Point-of-care neutrophil gelatinase-associated lipocalin (NGAL) tests

Patient Group and Use:

This emerging diagnostic technology could benefit patients in primary care at risk of AKI and CKD patients undergoing frequent kidney monitoring. If validated and accepted, NGAL point-of-care testing could help GPs detect renal impairment and CVD risk faster in these patients. This will ensure optimal management of these patients and a timely referral when required. Age and gender are critical determinants of NGAL concentration. Using a creatinine-based AKI definition and a standardized timing of NGAL measurement in relation to the occurrence of renal insult, a meta-analysis published in 2009 including data from 19 publications with 2538 patients reported that NGAL was substantially better at indicating acute kidney injury in children than in adults (24). A substantially lower occurrence of concomitant disease states in children may offer an explanation of why NGAL seems to perform better in children than in adults.

Importance:

Acute kidney injury is common; it is seen in 13–18% of all people admitted to hospital. Its complications include progression to more severe kidney injury (requiring renal replacement therapy), CKD, and death. AKI is also known to have effects on the cardiovascular, respiratory, hepatic, and neurological systems (25).  The incidence of AKI and, in particular, the most severe form of AKI (as defined by dialysis requirement) has risen over the past several years (26) and the serious and far reaching consequences of AKI highlight the need for early detection.

In the case of AKI, early recognition is of critical importance to the timely introduction of measures to reverse injury or prevent further damage and progression towards chronically lowered eGFR post recovery. Testing and then establishing protocols for monitoring AKI using NGAL may achieve this.

CKD is a progressive loss of renal function and is subdivided into stages 1-5, based on stable eGFR measurements and, for early stages, evidence of structural renal disease (imaging abnormalities, proteinuria). Most people with CKD only develop symptoms in advanced stages (stages 4-5) and, therefore, early CKD is rarely detected outside of opportunistic blood sampling for other reasons. CKD is predictive of increased all-cause and cardiovascular mortality (27) (28). Cardiovascular disease (CVD) is a major comorbidity and primary cause of mortality in CKD patients. Similar to AKI, early diagnosis and appropriate classification of CKD is crucial in order to ensure better management of CKD and its associated CVD and in slowing progression to End Stage Renal Disease (ESRD).

Concerning the prevalence of CKD in England, a cross sectional point prevalence study of more than 130,000 adults in primary care suggested an age-standardised prevalence of stages 3-5 CKD of 8.5% (29). In a second study, the Quality Improvement in CKD (QICKD) study, which also took place in primary care, suggested a prevalence of 6.8% for stage 3—5 CKD, which equates to approximately 3 million adults. The 2010 Health Survey for England, a smaller study using a stratified sample of adults from the community suggested an overall prevalence for CKD stage 3-5 of 6% in men and 7% in women. It also showed a strong age gradient with less than 1% of men and women in the 16-24 age category having CKD stage 3-5 whereas the numbers were much higher in the age 75 and over category (29% in men and 35% in women).

The financial burden of CKD on the NHS is increasing rapidly, with particularly high costs relating to renal replacement therapy (RRT) and cardiovascular complications (30) for people with ESRD. The cost of CKD to the NHS was estimated at about £450 million in 2002 growing to about £1.5 billion in 2009–10. This represented almost 1.5% of all NHS spending in 2009-10. More than half this sum was spent on RRT, with excess CVD events (strokes and myocardial infarctions) accounting for almost £200 million (30). The majority of these late-stage CKD patients have either been diagnosed or referred later than appropriate. Consequently, the objectives of current NICE CKD guidelines are moving towards timely and appropriate CKD detection and CVD risk assessment in order to reduce the risk of hospitalisation, ESRD and of CVD events (31).

Previous Research:

Accuracy compared to existing technology

The clinical NGAL assays have been tested in various clinical settings, however we did not identify any studies performed in primary care.

NGAL for the prediction of acute kidney injury after cardiac surgery

The studies listed in Table 3 have investigated the utility of NGAL to predict AKI in cardiac surgery patients; this setting presents the advantage that the time point of injury is known. Most of these studies showed NGAL both in the blood and urine to be a good early predictor of AKI, although areas under the receiver operating characteristic curves (AUC) have varied between 0.65-0.998 for urine and 0.64-0.98 in plasma (Table 3). There was a significant increase in NGAL levels measured by Western blotting, ELISA, and the clinical platforms (Abbott ARCHITECT and Triage® NGAL device) just hours after surgery, both in the urine and in blood with AUC-ROC of 0.61-0.99 for the urine NGAL and 0.56-0.96 for the plasma NGAL. These studies also confirmed a delay of between 1-3 days in the diagnosis of AKI using serum creatinine alone.

