Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics. Palgrave Macmillan Journals - partner of INASP, JDP, Cross Ref, COUNTER, COPE and iThenticate. In the absence of a reference standard, the performance of the test under evaluation can be compared to an existing test using a 2 2 table, which shows how the samples were classified by each test.
In determining the sample size, allowance must also be made for patients who do not meet the inclusion criteria and the percentage who are likely to refuse to participate in the study.If, when the study begins, it is not possible to estimate in advance what the sensitivity or specificity will be, then the safest option for the calculation of sample size is to assume these will be 50% (as this results in the largest sample size). Details of this information and the procedures to be followed should be stated in the study protocol. In general, the only payment to study subjects should be for compensation for transport to the clinic and loss of earnings because of clinic visits related to the study.
A company registered in England and Wales under Company Number: 785998 with its registered office at Brunel Road, Houndmills, Basingstoke, Hants, RG21 6XS, United Kingdom. IntroductionA diagnostic test for an infectious agent can be used to demonstrate the presence or absence of infection, or to detect evidence of a previous infection (for example, the presence of antibodies).
Operational characteristicsOperational characteristics include the time taken to perform the test, its technical simplicity or ease of use, user acceptability and the stability of the test under user conditions. Defining the need for a trial and the trial objectivesBefore conducting a trial, the specific need for the trial should be assessed. The values for percentage agreement positive, percentage agreement negative, percentage negative by test 1 and positive by test 2, and percentage positive by test 1 and negative by test 2 can be derived from such a table. Alternatively, sometimes it will be useful to conduct a pilot survey to estimate the prevalence of infection and to obtain a preliminary estimate of sensitivity and specificity. External validation can be performed by sending all positive specimens and a proportion of the negative specimens to another laboratory for testing. Defining the target population for the test under evaluationThe characteristics of the study population should be fully described (see section III, 2.1)2.
Payment should never be excessive, such that it might constitute an undue incentive to participate in the study.Treatment should usually be provided free of charge.
Defining methods for the dissemination of trial resultsThis can involve submitting results for publication to a scientific journal, but most importantly, there should be a plan to inform those responsible for procuring or authorizing tests of the study findings.
Demonstrating the presence of the infecting organism, or a surrogate marker of infection, is often crucial for effective clinical management and for selecting other appropriate disease control activities such as contact tracing. The ease of use will depend on the ease of acquiring and maintaining the equipment required to perform the test, how difficult it is to train staff to use the test and to interpret the results of the test correctly, and the stability of the test under the expected conditions of use. Diagnostic evaluations can be performed both retrospectively, using well-characterized archived specimens, and prospectively, using fresh specimens. The eligibility criteria are generally defined by the choice of the target population, but additional exclusion criteria can be used for reasons of safety or feasibility. The outcomes of the evaluation, such as performance characteristics, should be clearly defined. In such a study, the feasibility of the proposed study procedures can also be evaluated.In some circumstances it might be possible to state the minimal acceptable sensitivity (or specificity) for the intended application of the test.
Informed consent is usually not required for trials using archived specimens from which personal identifiers have been removed.
Developing methods for the recruitment of study participants and informed consent proceduresConsider the following:Who recruits the study subjects? Any treatment decisions (if appropriate) should not be based on the results of the test under evaluation but on the reference test.
There appears to be a strong positive correlation between confidence interval size and the accuracy of the GADA breakpoint estimates, indicating the CGH data contains useful information on the uncertainty in breakpoint location.
To be useful, diagnostic methods must be accurate, simple and affordable for the population for which they are intended. All of these characteristics are important for determining the settings in which a diagnostic test can be used and the level of staff training required.
