Adding clinical utility to the laboratory reports: automation of interpretative comments

Introduction

Laboratory testing is the single highest-volume medical activity. It has been claimed that two-thirds of clinical decisions are based on laboratory test information [1], [2], [3]. Although this claim may be too high, the value of laboratory medicine in patient care is undisputed [4]. The core business of the clinical laboratory is to provide results of tests requested by physicians and other health care workers, whereas the task of the laboratory can be defined in broader terms – to participate in solving diagnostic challenges. What are the possibilities to add diagnostic value to laboratory results? What further options can the laboratories have to improve consultations and support physicians and patients?

Consultation

Looking back at the developments in the last decennia, the importance that is attached to consultation is closely related to the changing views on the position of clinical chemistry in health care. In the 50s and 60s, the distance between laboratory and clinic was smaller than is now. The increasing automation and the associated increase in the number of tests, and almost completely automated reporting of results, distanced the laboratory specialist from the clinic [5], [6]. The increasing scale and emphasis on the analytical process resulted in large laboratories mainly focused on a fast response time, but with inherently less attention for clinical support. Automation, cost savings and streamlining of analytical techniques, with the reduced focus on supporting the clinical process, has been identified as a threat to clinical chemistry, even to the point that it was suggested that clinical chemistry may not survive [7]. Others were more optimistic, arguing that we needed to move quickly to meet new challenges and to seize the opportunities in the preanalytical and the postanalytical phases, meaning in consultation, with a need for better integration of the clinic and laboratory [8], [9]. Already in 1996 two independent reports appeared that favored this integration [10], [11]. The laboratory should not be seen as a “number factory”. In a recent review, it was argued that some tasks of the extra-analytical phase should become primarily the responsibility of laboratories, including individualized interpretative commenting [12]. Presently, ISO 15189 states explicitly: “The laboratory shall establish arrangements for communicating with users on the following: advising on choice of examinations and use of the services, including required type of sample, clinical indications and limitations of examination procedures and the frequency of requesting the examination; advising on individual clinical cases; professional judgments on the interpretation of the results of examinations”. This all points to the same conclusion: consultation is regarded as a central task and competence of the laboratory specialist. In the above, the problem to be solved by the laboratory specialist is: how should one organize the consultation service in these times high throughput laboratories?

What is the consultation we can do?

Questions concerning individual cases are part of the daily routine, and in that sense, consultation is a task that is inherent to the work of every laboratory specialist. What we are addressing here is consultation – adding specialist knowledge – on a larger scale, and what means do we have to influence the pre- and postanalytical phase?

With regard to the preanalytical phase, most laboratories will apply simple rules in defined cases to add additional tests when appropriate. This is called reflex testing: a predetermined test protocol is automatically completed. Examples are the addition of free thyroxin (T4) when thyroid-stimulating hormone is abnormal, triglycerides in lipemic samples or bilirubin in icteric samples. More extensive protocols are being used, such as in anemia diagnosis [13]. In some cases, a comment may be added automatically to the test results.

The laboratory specialist might interpret abnormal test results personally, take other available (medical) information into account (e.g. age, gender, previous laboratory test results and clinical information) and determine whether additional tests are indicated. In most cases, these tests may be performed with the patient’s material already available in the laboratory. Comments can also be added to the report to serve the requesting physician. This process has been called “reflective testing” [14], [15]. The term reflective testing was chosen because this activity is based on the clinical judgment (reflection) of a laboratory specialist regarding the interpretation of laboratory results. In this way, laboratory professionals could add value over the purely analytical service using their specialist knowledge. It is no exception that in a laboratory examination of a patient, abnormal results may be found that could indicate some unexpected pathology. Recognition and interpretation of pathological results by the laboratory specialist may be helpful for physicians and patients. Examples of disorders typically recognizable by distinct laboratory findings are hemochromatosis, m-proteins, hyperparathyroidism, vitamin B12 deficiency, thalassemia, hepatitis, pituitary dysfunction or Gilbert’s syndrome [16].

