Patient testing is increasingly being carried out at the bedside. Indeed the availability of point-of-care testing (POCT) instruments and devices has grown significantly in recent years. Undoubtedly POCT helps speed up the availability of results, but when such testing is moved outside of the laboratory setting how can accuracy be ensured? `

by Sarah Kee

In all patient testing, Quality Control (QC) exists to ensure accuracy and reliability. For many of the health care workers using POCT instruments, QC will be unfamiliar territory. Many of the standard QC procedures applied in laboratories cannot be applied to POCT devices.  However, it is essential that both primary and community care settings apply well-structured QC procedures to ensure the accuracy and reliability of results, minimizing risk to patients and improving patient outcomes.

Designing a QC strategy for POCT
When designing a QC strategy for POCT devices there are three main issues that need to be considered:

1. Design of the devices
POCT devices can be broadly split into three categories with procedures varying according to instrument design:

• “Laboratory Type Instruments”- Full size instruments used at the point of care, e.g.: blood gas analysers.
• “Cartridge-Based Instruments”- E.g.: HbA1c and INR analysers.
• “Strip-Based Instruments”- e.g.: electrochemical or reflectance strip based glucose meters and INR analysers.

For laboratory type instruments the design mirrors that of analysers found within the laboratory environment. Therefore, QC procedures should mirror those found within the laboratory: if patient tests are performed every day, then multi-level QC samples should also be run every day. The accuracy and reliability of these results should be monitored over time to provide a true reflection of performance. External Quality Assessment should be run in conjunction with Internal Quality Control (IQC).

For cartridge-based instruments, the technology differs from that found in standard laboratory type analysers and therefore to reflect this, QC should be performed differently.

Cartridge-based devices usually consist of a cartridge-based component and an electronic reader based component.  The cartridge-based component contains all the necessary “ingredients” for the analysis of the patient sample while the electronic reader component is responsible for converting the result from the cartridge component into a numerical value.  QC can be problematic as the QC technician is only ever testing the one particular disposable cartridge and the electronic function of the analyser that is in use at that specific time.  Nevertheless, performing QC for these devices is still essential to ensuring the cartridge is performing correctly as damage may have occurred during transport, or the on-board reagents may have deteriorated. As a minimum, QC should be run when changing cartridge lot and periodically throughout the lot’s lifespan to ensure the stability of the on-board components. To fully ensure the instrument’s accuracy over time, technicians should also participate in an EQA scheme.

Strip-based instruments are very similar in design to cartridge-based instruments. Like cartridges, the strips are responsible for analysis of the sample, however, as the electronic component has no QC self-check feature, a faulty analyser could be producing erroneous results which remain undetected for some time.  Because of this, QC processes should be more stringent for strip-based devices than cartridge-based devices. Strips should be checked on delivery using multi-level QC to ensure they have not been damaged during transit, as well as every day of patient testing. It is also important to participate in a frequent EQA scheme. 

2. Possible risks to the patient
When implementing QC for POCT devices the risk of harm to the patient should be the foundation of the QC strategy: where and why do errors occur and what are the consequences of an erroneous result to the patient?

The QC strategy should balance the risk of harm to the patient with the stringency of the QC procedure applied. Studies have shown that the most common phase for errors in POCT is analytical, with 65.3% of errors occurring during this phase. In contrast, the analytical phase in laboratory testing is the least common source for errors. This highlights the need for QC procedures for POCT devices as the potential risk of harm to the patient is greater for POCT than laboratory-based tests.

As many POCT are used by non-laboratory professionals it is vital that users are trained to undertake QC – without QC results may not be accurate. Inaccurate results could have serious implications for the treatment the patient receives.

3. Who is responsible for QC in POCT?
According to ISO 22870:2006, a POCT management group should be set up with responsibility for managing and training staff using the equipment.  This group should be responsible for the quality management strategy and implementing a programme of staff training, to include quality control, for all personnel performing POCT and interpreting results.

The running of QC samples on POCT devices should be performed by those who are using the devices regularly, as QC samples should be run as a patient sample would be and therefore must be performed by personnel who are responsible for patient testing.

IQC and EQA/PT – making appropriate choices for POCT Devices
Internal Quality Control (IQC) involves running samples containing analytes of known concentration, to monitor the accuracy and precision of the analytical process over time. Depending on the design of the device and risk of harm to the patient the IQC strategy will differ accordingly. When choosing appropriate IQC material for performing QC on POCT devices, it is important to look for material that offers the following benefits:

• ease of use – many QC materials come in ‘liquid ready-to-use’ formats for convenience
• a matrix similar to the patient sample
• analytes contained at clinically relevant concentrations
• accurately assigned target values
• a third party control, as recommended by ISO15189, to ensure an unbiased, independent assessment of performance 