The choice depends on the availability of appropriate specimens and whether the research question can be answered wholly or in part using archived specimens. The researcher must consider, for example, whether or not patients with co-morbidity or other conditions likely to influence the study results will be excluded. So, if it is suspected that the sensitivity (or specificity) of the test under evaluation is p (for example, 80%) but it is considered that p0 = 70% is the minimum acceptable sensitivity (or specificity), then n might be chosen so that the lower limit of the confidence interval is likely to exceed p0. Some ethics review committees require the investigator to provide information on how the specimens can be made anonymous and require assurance that results cannot be traced to individual patients.V. Ideally, this should not be the clinician caring for the participants, as this might influence the participants' decision.Who is eligible for enrolment?How will informed consent be obtained? Refusal to participate in the study should not prejudice access to treatment that would normally be accessible.3. Laboratory facilities and equipment should be available and adequately maintained for the work required, for example, suitable work areas, lighting, storage, ventilation and hand-washing facilities should be available. They must also provide a result in time to institute effective control measures, particularly treatment. For infectious diseases, additional exclusion criteria might include recent use of antibiotics or other treatments. With the test requirement formulated in this way the sample size formula is given by equation 6:For example, if it is anticipated that the sensitivity of a new test is 80% and to be acceptable for use in a given setting it must be at least 70%, then it will be necessary to recruit, or have archived specimens from, 168 infected study subjects. Designing study instrumentsEach item on the patient data form should be considered with respect to the stated aims and objectives of the trial. Before the trial starts, the laboratory should be able to demonstrate proficiency in performing the reference standard tests as well as the tests under evaluation. For some infections, early diagnosis and treatment can have an important role in preventing the development of long-term complications or in interrupting transmission of the infectious agent.
Essential elements in the design of diagnostic test evaluationsThe design of a study is likely to be greatly improved if this process is approached systematically along the lines outlined in Figure 1.
Planning a study should include a comprehensive review of the relevant literature for the diagnostic test under evaluation and other relevant tests for the infection under study, including an assessment of the strengths and limitations of previous studies. The key question to be addressed before embarking on a study, and the question that is often hardest to answer, is what level of performance is required of the test. Where possible, manufacturers' clinical and analytical data for the new test should be assessed.
As our test statistic, we used the number of true breakpoints covered by a set of confidence intervals. Whether these tests are useful in a given setting and, if so, which test is most appropriate are questions that can be answered only through evaluations in the appropriate laboratory, clinical or field settings.Many variables can influence the performance of tests in different settings. The outcome of a review of previous work should inform assessment of the need for another trial and the specific areas in which further information is needed.
The study group can consist of all subjects who satisfy the criteria for inclusion and are not disqualified by one or more of the exclusion criteria.
The reproducibility of a test is a measure of the closeness of agreement between test results when the conditions for testing or measurement change. Consider the paper size and colour, the format of records (record books with numbered pages are preferable to loose sheets of paper) and the use of boxes or lines for multiple-choice responses. A null distribution for this statistic was generated using 1,000 permutations of m1 confidence intervals across CNVs (shown here as a black curve). These include differences in the characteristics of the population or the infectious agent, including the infection prevalence and genetic variation of the pathogen or host, as well as the test methodology — for example, the use of recombinant or native antigen or antibody, whether the test is manual or automatic, the physical format of the test and local diagnostic practice and skills. The level and availability of healthcare resources and disease prevalence all have a bearing on setting the acceptable performance of a test.Increasing the sample size reduces the uncertainty regarding the estimates of sensitivity and specificity (the extent of this uncertainty is summarized by the confidence interval).


For example, reproducibility can be measured between operators (inter- and intra-observer reproducibility), between different test sites, using different instruments, between different kit lots (lot-to-lot reproducibility) or on different days (run-to-run and within-run reproducibility).
The number of true breakpoints covered with the correctly assigned confidence intervals (indicated by a vertical red line) was 13 s.d. Therefore, wherever possible, test evaluations should be performed under the range of conditions in which they are likely to be used in practice.
General considerations in the design of evaluation trialsThe design of the evaluation trial will depend on its purpose and the population for which the test is intended. Alternatively, the study group can be a sub-selection, for example, only those who test negative by the reference test. The Kappa statistic9 provides a useful measure of agreement between test types or lots, and between users.
Structured responses limit allowable responses to a predefined list, whereas open responses allow freedom to record unanticipated answers, but are more difficult to code and analyse.It should be ensured that those who will be completing the forms fully understand the forms and know how to complete the forms correctly.
This is essential to ensure the information is understood by study participants and that the questions are appropriate.
In some situations, such evaluations can be facilitated through multi-centre trials.Lack of resources and expertise limit the ability of many developing countries to perform adequate evaluations of diagnostic tests, and many new tests are marketed directly to end-users who lack the ability to assess their performance. A 95% confidence interval is often used — that is, we can be 95% certain that the interval contains the true values of sensitivity (or specificity). SOPs should be prepared for for all clinical and laboratory procedures required in the study protocol (see Ref. Translation of the informed consent information sheet into the local language is also essential.
