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The first obstacle I encountered for the first assignment was how to formulate a relevant question. Formulating a question was more challenging than I expected. To compose a good research question, a thorough search for relevant literature should be performed to become more familiar with a particular field. Additionally, current healthcare needs and/or issues that are common in that field need to be found. Assignment 1 and formulating the question stage helped me to realize that a good question formulation is essential for all subsequent steps of evidence-based practice literature searches. Additionally, it showed me how an informed and educated question can only be asked after a deeper understanding of a field is obtained. In the Bayesian approach, I learned to appreciate the significance of prior knowledge and its impact on future ideas and research course. As prior knowledge only helps to define the research question, a more directed literature search was needed to gather all data on the topic and critically appraise the evidence.
After formulating a question, I faced a second challenge. Before completing the first assignment, I thought that in the era of instant access to information, it would be very easy and straightforward to find answers to any question using the internet. However, what I did not expect was that simply using “googling” techniques would not be adequate for advanced scholarly literature searches.
The first assignment gave me the opportunity to learn a lot about evidence-based practice literature searches using specialized scholarly search engines, such as PubMed, especially its advanced search features. I observed different search engines have different search algorithms and the same keywords can yield different results. Because of this, I found combining different search engines is beneficial in completing assignments like this one as the strategy expands on the quantity of journal ‘hits’ and increases the probability that relevant articles will be found and selected.
The final important lesson I learned from completing the assignment 1 was the ability to screen many articles based on their abstracts and decide the relevance of each for my particular purpose. By going through different abstract formats and individual writing style differences, I learned what information should be written in abstracts, i.e. I realized what information I would like to see when quickly screening relevant studies. For many abstracts selected, I found them to lack some essential information that would be very useful for my decision on whether to include the article or not. For example, the study population and sample size were not always included in abstracts, and sometimes even a study design was omitted. After completing assignment 1 I feel like I learned how to structure my abstracts in papers I would author in the future, and I find that very useful and beneficial.
I did not make any changes in my question nor basic search strategy I used in assignment 1, as the articles it yielded were relevant and enough so I can get the good idea of the present state of the practice and critically appraise available evidence and propose solutions or directions for the future. The only thing I would change is to add appropriate additional filters to filter out review papers and posters and papers not published in English language. Even though initial filters did call only for papers in English, I found that the search is “tricked” by abstracts being in English but the full text of the papers is in another language. Other filters used were appropriate and have brought me a list of articles that are relevant to the question I am asking.
Critical Appraisal of Literature
From the relevant papers found in assignment 1, I have chosen seven which I believe to be the most relevant for the question posed. Here they will be critically appraised individually, focusing on their level of evidence, strengths, weaknesses, and overall conclusions.
Wheeler et al. (2017) were investigating whether LC MS/MS is a better method of measuring thyroglobulin (Tg) in the presence of Tg autoantibodies which might interfere with radioimmunoassay (RIA) tests. They concluded that the mass spectrometry approach may not be as sensitive as RIA, as the detection threshold for LC MS/MS is higher than the threshold of RIA. The level of evidence from this study is: IV. One of the strengths of this study was the relevant control group composed of healthy individuals who did not have any disorder that might interfere with Tg metabolism. Also, the statistical methods were appropriate. One of the major weaknesses of this study is the external validity is questionable, i.e. generalization of results is not possible as the study was performed in a single center and a single clinical laboratory. Additionally, the study was performed on a limited sample size, without sample size calculation required to make sure the statistical analysis has the acceptable power. Another threat to external validity is the skewed demography of the study population, i.e. the majority of subjects were women (66%) and Caucasians by race (72%). Another weakness stems from the selection bias. Namely, authors have only assessed the patients with anti-Tg antibodies in their serum, and not those without anti-Tg antibodies. Therefore, the findings of this study cannot be applied to a wide population of patients who do not have anti-Tg antibodies. Another weakness is the length of follow-up. Namely the follow-up period was up to 24 months, while longer follow-up periods are suggested for measuring the dynamics of Tg serum measurements.