Interlaboratory data management software is available that will allow a laboratory to manage and interpret their QC data.  This software is an extremely cost effective and efficient way to ensure that a laboratory’s POCT devices are performing at a high standard, allowing accuracy and precision to be monitored over time, thus providing a true reflection of performance of both the device and the personnel using the device.
This software is usually available with a peer group comparison functionality that will allow a laboratory to directly compare the results of their POCT devices to other laboratories using the same  devices worldwide.
Proficiency Testing (external quality assessment) is strongly recommended for all point of care devices. ISO 22870:2006 states, “There shall be participation in external quality assessment schemes”. An EQA scheme assesses the accuracy of the POCT devices through direct results comparison of one device to identical devices worldwide. This peer comparison allows a laboratory to assess the accuracy of a device over time and provides confidence that the patient results being  reported are accurate.
There are many PT schemes available for POCT devices; when choosing a scheme it is important that a laboratory considers the following:

• frequent reporting to minimize the amount of time an error can go unnoticed
• quality material provided in a format suitable for use with POCT devices
• well-designed reports that allow for quick and easy troubleshooting of erroneous results at a glance
• choose an international scheme with a large number of participants to ensure a more accurate reflection of performance

The benefits of POCT are undisputed but only if we are assured of accurate results. Getting the right QC strategy in place now will ensure the contribution POCT makes to patient testing is a wholly positive one.

The author
Sarah Kee, BSc PGCE
QC Scientific Consultant
Randox Laboratories Ltd
E-mail: sarah.kee@randox.com
www.randox.com

Vitamin D is derived from food, and human beings need exposure to sunlight for its synthesis. This is achieved through the absorption of ultraviolet B radiation by 7-dehydrocholesterol in the skin.  However, certain sections of the population cannot produce Vitamin D in sufficient quantities; such at-risk groups are the focus of screening.
The principal function of Vitamin D is to enable absorption of calcium and phosphorus and promote bone health. It is metabolized in the liver to 25-hydroxyvitamin D (25OHD). The kidneys activate 25OHD to 1,25-dihydroxyvitamin D, which in turn regulates calcium, phosphorus and bone metabolism.
25OHD is the key circulating form of vitamin D, and as a biomarker, is generally the target of screening.

 
The deforming condition known as rickets, caused by a deficiency of Vitamin D, was a scourge in children until the early 20th century. The vitamin was identified in the 1920s. Though the crucial role played by sunlight in avoiding rickets had been known since the 1820s, it was only endorsed officially after over a century. Accompanied by fortification of milk and infant food with Vitamin D, rickets in industrialized countries soon became a thing of the past.
Rickets has, however, recently returned. One reason is ironic: the excessive promotion of breastfeeding and an unawareness that human milk does not suffice for an infant’s Vitamin D needs. This is exacerbated by modern lifestyles which discourage exposure to the sun, along with an overuse of sun screens and other forms of protection.

Benefits likely for several diseases
More recently, researchers have found that Vitamin D may also play a role in controlling a host of other diseases. This has revived the debate about screening.
Diseases against which Vitamin D provides benefits role are believed to include cancer, cardiovascular and cerebrovascular disease, diabetes and metabolic disorders, multiple sclerosis, inflammatory bowel diseases and certain neurological conditions.

Ethnicity, age and gender
Since the mid-1980s, it is accepted that Vitamin D’s role in the context of certain major medical conditions depends on ethnicity. The re-emergence of rickets has been concentrated, for example, in African Americans in the US and Asians in the UK.
In 1988-1994, the third US National Health and Nutrition Examination Survey (NHANES III) found significant differences between different ethnic groups in terms of 25OHD levels, which in turn correlated to a predisposition to both high blood pressure and diabetes.
In 2002, researchers found that Vitamin D’s role in pediatric Crohn’s disease was particularly pronounced in African-American children. Likewise, in the case of coronary artery disease, one high risk group consists of African-Americans with HIV.

Age-specific risks too are an area of concern. The elderly have been specifically targeted to study Vitamin D’s role in hypertension and in cognitive decline. Older women, in particular, seem prone to suffer from its deficiency, and thereby to adverse effects on their musculoskeletal system.
On the other side of the age scale, Vitamin D deficiency in infants seems associated with a range of chronic diseases in later life, from multiple sclerosis to Type 1 diabetes and schizophrenia.

More research still needed
Nearly all the research efforts cited above add caveats to their findings, underlying the role of Vitamin D in avoiding several diseases, but also calling for further investigation. Two recent meta-studies, which assimilate the results of previous research in this area, illustrate the problem.
One meta-study, published at the end of 2012, focuses on Vitamin D and cardiovascular disease (CVD). Its scope extends to 19 previous studies covering 6,123 CVD cases in nearly 66,000 subjects. It notes that, in spite of evidence about a link between CVD and Vitamin D deficiency, “optimal” levels of 25OHD for cardiovascular health “remain unclear,” and underlines that there is a “generally linear, inverse association” between circulating 25OHD in the range of 20-60 nmol/L and a risk of CVD. However, it calls for “further research” on 25OHD levels higher than 60 nmol/L.
The second meta-study dates to the end of 2013 and covers 18 prospective studies on Type 2 diabetes and metabolic disorders, involving 210,107 participants. It begins by observing that though “several studies have assessed Vitamin D in relationship with metabolic outcomes”, “results remain inconsistent.” It concludes that Vitamin D-targeted interventions “may be a useful preventive measure for metabolic diseases”, but also warns that “reliable evidence from carefully designed intervention studies, particularly those based on healthy populations, is needed to confirm observational findings.”