Changes to SOPs should be documented, signed off by the responsible supervisor, dated and disseminated to the study team.4.
The onus is therefore on those who perform the evaluations to ensure that the quality of the methods and the documentation used is such that the findings add usefully to the pool of knowledge on which others can draw.
The extent to which a test will produce the same result when used on the same specimen in identical circumstances (repeatability) should be distinguished from operator-related issues affecting reproducibility, which might be improved by further training.The study protocol should describe how the reproducibility of the test will be measured and what aspect of reproducibility is being evaluated. Where items are to be skipped, the form should contain documentation of the legitimacy of a skipped answer.4. Back-translation is desirable to ensure the accuracy of the information provided to the study participants to allow them to make an informed decision whether or not to participate in the study.VII. Quality assuranceThere should be arrangements in place (a QA unit or designated person) to ensure that the study is conducted in accordance with the study protocol. The Standards for Reporting of Diagnostic Accuracy (STARD) initiative has developed a sequenced checklist to help to ensure that all relevant information is included when the results of studies on diagnostic accuracy are reported1, 2, 3, 4 (APPENDIX 1).Evaluations of diagnostic tests must be planned with respect to their use for a clearly defined purpose, carefully and systematically executed, and must be reported in a way that allows the reader to understand the study methods and the limitations involved and to interpret the results correctly. In general, a diagnostic test should be evaluated using methods and equipment that are appropriate for that purpose.
Where possible, all tests under evaluation should be compared with a reference (gold) standard. To do this, we must first make a rough estimate of what we expect the sensitivity (or specificity) to be. Develop plans to pilot study instrumentsPlans should be developed to determine whether the study instruments, such as questionnaires and data-collection forms, are appropriate. A system should be established so that corrective actions suggested to the study team are properly and rapidly implemented.5. This will help to avoid the financial and human costs associated with incorrect diagnoses, which can include poor patient care, unnecessary complications, suffering and, in some circumstances, even death.This document is concerned with general principles in the design and conduct of trials to evaluate diagnostic tests.
The choice of an appropriate reference standard is crucial for the legitimacy of the comparison. Reproducibility testing should be conducted in a blinded fashion, that is testers should not know the results obtained previously.The size of the evaluation panel for reproducibility studies should be dictated by the degree of precision needed for the relevant clinical indication. For example, a serological assay should not usually be compared with an assay that detects a microorganism directly, and clinically defined reference standards are not usually appropriate when clinical presentation is not sensitive or specific. The panel should include at least one positive and one negative control, and, if appropriate, two or three different operators, with the samples evaluated on three different days. So far as is possible, all aspects of the study should be piloted in a small study so that the methods and procedures can be modified as appropriate. If this is not possible in the field, or cannot be ensured during transport, this should be made clear when the study is reported. Data analysisThe data should be analysed according to the analysis plan after checking, and if necessary correcting, the study data.
There should be clear specification of the eventual target population in which the diagnostic test will be used. Non-commercial or 'in-house' reference standards are legitimate only if they have been adequately validated.
For example, if we estimate that the sensitivity of a new test is 80% and we want the confidence interval to be 6%, we will need to recruit, or have archived specimens from, 170 infected study subjects by the reference standard test. The pilot study also provides the ability to make a preliminary estimate of infection prevalence, which might aid planning the size of the main study.5.
If a desiccant is included in the package, the kit should not be used if the desiccant has changed colour.Generally, if test kits are stored in a refrigerator, they should be brought to room temperature approximately 30 minutes before use.
The sensitivity and specificity of a test can be calculated by comparing the test results to the validated reference test results. Sometimes, composite reference standards might have to be used in the absence of a single suitable reference standard. If the prevalence of infection in the study population is 10%, then there will be 10 infected subjects per 100 patients seen at the clinic.
Evaluating operational characteristics.An evaluation of a test can also include an assessment of its operational characteristics and cost-effectiveness.
Performance characteristicsThe basic performance characteristics of a test designed to distinguish infected from uninfected individuals are sensitivity, that is, the probability that a truly infected individual will test positive, and specificity, that is, the probability that a truly uninfected individual will test negative. For example, will it replace an existing test, will it be used as a triage instrument to identify those in need of further investigation, or will it be used as an additional test in a diagnostic strategy for case finding or for screening asymptomatic individuals? Results from two or more assays can be combined to produce a composite reference standard6. Developing a plan for the study logisticsA plan should be developed for safe specimen collection, handling, transport and storage. This can be important in defined circumstances, but the fact that it is off-label use must be clearly stated when the results are reported.2. These measures are usually expressed as a percentage.Sensitivity and specificity are usually determined against a reference standard test, sometimes referred to as a 'gold standard' test, that is used to identify which subjects are truly infected and which are uninfected.