Mishra et al. were first to show the utility of both serum and urine NGAL for early detection of AKI in a paediatric population of 71 children undergoing cardiac surgery of whom 20 developed AKI. NGAL levels at 2 hours after the procedure were found to be powerful predictors of AKI with AUC for urine NGAL of 0.998 and plasma NGAL of 0.91 (32). In another study of 120 children undergoing cardiopulmonary bypass (CPB), 45 developed AKI and the NGAL concentration measured using the Triage® NGAL device was found to triple within two hours of the procedure. Multivariate analysis showed that plasma NGAL concentration at two hours after injury was the most powerful independent predictor of AKI. Using a cut off value of 150 ng/mL, AUC was 0.96, sensitivity was 84% and specificity was 94% for prediction of AKI (33). There was also a strong correlation between two hour NGAL measurement and change in creatinine concentrations, duration of AKI and length of hospital stay (33). In addition, the 12 hour measurement of plasma NGAL also strongly correlated with mortality (33).  Similarly, a prospective study by Bennett et al. in 196 children undergoing CPB found that urinary NGAL measurements at 2, 4 and 6 hours after the procedure predicted severity and duration of AKI, length of hospital stay, requirement for renal replacement therapy and mortality (34).

In a retrospective observational study involving 879 patients post coronary artery bypass graft surgery of whom 8.6% of patients developed AKI, plasma NGAL levels measured immediately after CPB were higher in patients who subsequently developed AKI than in those who did not, but using a cut-off of 353.5 ng/mL had a low sensitivity of only 38.7% (35).

More recently, as part of the multicentre TRIBE (Translational Research Involving Biomarkers and Endpoints) study, Parikh et al. prospectively assessed the utility of NGAL in 1219 adults undergoing coronary artery bypass grafting and/or valvular surgery cardiac surgery (36) and 311 children undergoing surgery for congenital cardiac lesions (37). Postoperative blood samples were collected at the time of admission to the Intensive Care Unit and then daily for 5 days. Urine was collected four times during the first postoperative day and then daily until day 5. In both groups NGAL in urine and blood peaked within 6 hours of ICU arrival, which was well before increases in serum creatinine (24–72 hours postoperative). NGAL measurement significantly improved risk prediction over the clinical models alone. Multivariate analysis revealed that both plasma and urine NGAL are associated with a risk of AKI and with longer length of hospital stay, longer intensive care unit stay, and higher risk for RRT or death.  In the adult population, urine NGAL had a sensitivity of 46% and a specificity of 81%, at a cutoff point of 102 ng/mL. Plasma NGAL had a sensitivity of 50% and a specificity of 82% at a cutoff point of 293 ng/mL. Plasma but not urine NGAL improved the AUC of the clinical model (36). In the paediatric population, the accuracy of urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.71. The addition of urinary NGAL measurement also improved risk prediction over clinical models alone (measured by net reclassification improvement and integrated discrimination improvement). In this population, urine NGAL, but not plasma NGAL, was associated with subsequent AKI and poor outcomes (37).

Krawczeski et al. recently investigated the importance of timing of NGAL measurement. They investigated four AKI biomarkers in the urine of 220 children, without other pre-existing major comorbidities, at several time points after CPB.  NGAL, IL-18, L-FABP, and KIM-1 were measured at 2, 6, 12, and 24 hours after CPB and urine NGAL was the first to rise in AKI patients, even at the first 2 hour measurement. In addition, NGAL maintained the best predictive performance at all time points (AUC 0.90, 0.91, 0.90, and 0.87 at 2, 6, 12, and 24 hours, respectively) (38). In a further study, NGAL was investigated as an early biomarker of AKI after neonatal and paediatric CPB. in 374 patients before and at intervals after surgery. NGAL levels were found to be significantly increased in patients with AKI at 2 hours after CPB (for every 10 ng/mL increase in 2-hour plasma NGAL, the odds of AKI increased by 47% and for every 10 ng/mL increase in 2-hour urine NGAL threshold, the odds of AKI increased by 32%) and remained elevated at all points. The 2-hour plasma and urine NGAL measurements correlated strongly with length of hospitalisation (correlation coefficient being 0.35 for plasma and 0.44 for urine, P < 0.0001) as well as severity (correlation coefficient 0.64 for plasma and 0.65 for urine, P < 0.0001) and duration of AKI (correlation coefficient 0.28 for plasma and 0.37 for urine, P < 0.0001).