A recent Best Practice Report of the Association for Clinical Biochemistry (ACB) [17] states the following on reflective testing:

“There can be circumstances where the result of a test or group of tests will suggest that further investigations should be made to provide a clearer interpretation or confirm a diagnosis in a patient.

Best practice: When the reflective test has obvious relevance to the initial test(s) requested and/or to the medical condition being investigated or diagnosed then the additional tests can be performed without necessarily contacting the requestor or patient. However, this general principle might first need to be agreed with the service commissioners and users”.

This practice is however laborious and needs harmonization between specialists to maintain a comparable quality level [18].

What is the need for adding tests and comments?

Several studies have been published on the opinions on and effects of reflective testing. Some studies focus on the opinion of the general practitioners or other clinicians [19], whereas other studies prioritized the patient’s perspective [20]. Overall, reflective testing was judged by physicians as a useful way to improve the process of diagnosing (and treating) patients. It has also been shown that patients will value and support this activity [20].

To study the opinion on reflective testing, 10 clinical scenarios were circulated to both specialists and general practitioners, each involving the possible addition of a specific test [19]. Response options ranged from adding further tests, phoning the clinician, adding a comment or just reporting the results. It was concluded that reflective testing is generally welcomed by the doctors, with the last option – just reporting the results – as the least favorable. These results were confirmed in a study in The Netherlands, where reflective testing was judged to be useful by general practitioners in almost all of the presented cases [21], [22]. Another study showed a learning effect: the results showed a better concordance between the suspected diagnosis and the actions suggested by the general practitioners if they were or were not familiar with reflective testing by their laboratory (50.8% vs. 38.2%) [23]. It was concluded that reflective testing as a form of consultation can be seen as an added value in the service of the clinical chemistry laboratory to primary health care and can also be rewarding for patients.

Interpretative comments for patients

Apart from adding interpretative comments to reports for physicians, comments could also be created for patients. The better-informed patient has been shown to be better equipped to participate in medical decision processes [24], [25], contributing to patient empowerment and shared decision making. Several studies have shown that patients who are better informed will be better motivated to adhere to treatment options and that patient empowerment will result in improved treatment outcomes [26].

Patients express there is a growing demand for better information in order to participate more actively in treatment decisions. More and more initiatives are being started to give patients access to their medical records, often in the form of patient portals, empowering patients for real participation in diagnosing, treating and monitoring chronic disease.

Although much time, energy and money have been invested in providing patients with direct access to laboratory test results, this access alone is, however, in general insufficient for actionable patient knowledge [27]. There is a fundamental problem of patients not being able to fully understand their medical data and records. If we burden patients with the task of figuring out what test results mean and with the responsibility to act (or not act) based on that information, then we should take the responsibility of making these data as meaningful as possible.

The European Federation of Clinical Chemistry and Laboratory Medicine has recognized these developments. To this end, the working group Patient Focused Laboratory Medicine was established, with the aim to develop new and direct ways of communication of laboratory specialists with patients, supporting the role of the laboratory in informing the patients about their test results and their meaning to them [28].

It should be noted, however, that there is a wide variation within Europe with respect to patients’ access to medical records and to laboratory results [29].

In a survey conducted by this working group among professionals and patients across Europe, it was shown that there is resistance by some professionals in making results available directly to patients. In some cases, this is regulatory, but also because of doubts that patients will understand the meaning of these laboratory results [30].

With respect to patients, a clear proportion of patients are interested in receiving their laboratory medicine results, the majority with explanatory notes; a role for specialists in laboratory medicine is acceptable to them and raises the potential for direct engagement by the laboratory with patients offering a new paradigm for the provision of laboratory medicine activities [30]. This is a potential paradigm shift in laboratory relationships with patients and physicians, and there appears to be an appetite for such progress [27].

Automation of interpretative comments

Automation of commenting is inevitable if this service is to be offered on a larger scale, with guarantied continuity and quality. It should be noted that although reporting to patients would require different texts than for physicians, the basic technical solutions will remain the same. It is expected that the process of the automated generation of interpretative reports would be considerably improved when inconclusive laboratory test results are supplemented with additional tests. In that way, the options to be considered for differential diagnosis can be reduced, and an effective interpretation becomes much more likely.