The actions that are to be guided by the use of the test, such as starting or withholding treatment, must also be considered. For example, if there are two possible 'gold standard' tests, both of which have high specificity but poorer sensitivity, then positives can be defined as samples that test positive by either test.
Some operational characteristics, such as simplicity, acceptability of the test to users, the robustness of the test under different storage conditions and the clarity of instructions, are qualitative and subjective, but assessment of these can be crucial for decisions regarding the suitability of a test for a specific setting. Consider using pre-printed unique study numbers for forms and specimens (labels should be tested for adherence when samples are frozen, if necessary). Biosafety issuesThe investigators must comply with national workplace safety guidelines with regard to the safety of clinic and laboratory personnel and the disposal of infectious waste. Inter-observer variability is calculated as the number of tests for which different results are obtained by two independent readers, divided by the number of specimens tested.VIII.
Errors in measuring the sensitivity and specificity of a test will arise if the 'gold standard' test itself does not have 100% sensitivity and 100% specificity, which is not infrequently the case. In other circumstances, positives can be defined as those that test positive by both tests, negatives as those that test negative by both tests, and others omitted from the evaluation as indeterminate.New tests under evaluation that are more sensitive than the existing reference standard usually require a composite reference standard.


In particular, the robustness of the test under different storage conditions is an area of concern for tests that will be used in remote settings.Diagnostic tests can contain biological or chemical reagents that are heat-labile and might be affected by moisture, making the shelf-life of the test dependent on the temperature and humidity at which it is stored. Also, develop a flow diagram for specimen handling that can be distributed to laboratory staff.7.
Reporting and disseminating resultsWherever possible, study participants should be given feedback on study results by, for example, meeting with the study community or having a readily accessible contact person at a clinic to answer specific queries. Evaluating a diagnostic test is particularly challenging when there is no recognized reference standard test.Two other important measures of test performance are positive predictive value (PPV), the probability that those testing positive by the test are truly infected, and negative predictive value (NPV), the probability that those testing negative by the test are truly uninfected. Defining the blinding of resultsSpecimens will be tested to ensure blinding of results of the reference standard test from the results of the test under evaluation. The results can also be disseminated by publication in peer-reviewed journals or posted on relevant websites. PPV and NPV depend not only on the sensitivity and specificity of the test, but also on the prevalence of infection in the population studied (Box 1). In situation (b), if the infection is rare, high specificity will be required or else a high proportion of those who test positive could be false positives (that is, the test will have a poor PPV). If more than one test is being evaluated, the evaluations can be sequential or simultaneous. Transport and operational conditions in the tropics commonly exceed 30°C, especially for point-of-care tests used in remote areas.
Steps must be taken to ensure that the staff performing the reference test are not aware of the results from the test under evaluation, and vice versa. ConclusionsThe rapid advances that have been made in molecular biology and molecular methods have led, and continue to lead, to the development of sensitive and specific diagnostic tests, which hold the promise of substantially strengthening our ability to diagnose, treat and control many of the major infectious diseases in developing countries. The reproducibility of a test is an assessment of the extent to which the same tester achieves the same results on repeated testing of the same samples, or the extent to which different testers achieve the same results on the same samples, and is measured by the percentage of times the same results are obtained when the test is used repeatedly on the same specimens.
In either circumstance it is necessary to identify a group of truly infected and truly uninfected individuals to assess sensitivity and specificity, respectively.For situation (a), a common design for an evaluation study is to enroll consecutive subjects who are clinically suspected of having the target condition.
Exposure to humidity can occur during delays between opening of the moisture-proof packaging and performance of the test procedure.During evaluation of diagnostic tests, it is essential to inspect test kits for signs of damage caused by heat or humidity, and to record the conditions under which the tests have been stored and transported.