Table 3: Studies investigating plasma and urine NGAL for the prediction of acute kidney injury after cardiac surgery.

NGAL in critically ill and septic patients

In contrast with cardiac surgery patients, critically ill patients suffering from AKI and those admitted from the emergency department have a timing of renal insult that is generally not entirely clear. This makes it difficult to interpret an elevated NGAL result, in particular in the presence of sepsis. Studies concerning critically ill and septic patients are presented in Table 4.

Wheeler et al. conducted a multicentre observational cohort study involving 143 critically ill children in America with systemic inflammatory response syndrome (SIRS) or septic shock admitted to paediatric intensive care units (PICU) (49). Serum NGAL was measured during the first 24 hours of admission to the PICU. There was a significant difference in serum NGAL between healthy children (median 80 ng/mL), critically ill children with SIRS (median 107.5 ng/mL), and critically ill children with septic shock (median 302 ng/mL). Serum NGAL was also significantly increased in critically ill children with AKI (median 355 ng/mL) compared to those without AKI (median 186 ng/mL). AUC of serum NGAL on admission to the PICU for the prediction of AKI was 0.677 with an optimal cut off value of 139 ng/mL. Zappitelli et al. (50) carried out a prospective cohort study of 140 critically ill mechanically ventilated children. Serum creatinine was collected daily for up to 14 days, and urine was collected once daily for up to 4 days for urinary NGAL measurement. A significant rise (16 times) in levels of urine NGAL occurred 48 hours earlier than a 50% increase in serum creatinine levels. Urine NGAL levels increased in a stepwise fashion with worsening RIFLE class. The AUC for urine NGAL for predicting AKI in was 0.78.

Martensson et al. studied the impact of inflammation on NGAL concentrations in plasma and urine in patients with SIRS, severe sepsis and septic shock with and without AKI (51). In this cohort of 45 adult patients, 27 patients with SIRS, severe sepsis, or septic shock without AKI and 18 patients with septic shock and concomitant AKI were included. Plasma and urine were analysed twice daily for NGAL levels and both plasma (AUC 0.85) and urine NGAL (AUC 0.86) were good predictors of AKI developing within the subsequent 12 hours. However, the ability of plasma NGAL to predict AKI (AUC 0.67) compared to urine NGAL (AUC 0.86) in patients with septic shock was less robust.

Bagshaw et al. showed similar results in a prospective observational study involving 83 critically ill patients with septic and non-septic AKI. Specimens for blood and urine NGAL were collected at enrolment, 12, 24 and 48 hours (52). Septic AKI patients displayed the highest concentrations of both plasma and urine NGAL when compared with those with non-septic AKI. Urine NGAL remained higher in septic compared with non-septic AKI at 12 and 24 hours. Plasma NGAL showed reasonable discrimination for AKI progression (AUC 0.71) and renal replacement therapy (AUC 0.78). Although urine NGAL performed less well (AUC 0.70 and 0.70 respectively), peak urine NGAL predicted AKI progression better in non-septic AKI. The multiple insults and higher baseline NGAL levels in these patients may be a confounding factor that may add to the heterogeneity of the results in the critical care setting.

In one of the largest recent studies, De Gues et al. carried out a prospective cohort study consisting of 632 consecutive adult patients admitted to ICU. Plasma and urine NGAL were measured at ICU admission and predicted the development of severe AKI similarly to eGFR. However, when patients with eGFR<60 mL/min/1.73 m2 were excluded, plasma (AUC 0.75) and urine NGAL (AUC 0.79) displayed diagnostic superiority over serum creatinine (AUC 0.65) and eGFR (AUC 0.67) for predicting AKI (53). Thus, the accuracy of NGAL in predicting AKI is highest in patients with normal kidney function before the acute illness.