Netzel et al. (2015) have performed a pilot study of comparing different liquid chromatography tandem mass spectrometry (LC MS/MS) data acquisition methods to measure Tg in the presence of anti-Tg antibodies. They concluded that different vendors’ MS instruments yield comparable measurements and that final results can be comparable between different laboratories. The authors started with a premise that LC MS/MS is a better method to use in the presence of anti-Tg antibodies and have not evaluated its advantage over RIA per se. Rather, they performed an intra-MS study to evaluate the reproducibility of LC MS/MS as a method and compared if the result trends are similar to those obtained by RIA. The level of evidence of this study is: IV. The strength of the study was the use of 4 different laboratories with different instrumentation and general workflow protocols, which ensures the external validity of the study findings. However, this is a pilot study published in the form of a letter to the editor and therefore, its major weakness is the low sample count (40) and lack of replicates in their data analyses. They also did not directly statistically compare MS and RIA methods.
Powers et al. (2017) have focused on assessing economic benefit of performing LC MS/MS measurement of Tg only in samples which are anti-Tg positive. They have concluded that choosing more expensive method (such as MS-based technologies) for measuring Tg only in cases when other and cheaper methods become unreliable is cost-beneficial. Even though this study does not directly examine the sensitivity and specificity of MS versus RIA, I considered it was important to include it in the review for another piece of data they have presented in this paper. That data shows that, when used in selected cases when RIA is not the best choice, LC MS/MS performance as a method improves compared to cases when MS is used on all samples, indiscriminately. The disadvantage of this study in the context of my primary research question is that it does not offer a direct comparison between the two methods, but focuses on the economic impacts and/or benefits of one method versus the other. The level of evidence of this study is IV, however, its use in making final conclusions for this project is restricted and it will be used solely as an aid to justify the LC MS/MS strategies from the economic point of view.
Clarke et al. (2012) have directly investigated and compared side-by-side the RIA and MS-based methods for detecting Tg in serum samples. The level of evidence of this study is: IV. The authors have concluded that LC MS/MS method is comparable to RIA based methods for measuring Tg when serum is negative for anti-Tg antibodies. However, when anti-Tg antibodies are present, the MS-based measurement is more reliable and accurate. The major strength of this study is that they did not rely on only one MS and RIA method, i.e. system, but they have used multiple approaches from different manufacturers of both methods to asses Tg levels in the patient sera. This provides the study conclusions with external validity capabilities, i.e. it is likely that results can be compared to other instruments from other vendors which are based on the same technology. On the other hand, the external validity in terms of data generalization to a wider population is questionable, as all samples came from a single source. Another strength is that all experiments were done in at least duplicates which was important for assessing the reproducibility of results. The major drawback of this study is the lack of detailed demographic information about the patients whose samples were used for studies.
Netzel et al. (2015) have performed a study aiming to evaluate two different MS-based assays and compare them with immunoassays (RIA) for measuring Tg in the cohort of patients with thyroid cancer. They concluded that the method of choice for Tg detection is still RIA, even though they re-verified its problematic use and false-positive results in the presence of anti-Tg antibodies. The level of evidence of this study is: III. The major advantage of this study is its neat design, with appropriate control groups. Another advantage is the large sample size (589 samples from 495 patients), which contributes to the statistical power of the analysis performed. Additionally, the researchers have used several MS and RIA methodologies from different vendors to evaluate their research questions which adds to the results’ reliability and reproducibility, and positively supports external validity application to other vendors’ instruments. The weakness of the study is the nature of serum samples used for the study. Namely, the authors have used residual samples that were about to be discarded after the major fraction of which were used for some other studies. This is the source of a potential selection bias, because the samples were not randomly selected.