Also, laboratory staff should not be aware of clinical findings or of the results of other laboratory tests.It can be difficult to ensure blinding if several tests are being evaluated at the same time. It is imperative that these new diagnostics are rigorously and properly evaluated in the situations in which they will be deployed in disease control before they are released for general use. Reproducibility can therefore be measured between operators or with the same operator, or using different lots of the same test reagent. The suspicion of infection can be based on presenting symptoms or on a referral by another healthcare professional. A poorly performing diagnostic might not only waste resources but might also impede disease control. The accuracy of a test is sometimes used as an overall measure of its performance and is defined as the percentage of individuals for whom both the test and the reference standard give the same result (that is, the percentage of individuals whom both tests classify as infected or uninfected).
These participants then undergo the test under evaluation as well as the reference standard test. A product dossier of test characteristics, including heat-stability data, should be available from the manufacturer of the diagnostic test. Defining a QA planA QA plan should be developed for quality management of the diagnostic trial. In studies in which only a small proportion of those tested are likely to be infected, all subjects can be subjected to the reference standard test first.
This will assist in extrapolating the results obtained under trial conditions to the results expected if the test kits had been stored under the anticipated operational conditions.If there is uncertainty about the test stability, storage outside the manufacturer's recommendations is expected during operational use or there are insufficient data on temperature stability, the addition of thermal-stability testing to the trial protocol should be considered. This includes ensuring that the study personnel are proficient in performing both the tests under evaluation and the reference standard test. All positives and only a random sample of test negatives can then be subjected to the test under evaluation. Before the start of the trial, the laboratory (or whoever is to perform the tests) should be able to demonstrate proficiency in performing the reference standard test(s).
This can lead to more efficient use of resources if the target condition is rare.Tests can sometimes be evaluated using stored specimens collected from those with known infection status. The personnel performing the test under evaluation should also demonstrate proficiency at performing and reading this test. Such studies are rapid and can be of great value but there is a risk that they can lead to inflated estimates of diagnostic accuracy (when the stored samples have been collected from the 'sickest of the sick' and the 'healthiest of the well'). Study QA procedures should be established to ensure that the studies are conducted and the data are generated, documented and reported in compliance with good clinical laboratory practice (GCLP). The setting where patients or specimens will be recruited and where the evaluation will be conducted should be defined. Developing a plan for data collection and data analysisStudy results entered into workbooks or directly into computer spreadsheets should be checked daily and signed off by the clinic or laboratory supervisor if possible.
When entering results into a computer database, consider double data entry to minimize inadvertent errors. Tests will probably perform differently in a primary care setting compared with a secondary or tertiary care setting. Laboratory QA comprises internal quality control (IQC), external quality assessment (EQA) and quality improvement measures.
The spectrum of endemic infections and the range of other conditions observed can vary from setting to setting, depending on the referral mechanism.
IQC refers to the internal measures taken to ensure that laboratory results are reliable and correct, for example, the existence of SOPs for each test procedure, positive and negative controls for assays, stock management to prevent expired reagents being used, and monitoring of specimen quality.
Review processes for the study database and approval mechanisms for items to be added or deleted should be established.
Other factors that can affect test performance and differ between sites include climate, host genetics and the local strains of pathogens. EQA, which is sometimes referred to as proficiency testing, is an external assessment of the laboratory's ability to maintain satisfactory quality, ensured by regular testing of an externally generated panel of specimens. The form of the tables that will be used in the analysis and the statistical methods that will be used in the interpretation of the study results should be drafted before data have been collected to ensure that all the relevant information will be recorded.10. Because the test characteristics can vary in different settings, it is often valuable to consider conducting multi-centre studies.
Quality improvement is the process through which deficiencies identified through IQC or EQA are remedied and includes staff-training sessions, recalibration of equipment and assessment of the positive and negative controls used for particular tests.IV. Developing plans to ensure the confidentiality of study dataAll study data should be kept confidential (for example, in a locked cabinet and a password-protected database, with access limited to designated study personnel).11. The design of diagnostic evaluations using archived specimensIf the test evaluation can be undertaken satisfactorily using archived specimens and a panel of well-characterized specimens is available, a retrospective evaluation can be conducted with both the new test and the reference standard.
Scientific and ethical review of study protocolThe study protocol should undergo scientific and ethical review by the relevant bodies. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD Initiative.
As a minimum, the application document for ethics committee approval should contain the information shown in Box 8. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration.
International Ethical Guidelines for Biomedical Research Involving Human Subjects (2002).Nuffield Council on Bioethics.



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