Table 4: Studies investigating the use of plasma and urine NGAL critically ill and septic patients

NGAL in the Emergency Department

A single-centre prospective study involving 635 patients admitted to an Emergency Department assessed the use of NGAL for emergency admissions (58). A single measurement of urinary NGAL was obtained at presentation and patients were separated into diagnostic groups according to currently used criteria: normal kidney function, intrinsic AKI, prerenal azotemia, and non-progressive CKD. At a cut-off level of urine NGAL of 130 μg/g of creatinine, intrinsic AKI could be distinguished from the other clinical groups, with an AUC of 0.95, sensitivity of 99% and specificity approaching 100%. Furthermore, a urinary NGAL level of more than 130 μg/g was highly predictive of adverse clinical outcomes, including need for nephrology consultation, dialysis and admission to the ICU.

These findings have been corroborated in a large, multicenter prospective cohort of 1635 patients admitted to an Emergency Department (59). At a cutoff concentration of 104 ng/ml, urine NGAL measured on admission predicted AKI (AUC 0.81; specificity 81%), the severity and duration of AKI, and a composite outcome of dialysis initiation or death during hospitalization. Net risk classification also improved when urinary NGAL was added to clinical risk-prediction models (59). In another multicentre cohort study involving 661 adult patients, Shapiro et al. investigated the diagnostic accuracy of plasma NGAL for the prediction of AKI in the emergency department (60). In this study a plasma NGAL level of more than 150 ng/ml, measured using the rapid POC Triage® NGAL assay at the time of presentation to the Emergency Department, predicted AKI within the first three days of hospitalisation, with a sensitivity of 96% and an AUC of 0.82.

These results were validated by a recent prospective study by Soto et al. involving 616 patients admitted from the Emergency Department who had plasma NGAL levels measured, using the Triage® NGAL assay, at five different time points (at presentation then 6, 12, 24, and 48 hours from admission) to better understand how NGAL would perform over 48 hours (61). Following admission GFR was estimated and patients were separated into one of four diagnostic groups: normal kidney function (GFR greater than 60 ml/min per 1.73 m² and no increases in serum creatinine during the hospital stay), stable CKD (stably reduced estimated GFR<60 ml/min per 1.73 m² before admission and <25% change from baseline during the hospitalization), transient azotaemia (new-onset increase in serum creatinine that satisfied any grade of RIFLE) or AKI (defined according to the RIFLE and AKIN criteria). NGAL levels were highest in the AKI group (146–174 ng/ml) and increased with AKI severity (207–244 ng/ml for AKIN stage >2). The ability of plasma NGAL to predict AKI (AUC 0.77–0.82 at different time points) improved with increasing severity of AKI (AUC 0.85–0.89 AKIN>2). Plasma NGAL values taken at 12 hours after hospitalisation reliably distinguished intrinsic AKI from transient azotaemia (AUC 0.73) and CKD (AUC 0.82). Plasma NGAL also discriminated AKI from normal function and transient azotaemia (AUC 0.85 and 0.73, respectively).

The concept of NGAL cutoff values was also re-examined in the study by Soto et al. A distinct plasma NGAL cut-off for differentiating between AKI and non-AKI could not be identified. Instead, the authors identified a grey zone of plasma NGAL concentrations (97 to 133 ng/mL) that was associated with a moderate risk for AKI. Patients who had plasma NGAL concentrations above 133 ng/mL were found to have a 10-fold greater risk of AKI. Therefore, patients who are at risk for AKI according to clinical presentation would benefit from point-of-care plasma NGAL measurements and could be triaged and managed as having true intrinsic AKI. Patients whose plasma NGAL levels fall within the ‘grey zone’ and who have clinical AKI risk factors should also be considered at high risk for intrinsic AKI.