Hoofnagle et al. (2008) have investigated the tandem MS in detecting Tg, aided with preceding immunoaffinity purification step. The level of evidence is: IV. The conclusion of this study were that MS-based Tg measurement is comparable to immunoassay methods, and additionally, MS sensitivity can be improved by adding immune-purification step for Tg tryptic peptides before the before MS analysis. The strength of this study is that it was designed with substantial scientific rigor, and all experiments had several validation steps using different methods. However, besides using a limited number of samples and replicated, this study’s major weakness is that the method they are proposing is too complicated and probably not cost-effective. Namely, affinity purification step before MS analysis is not automated and requires a skillful technician with an equipped research laboratory, in addition to what standard clinical laboratories possess. While their conclusions are very interesting as they succeeded to decrease the sensitivity thresholds of MS technology to detect Tg, the immediate clinical and routine application is not available. This article is, however, included in this project as relevant because it confirmed with original data that MS-based Tg measurement is comparable to the data performed by RIA methods, and because it offers the window in to the future, i.e. what the future directions in the development of Tg detection strategies might be. This early stage research study might provide a good basis for improving and automating affinity purification methods as a supplement to mass spectrometry.
Azmat et al. (2017) have performed a retrospective study using thyroid cancer patients’ serum samples to determine the usefulness of LC MS/MS method for the measurement of Tg in the presence of anti-Tg antibodies. They have concluded that MS lacks necessary sensitivity to detect patients with the disease and that immunoassays should remain tests of choice. The level of evidence of this study is: IV. The strength of this study is that study subjects were evaluated in the clinic dedicated to thyroid cancer. Therefore, the healthcare professionals treating the patients and performing this study were very well versed in the thyroid cancer evaluation field, compared to other departments which have a broader focus and therefore, less specific and focused experience. Another strength was that number of patients included was relatively large (154) and all patients included in the study had several measurements of Tg levels performed, which largely increases the number of samples used for methods comparison overall. The major limitation of the study is that it was of a retrospective design, i.e. it was performed only on patients who had their Tg levels measured with MS before. An additional issue is that, as it is common in retrospective studies, there is a substantial inter-patient variability stemming from the fact that they were treated by different physicians. Therefore, the inter-rater bias is likely affecting the results of this study. The reasons for ordering MS testing for Tg levels was not always clearly stated in the patient records and therefore it is hard to eliminate the selection bias as well, as there might have been a variable that selected certain patients with certain characteristics to get MS-based Tg testing. Another limitation which questions the validity of all data pairs (Tg and anti-Tg antibodies) used for analysis is the fact that the levels for Tg and anti-Tg were not always measured from the same sample but were approximated from samples drawn in a short period of time. The usefulness of Tg MS measurements is also questioned because not all patients were treated according to the same protocol. Namely, some patients, as deemed by their clinician, got CT scan of their neck, while others were evaluated by ultrasound only. This is a variant of detection bias because patients who had CT scans were more likely to be diagnosed with a disease than those who got only ultrasounds, simply because a CT scan is more sensitive in detecting thyroid cancer than ultrasound. This fact might have skewed the distribution of patients with active versus patients with undetectable disease, which was used as a differentiation method in the final analysis of the data.
Conclusions from Evidence
Based on the above-mentioned primary studies, it can be concluded that MS-based detection of Tg is not sensitive enough and should not be used as a replacement for RIA. I.e. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) does not improve sensitivity, specificity and turnaround times compared with radio-immunoassays in the measurement of thyroglobulin. The grade of recommendation is 2C, because all studies investigating this issue are observational, or small experimental quasi-trials, without randomization and blinding.
Based on the available evidence, the current method of RIA to detect Tg in patient sera should not be replaced by MS methods. Therefore, if any action should be taken it would be to further fine-tune and perfect MS-based detection strategies by decreasing its detection threshold.
This information should be disseminated to members of staff in the department. There are various methods that can be used including electronic messages, departmental bulletins, continual professional development lectures (where staff can present cases to be discussed), departmental meetings and section meetings. The most effective method in this case would be to raise the findings in the section meeting. This would allow other members of staff who specialize in the studies field to raise their opinions and express possible suggestions.
