A clinical laboratory functions to assist the management of patients by providing information to aid in the diagnosis, treatment, and prevention of disease, all based on the analysis of patient samples. The aim of the lab, therefore, is to generate this information and communicate it to the physician as accurately and as quickly as possible. The laboratory analyzer, with its specialized hardware and software, processes the patient samples, analyzes the results, and provides the data for further interpretation by the physician and communication to the patient. The analyzer is the key to the functioning of a successful clinical laboratory.
A history lesson
That was not, however, always the case. In the early twentieth century, clinical diagnoses depended almost solely on a physician’s ability to identify disease based on the patient’s history and physical examination. The physician diagnosed and treated patients via his observations and incisive questioning. Physicians prided themselves on their intuitive skills in making a diagnosis by the use of their senses alone; to a significant degree, diagnosis was more of an art than a science. At that time, due to the limitations in available methodologies, the diagnostic and therapeutic value of laboratory testing was not appreciated, and many physicians viewed clinical laboratories simply as an expensive luxury that consumed valuable space and time.1
By the end of the 20th century, however, clinical diagnostics had undergone a significant change. Due to an ever-increasing appreciation of the complexity of disease and a need for more “transferrable” medical knowledge, practitioners looked for more objective methods to assess the health of a patient so that they could more consistently and reliably manage different patients with apparently similar symptoms.
In the early decades of modern clinical laboratory result-based diagnostics, laboratory tests revolved around the areas of Clinical Chemistry, Immunology, Hematology/Cytology, and Microbiology. All used “simple” laboratory analyzers that relied on technologists to process each sample, and the instrumentation was just analytical machines that gave an accurate result with “reasonable” throughput. For many years, this was acceptable laboratory procedure, as the clinical tests required just one analyte, with just one reaction. Further developments served to increase the throughput of the systems via enhancements that led to reduction of operator intervention.
A paradigm shift
With the entry of molecular diagnostics into the clinical laboratory, beginning in the 1990s, however, additional requirements became evident. Due to the innate complexity of molecular medicine, it was apparent that relying on a laboratorian to do the processing and hardware to do the analytics was not going to be sufficient. The use of heavily multiplexed panels that could provide a clinically actionable result required the simultaneous analysis of multiple analytes, each requiring multiple reactions. It quickly became apparent that the biggest issue that needed to be addressed in every molecular diagnostic laboratory was how to automate or simplify the DNA testing process (Figure 1).
| Figure 1. Molecular testing workflow (courtesy AutoGenomics) |
This need led to the first true evolution of the molecular diagnostic analyzer. Previously, laboratory technicians relied on a combination of manual preparation steps with a thermal cycler and crude data capture systems to generate a usable result. The changing need led to the emergence of two kinds of instrumentation.
- Automated liquid handlers, platforms which can be integrated onto a singular automated platform that can automate most of the manual preparation steps and thermal cycling. By adding a data analysis platform to the back end, the system is able to achieve a high degree of semi-automation for a completely manual lab testing process. The automated liquid handlers, with their open architecture, help to automate the entire test process, no matter what the test process is, as long as it can be split into logical steps.
- Commercial analyzers, which use manufacturer specific reagents, mostly on a closed mechanical analytics system. These resemble the analyzers for other areas of the clinical lab but with a key, distinct feature. Rather than improving upon speed or throughput, the core enhancement made was with regard to ease of use: how much the system can automate in order to minimize user intervention. For the molecular diagnostics laboratorian, running a singular sample for a panel of 20 mutations manually in the “old way” is a monumental task; each mutation can require as many as 10 pipetting steps, which means nearly 200 manual processes for just one sample. But with the new automated analyzers, running a test becomes as simple as adding the sample and loading the analyzer with consumables, and clicking the start button.
With the arrival of the automated molecular diagnostic analyzers, the molecular laboratory underwent rapid growth and expansion. Automated analyzers provided a number of benefits: the ability to process a large number of samples simultaneously; the elimination of human error to increase accuracy and reliability of results; the reduction in labor costs to enable the performance of “complex” genetic testing.
The expansion of MDx
This growth eventually led to the development and adoption of molecular diagnostics in many new fields, each with varying requirements on laboratory capabilities:
Microbiology, to detect infections (qualitatively and quantitatively) caused by viruses, bacteria, fungi, protozoa, etc., in symptomatic or asymptomatic patients, and monitor the effects of therapy. Because these tests deal with infectious agents, an analyzer is required that eliminates the need for the operator to handle these agents. A secondary requirement is sufficient throughput to enable population screening for these agents.
Oncology, to determine predisposition to a particular cancer by detecting mutations, to detect and determine the extent of disease progression, and to guide appropriate treatment based on individual genetic make-up. Due to the complexity of oncology marker testing, these platforms need to be able to be highly multiplexed.
Genetic disorder testing, to identify the presence of any genetic disorders in fetuses, children, or adults by detecting mutations or copy number variations. As with oncology, because each disease state can have a large number of variants that cause or impart risk, the ideal platform needs to be highly multiplexed.
Pharmacogenomics testing, to enable accurate and targeted treatment selection tailored to individual genetic make-up by detecting mutations and copy number variations. While the number of markers needed for this is not as large in as oncology or other disease state identification assays, due to the large potential volume of testing, a high throughput system would be required.
Sample-to-result and high-throughput
Responding to the new requirements linked to the types of testing outlined above, the evolution of the molecular analyzer has continued, and two additional types of analyzers emerged. The first is the sample-to-result analyzer, which can take any test from primary sample tube to result without the need for any operator manipulation of the sample. Essentially, this directly evolved from the previous iteration of automated analyzers by adding on a primary sample handling system. While it may seem like a relatively simple matter to improve, the benefit of this is nonetheless extremely significant since it removes a key complication in infectious agent testing.
The second new development is the emergence of the high-throughput systems. These new workhorses can provide an output of several thousand (or more) sample results in the same amount of time. In most cases these benchtop “factories” are not as automated as any of their ancestors, but their ability to run at rapid speeds compensates for their higher manual requirement.
Looking ahead
So, we now have four distinct types of analyzers that can populate a modern molecular diagnostic clinical laboratory to meet the needs of multiple forms of testing: automated liquid handlers, ease-of-use commercial analyzers, sample-to-result analyzers; and high-throughput systems. What’s next? Currently, laboratories are observing two new trends:
- Consolidation of testing. As many smaller labs are joining forces, and large labs are looking to absorb smaller regional players, there is a need for analyzers to not only be high-throughput but to have sufficient automation to handle the more complex panels and the ability to perform different kinds of tests in the same system.
- Rapid point-of-care testing. Many physician-offices and small clinics are gearing up to provide rapid genetic testing to their patients. They require analyzers that are fast, easy to use, and have small footprints.
However these new trends develop, they reflect the increased rate of adoption of molecular medicine in the clinical lab. Molecular diagnostics is transforming healthcare, and analyzers with novel technologies may soon emerge to push the molecular diagnostics laboratory into yet another stage of evolution.
References
- Kotlarz VR. Tracing our roots: origins of clinical laboratory science. Clin Lab Sci. 1998;11(1):5-7.