The automated generation of interpretative comments will mean the application of expert systems. Although the history of expert systems in medicine is long, routine applications are scarce and aimed at confined areas. Several techniques have been applied [31]: discriminant analysis was an early technique for the interpretation of sets of data and was early on believed to find wide application in clinical chemistry [32]. In Bayesian reasoning, the conditional probability of a diagnosis is calculated given the occurrence of the patient variables [33]. Neural networks exist of nodes and weighted connections, with the nodes distributed on three main layers: input data, output (diagnosis) and hidden. Based on historical data, the system will construct the optimal network, and the larger the amount of data, the more efficient will be the outcomes.

Although these techniques have and have had some routine applications, such as in Down syndrome screening [34], they pose very substantial demands on the construction of the database and harmonization of input data in order to be transferable [35].

Rule-based systems intend to capture the knowledge of domain experts into expressions, most often in the form of if-then statements. A rule-based expert system makes the storing of large amount of data easy. The rules help to clarify the logic that is used in the decision-making process, an advantage over other systems, e.g. neural networks, where the reasoning might be obscure.

Current commercial applications in this field are rule-based systems such as the Gaston system of Medecs [36] and the RippleDown system of Pacific Knowledge Systems (PKS) [37].

The Gaston system developed by the ICT Company Medecs constitutes an advanced knowledge system model using techniques of artificial intelligence. The Gaston system is a guideline-based decision support system [38], [39]. It is currently applied to identify drug-drug interactions [40]. A new application is directed at drug-test interactions [41].

Ripple-Down Rules (RDR) as applied by the system of PKS is a general knowledge acquisition technique to build knowledge-based systems (KBS) incrementally, while the system is in routine use. It starts with an empty KBS and is built gradually over time as cases are processed. The laboratory experts build rules as a minor extension to their normal duties and are able to keep refining rules as KBS requirements evolve [42].

The two key features of RDR to facilitate adding knowledge in context are as follows [42]:

1. when a conclusion provided by a KBS is incorrect, a refinement rule is linked to the incorrect rule so that the refinement rule is only ever evaluated in the same context, that is, when the parent rule is also valid.

2. the expert only ever adds a rule to deal with a particular case, so that every rule has an associated case called a cornerstone case. If the expert creates a rule that is valid not only on the case in hand but also on other cornerstone cases, they are asked to add conditions to the rule to distinguish the case from the other cornerstone cases or to accept that the refinement rule should apply to one of more cornerstone cases.

Commercial systems are now used routinely to provide detailed interpretative comments to physicians.

It should be recognized that the applications as mentioned could find a place in several other related purposes and fields, including, e.g. intensive care units and applications for handheld devices. A better use of graphics and graphical symbols will improve understanding. The use of international standards, e.g. for nomenclature and coding of laboratory results, will be necessary for proper transferability.

It is also a new and interesting development that larger companies such as Philips and Abbott have recognized the potential of expert system technology to supplement their diagnostic services. Philips and PKS have signed an agreement to enhance its laboratory information management system (LIMS) LABOSYS. Philips has linked the RippleDown system of PKS to their LIMS. This promises to offer the possibility to use this system to add comments (and tests). Abbott started the AlinIQ clinical decision support initiative, which includes the cooperation with PKS to enhance patient-specific interpretation of laboratory test results [43].

Conclusions

There is a wide consensus among specialists in clinical chemistry that consultation – adding value to test results – is not only an opportunity but also a prerequisite for the successful development and future of our field. Studies have shown that specialists, general practitioners and patients alike wish better information and support in the interpretation of laboratory tests. If the laboratory is to fulfil this role, a paradigm shift is needed in reporting of the results, including interpretative support to patients.

However, we are challenged to find a solution to the problem of fulfilling this task of adding meaningful interpretative comments (and tests where appropriate) while dealing with the almost overwhelming numbers of test results in the present-day laboratory. The only solution lays in the application of improved information technology and of expert systems. Applications of this kind are already available for use on a small scale. However, substantially more research and developments are needed for the introduction of such systems on the scale needed.