,ot. 7 peripheral neuropath*.tw,ot. 8 (peripheral nervous adj6 (diseas* or disorder*)).tw,ot. 9 or/4‐8 10 3 and 9 11 exp diabetic neuropathy/ 12 (diabet* adj6 (neuropath* or polyneuropath*)).tw,ot. 13 11 or 12 14 10 or 13 15 exp scoring system/ 16 ((neurological symptom* or diabetic neuropathy symptom*) adj6 scor*).tw,ot. 17 composite scor* system*.tw,ot. 18 (scor* adj3 (test* or examination* or instrument* or system* or symptom* or sign*)).tw,ot. 19 ((disability or impairment or utility) adj6 scor*).tw,ot. 20 ((diabetic neuropathy or clinical neurological) adj6 examination*).tw,ot. 21 ((neuro* or diagnos* or clinical) adj6 scor*).tw,ot. 22 ((Toronto or Michigan or Utah or United Kingdom) adj6 (scor* or test* or examination* or instrument* or method* or model*)).tw,ot. 23 neuropathy symptom profil*.tw,ot. 24 ((scale* or questionnaire* or scor* or instrument* or tool* or checklist* or index or indexes or indices or inventor*) adj6 (diagnos* or screen*)).tw,ot. 25 (MNSI or TCSS).tw,ot. 26 or/15‐25 27 14 and 26 28 limit 27 to human

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=(neurological symptom* scor*) OR Topic=(diabet* neuropathy symptom scor*) OR Topic=(composite scor* system*) # 5 Topic=(scor* test*) OR Topic=(scor* examination*) OR Topic=(scor* instrument*) OR Topic=(scor* system*) OR Topic=(scor* sign*) OR Topic=(scor* symptom*) # 6 Topic=(diabetic neuropathy examination*) OR Topic=(clinical neurological examination*) # 7 Topic=(neurologic scor*) OR Topic=(neuropath* scor*) OR Topic=(diagnos scor*) # 8 Topic=(disability scor*) OR Topic=(impairment scor*) # 9 Topic=(Toronto scor*) OR Topic=(Toronto test*) OR Topic=(Toronto examination*) OR Topic=(Toronto instrument*) OR Topic=(Toronto method*) OR Topic=(Toronto model*) # 10 Topic=(Michigan scor*) OR Topic=(Michigan test*) OR Topic=(Michigan examination*) OR Topic=(Michigan instrument*) OR Topic=(Michigan method*) OR Topic=(Michigan model*) # 11 Topic=(Utah scor*) OR Topic=(Utah test*) OR Topic=(Utah examination*) OR Topic=(Utah instrument*) OR Topic=(Utah method*) OR Topic=(Utah model*) # 12 Topic=(United Kingdom scor*) OR Topic=(United Kingdom test*) OR Topic=(United Kingdom examination*) OR Topic=(United Kingdom instrument*) OR Topic=(United Kingdom method*) OR Topic=(United Kingdom model*) # 13 Topic=(neuropathy symptom profile*) # 14 Topic=(scale diagnos*) OR Topic=(scale screen*) OR Topic=(scale scor*) # 15 Topic=(questionnaire* diagnos*) OR Topic=(questionnaire* screen*) OR Topic=(questionnaire* scor*) # 16 Topic=(MNSI) OR Topic=(TCSS) # 17 #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 # 18 #17 AND #3 # 19 Topic=(animal) OR Topic=(animals) # 20 #18 NOT #19

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 2. Outline of index test

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

Appendix 3. Outline of reference test

Characteristic Study ID	Time interval between scoring system and 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 4. 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 5. 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 6. 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 7. 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 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 scoring system(s) were not aware of the results of the NCS.	The outcome assessors for the scoring system(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?	Scoring system results were interpreted without any knowledge of other index test results or the previous test results.	Scoring system results were interpreted with knowledge of other index 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 curve.	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 scoring system(s) to permit its replication. 2. Scoring systems 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 scoring system(s) to permit its replication. 2. Scoring systems 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, like 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 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 NCS (thresholds, investigated sites, etc.) to permit its replication. 2. NCS were 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 scoring system(s) underwent the reference standard.	Not all patients receiving scoring system(s) underwent NCS, including the case in which a random sample of those who were tested negative by scoring system(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 procedures were performed for the patients.	Insufficient information is available to answer ‘yes’ or ‘no’.
4. 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 one of 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.

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

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

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

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

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

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

Siyan Zhan (SZ): conception of study, protocol draft, data extraction, quality assessment, 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.

RC: none known.

YZ: none known.

YH: none known.

TH: none known.

FS: none known.

LJ: 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