Differences in definition of risk persist 
This bewildering array of qualifiers makes screening for Vitamin D problematic, for now.
Making things even more di ficult are continuing doubts about what level of 25OHD indicates a risk, and for who, when and where.

In the UK, the National Health Service (NHS) considers concentrations of less than 25 nmol/L to indicate “deficiency”, with “insufficiency” at 25-50 nmol/L, and “adequate” levels at more than 50 nmol/L. The American Journal of Clinical Nutrition (AJCN) specifies 25OHD below 50 nmol/L as an indicator of “deficiency”, while 51–74 nmol/L does so for “insufficiency”; the 74 nmol/L margin (as discussed below) has also been adopted in Poland. On its part, the National Institutes for Health (NIH) defines less than 30 nmol/L as “deficiency”, 30-50 nmol/L as “generally considered adequate” and more than 125 nmol/L to be associated with “potential adverse effects.”
Although the NIH says a 50 nmol/L concentration covers the needs of 97.5% of the population, it still leaves 7.5 million Americans in need of screening.

Seasonal factors confound the playing field further. In the UK, for example, the  “insufficiency” concentration of 25-50 nmol/L for 25OHD is found in as much as half the country’s population, during spring.
Last but not least are doubts about the relevance of 25OHD concentration itself. For instance, the European Food Safety Authority (EFSA) stated, as recently as 2012, that while it “is a good marker of vitamin D status”, 25OHD can only be used “as a biomarker of vitamin D intake in people with low exposure to sunlight.”

Recommendations for screening
In the face of this, there is little consensus about screening for Vitamin D.
Nevertheless, national recommendations to prevent Vitamin D deficiency were instituted in Poland in 2009, and three years later in Hungary and Germany. Underlying the ongoing lack of clarity on the issue,  the German Nutrition Society, which issued the recommendations, also evaluated Vitamin D as part of a separate investigation into vitamin availability, but this time was sanguine, except in the elderly. The elderly were also the subject of nutrition recommendations by the the International Osteoporosis Foundation in 2010.
In much of continental Europe, 50 nmol/L of 25OHD concentration is used to indicate Vitamin D sufficiency, in line with Britain’s NHS and the US NIH. However, most east and central Europeans tend to follow the 2009 Polish recommendations, which specified less than 50 nmol/L as deficiency, 50-75 nmol/L as ‘suboptimal’, with an ‘optimal’ target of 75–125 nmol/L; the latter straddles the lower and higher margins prescribed in the US by the AJCN and NIH, respectively (see above).
Iterations on thresholds, meanwhile, continue to proliferate, even with regard to at-risk populations. For example, while both Germany and the International Osteoporosis Foundation suggest 25OHD concentrations of 60 nmol/L in the elderly, in 2013 the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) recommended 50nmol/L for elderly women, and 75 nmol/L for “fragile” subjects.

The VITAL trial
It is to be hoped that many questions about the precise role of Vitamin D in battling some of the largest challenges facing modern medicine are answered in the years to come.
One such effort has, in fact, recently been launched. Known as VITAL (‘VITamin D and OmegA-3 TriaL), this interventional, randomized clinical trial is recruiting 20,000 men and women in the US to investigate whether daily dietary supplements of Vitamin D or omega-3 fatty acids reduces the risk of cancer, heart disease and stroke in people with no prior history of these illnesses.

Targeted supplementation most likely course
The above developments indicate that the argument about routine supplementation making “more sense” than screening is likely to yield place to “targeted” screening for at-risk populations, with an especially strong case for the elderly and infants.
Both groups were, in fact, highlighted in July 2011 Clinical Practice Guidelines on Vitamin D by the influential US-headquartered Endocrine Society. The Society also included “pregnant and lactating women,” “obese children and adults”, and patients on “anticonvulsant medications, glucocorticoids, antifungals such as ketoconazole, and medications for AIDS.”

Standardizing lab tests
In the meanwhile, one major concern for clinical laboratories with regard to Vitamin D tests seems to have been addressed. Until recently, serum 25OHD concentrations showed considerable variations, depending on the type of assays used (the most common is liquid chromatography). This led to differences among laboratories in their findings. The implication of such differences has been significant, especially given the differences in definitions of Vitamin D sufficiency and insufficiency.
In 2009, the US National Institute of Standards and Technology (NIST) released SRM 972, a reference material for 25OHD. SRM 972, updated by NIST in February 2013 to SRM 972a, is also used in Europe.