Di Somma et al conducted a multicentre prospective cohort study involving 665 patients admitted to hospital from the Emergency Department in the period from November 2008 to April 2009. They evaluated the utility of POC blood NGAL measurement as an aid in the early risk diagnosis for AKI. NGAL and serum creatinine were determined at presentation, 6, 12, 24 and 72 hours after hospitalisation. The physician, while blinded to NGAL results, determined the clinical certainty of AKI. The physician’s initial judgement lacked sensitivity and specificity, incorrectly predicting a diagnosis of AKI in 27% of the cohort, while missing 20% of those with confirmed AKI. The AUC for blood NGAL obtained at presentation in the AKI group was 0.80. However, when NGAL was added to the physician’s initial clinical judgement, the AUC was increased to 0.90 and this was significantly greater than the AUC for eGFR obtained at presentation (AUC 0.78). In the net reclassification improvement analysis, the model obtained by combining NGAL with the physician’s initial clinical judgement compared to the model combining serum creatinine with the physician’s initial clinical judgement, resulted in a 32.4% improvement. Using a cutoff of 150 ng/ml and two serial NGAL measurements (at presentation and at 6 hours), AKI could be ruled out within 6 hours of patients’ arrival with a negative predictive value of 98%. On the other hand, an NGAL cut-off of 400 ng/ml was very specific for deciding on a diagnosis of AKI. Admission NGAL was also most strongly predictive of in-hospital mortality at a cut off above 400 ng/ml (AUC 0.76).

Table 5: Studies investigating the use of plasma and urine NGAL in the Emergency Department.

NGAL in prediction of contrast nephropathy

NGAL has also been shown to be useful as a biomarker of AKI in other settings. In a small cohort of 26 non-diabetic patients with normal serum creatinine, undergoing coronary angiography, a 25% increase in urine NGAL from baseline (measured using an ELISA) was found to be predictive of contrast nephropathy (defined as 25% increase in serum cystatin C), with a sensitivity of 80% and specificity of 83%. On the contrary, serum creatinine did not change significantly after the angiography (13). Another study assessed 91 children with congenital heart disease undergoing elective cardiac catheterisation and angiography with contrast administration. The authors found that significant elevation of NGAL in urine and plasma within 2 hours of predicted contrast induced nephropathy. Detection using serum creatinine was only possible after 6-24 hours (14).

Table 6: Studies investigating the use of plasma and urine NGAL in prediction of contrast nephropathy

It should be noted that the diagnostic ability of NGAL in these clinical studies is dependent on the gold standard used to detect the diagnostic outcome. Using a diagnosis of AKI based on creatinine may not be an accurate measure of kidney injury, particularly considering the aforementioned disadvantages. To avoid this problem, some studies have tried to differentiate between intrinsic and prerenal AKI based on clinical criteria e.g. recovery of creatinine when haemodynamic changes are corrected (59) (63). In these studies, the AUC-ROC ranged from 0.81-0.95, suggesting that NGAL may be better at identifying intrinsic nephron damage than predicting AKI based on conventional criteria. These studies are limited by the fact that clinical criteria were used rather than biopsy results to diagnose intrinsic damage. 

Impact compared to existing technology

NGAL is not currently used in clinical practice in the UK. Numerous studies have addressed the potential clinical utility of NGAL in AKI (Tables 3 – 6). All studies combined include more than 10,000 patients.

Health Economics:

Only one study was identified, which assessed the cost effectiveness of using urinary NGAL for the diagnosis of AKI after cardiac surgery compared to current diagnostic methods (64). Shaw et al. created a decision model using a base case to represent a typical patient: A 67-year-old man, in the UK with no history of CKD, having coronary artery bypass graft surgery and admitted to the intensive care unit immediately after the procedure. Cost per quality-adjusted life-year (QALY) was used as the measure for economic evaluation. A 25% improvement in outcomes from acute kidney injury because of early diagnosis, based on NGAL levels, was assumed and this was varied to 12.5% and 50% levels in the sensitivity analysis (65).

The base case demonstrated expected costs of £4244 and 11.86 QALYs for the NGAL strategy compared with £4672 and 11.79 QALYs for the current methods. The cost-effectiveness ratio for the NGAL strategy was £358 per QALY compared with £396 per QALY for the standard practice. Cost-effectiveness increased with treatment effect of the therapy triggered by an elevated NGAL level. Probabilistic sensitivity analysis supported the NGAL strategy as the most cost-effective option for 100% of the 1000 patient simulations. Therefore, the results suggested that the use of urinary NGAL is likely to be economically beneficial since AKI is diagnosed earlier. It should be noted that, because this study was a decision analysis model incorporating a nonspecific treatment for AKI, model structural assumptions might have underestimated mortality and the likelihood of developing AKI. Indirect costs were also not explicitly factored. It is also difficult to clearly identify the literature source and expert opinion used due to lack of description of the parameter estimates.

Guidelines and Recommendations

Current NICE guidance (NICE clinical guideline 169) (8) recommends using serum creatinine or urine output to detect acute kidney injury, and do not include a definition of acute kidney injury based on measurement of NGAL. Estimated glomerular filtration (eGFR) may also be used for children and young people. For each of these measurement methods, there are established ranges that define acute kidney injury: the recognised criteria of risk, injury, failure, loss of kidney function, and end-stage renal failure (RIFLE) (66) (67) (18).

In 2014 the NICE Diagnostics Advisory Committee considered The NGAL Test ^TM (BioPorto). They concluded that more research was needed prior to adopting NGAL testing, but that this was certainly an area of significant clinical need (65).

Research Questions:

1)      What is the accuracy of rapid or point-of-care NGAL tests in primary care populations?

2)      Could NGAL help improve targeted referral to secondary care when appropriate as opposed to current practice of relying upon clinical suspicion?

3)      Could NGAL help improve diagnosis and targeted treatment of AKI in primary care where appropriate?

4)      What is the cost: benefit ratio of implementing NGAL tests within primary care?

5)      Could NGAL help to distinguish between nephrotoxicity due to medication and acute rejection in patients after renal transplantation?

Suggested next steps:

Most studies on the clinical utility of NGAL have been conducted at secondary care level. More studies on the predictive value, suitability and utility of NGAL testing for AKI and CKD management are required in primary care settings. With NGAL levels also indicative of CVD outcomes, it will be helpful to determine if this marker can simultaneously predict progressive CKD and CVD risk in high-risk patients in primary care. Both serum and urinary NGAL have been suggested as potential markers of renal function. As previously discussed, NGAL has multiple molecular forms, a dimeric form synthesized in neutrophils and the other monomeric from kidney tubular epithelial cells (6). A clinical test method that can clearly distinguish between these two NGAL forms will undoubtedly be key to enhancing sensitivity for the purpose of monitoring renal and/or vascular integrity.

Expected outcomes:

Overall, the aforementioned considerations support the view that measurement of tubule damage markers, such as NGAL, would add substantial value to a consistent approach to early AKI diagnosis. However, once biomarkers of tubule damage are fully established, markers of renal function, such as creatinine, are likely to remain relevant. Markers of glomerular filtration are valuable for diagnosing and quantifying loss of excretory function and prognosis, for example in the context of drug dosing or in the development or deterioration of CKD. Similarly, urine output will remain important for fluid balance and for monitoring the progress of patients on RRT.

Based on the current evidence both urine and plasma NGAL measurement improve the prediction of AKI risk over the clinical model alone and, regardless of clinical setting, NGAL correlates with severity of AKI and can predict poor outcomes. With regards to urine vs. plasma NGAL, the availability of biofluid and the assay used are likely to be the key determinants. In the primary care setting the only available point-of-care test, the AlereTriage® NGAL test, uses EDTA anti-coagulated plasma or whole blood. It is also worth noting that there is no general consensus regarding a specific cut-off value for NGAL above which AKI can be diagnosed. However, based on the available data, an NGAL value of less than approximately 100 ng/mL, measured on a routine clinical platform in urine or plasma, seems to be useful for ruling out AKI in those with normal baseline kidney function and a cut-off value of greater than 150 ng/mL can be used as diagnostic for AKI. Further cutoffs for blood and urine NGAL and their bedside utility are impending and will be determined according to the clinical setting, regulatory intended use guidelines, clinical assay standardization, and laboratory and POC system calibration.

The available data suggest that patients with stable CKD display low concentrations of NGAL similar to normal controls, but those with progressive CKD may exhibit higher concentrations that may approach those seen in prerenal states or even in mild forms of AKI. The lack of a gold standard AKI definition, the lack of specific cut-off values for NGAL and differences in clinical assay characteristics are additional limitations to the widespread use of NGAL in clinical practice at the present time.

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Acknowledgements:

The authors would like to thank Nia Roberts for helpful discussions.  This work is supported by the National Institute for Health Research (NIHR) Diagnostic Evidence Co-operative Oxford at Oxford Health NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. 

This report was prepared by the Primary Care Diagnostic Horizon Scanning Centre Oxford

Authors: Roya Hassanzadeh, Daniel Lasserson, Samuel Fatoba, Carl Heneghan, Christopher P. Price, Ann Van den Bruel, Annette Plüddemann

Contact details:  Dr. Annette Plüddemann; Email: dec@phc.ox.ac.uk