However, it should be noted that the majority of studies evaluated the use of LC MS/MS method for detection of Tg as an alternative to RIA in all patients. A better approach, as suggested by Powers et al. (2017) would be to use MS-based technologies only in instances where RIA is unreliable and when the sensitivity drops substantially. One example is the stratification of patients according to the presence of anti-Tg antibodies. Anti-Tg antibodies are major interfering substance in RIA detection systems in patient sera. Therefore, using MS based technology for Tg measurement in those cases where RIA is unreliable is a goal that should be pursued and evaluated by larger studies. Powers et al. (2017) already evaluated the cost-benefit of such approach, and it is estimated to save more than £2.2 million compared to testing everybody using LC MS/MS. The cost-savings are even larger if the avoidance of false positive RIA tests are factored in, due to the presence of anti-Tg antibodies. This warrants a design of another study which would be prospective in nature, blinded, and would stratify patient samples according to the presence of anti-Tg antibodies into positive and negative categories. Only those samples which are anti-Tg antibody positive would be eligible for MS Tg measurement, while anti-Tg antibody negative samples would be tested by conventional immunoassay techniques.
Additional direction of future assay development by using MS-based approach is to go down the ideas of Hoofnagle et al. (2008) who tried to improve the sensitivity of LC MS/MS Tg detection and measurement by decreasing the detection threshold of the method. They did that by enriching the sample for Tg tryptic fragments by using affinity purification, as a preparatory step to mass spectrometry analysis. Based on their results, this significantly improved the MS sensitivity for detecting Tg. This approach warrants further studies in developing the technology, making it more affordable and automating the entire process, in order to decrease labor requirements, reagent costs and to standardize results. These novel and improved assays would need clinical evaluation as well, before their use is recommended to substitute immunoassays.
As a conclusion, even though current evidence does not support the use of MS-based technology to replace immunoassays in detecting and measuring Tg in patient sera, this technology has potential to further develop and become a diagnostic standard method. Therefore, it should not be discarded, but further researched and developed.
The key things I learned after completing this module are how to detect the needs for improvements in current clinical practice, how to find what is known about the issue, how to select relevant evidence that supports or rejects the current standards, and how to appraise evidence and critically evaluate it. So far, I have been pleased with the grades achieved, especially considering evidence-based practice is a totally new concept to me. I found the lecture notes to be very informative and they provided me with clear instructions necessary to complete the assignments.
In my future professional development, I will definitely appreciate evidence-based data more than I did before and will not rely only on what is written in textbooks or presented to us in online lectures and other forms of instruction.
While completing this assignment I felt lost many times, especially at the stage of literature search and selecting the right papers. Initially I was lost because I did not know how to properly use knowledge database search engines to get to the most relevant studies. Later, I struggled because many of the terms I encountered were new to me and I felt as though I was not performing the data analysis correctly. However, after completing this assignment I have found that my skills in evidence-based practice have advanced substantially and that my knowledge improved exponentially. Not only did my knowledge about this specific subject improve, but more importantly, my skills improved a lot and now I feel able to apply the skills from this module to critically evaluating any clinical question and to evaluate evidence-based data available about it.
Relevance of EBP
Maybe the best example of why evidence-based practice is important is the fact that for centuries bleeding was used as treatment for many illnesses and no one questioned the benefit for patients, and no one tried to evaluate it in the form of a well-done comparative study. Even if such cases existed they were rare, and the individuals were often labeled as heretics and sidelined in medical society. Another, newer example is nurses aspirating the needle when performing intramuscular injections: now, evidence says that aspiration is not beneficial. On the contrary, it might even cause harm to the patient.
These two examples (and there are many others in the history of medicine and most certainly in current practice as well) show that beliefs and what seems logical and rational is not always the best option for the patient. It is essential that every healthcare practitioner stays up to date with the latest evidence on procedures, policies and developments through continual professional development (CPD). By using evidence-based data, patient outcomes improve, and all healthcare practitioners continue achieving one of the ultimate postulates of Medicine: First, do no harm.
It is never too early to start using evidence-based resources and databases, instead of textbooks. Even in school years, education should be focused on seeking answers and not absorbing them. In that way, we are not becoming practitioners of the past and present, but we are creating practitioners of tomorrow.
- Azmat, U. et al. (2017). Thyroglobulin Liquid Chromatography-Tandem Mass Spectrometry Has a Low Sensitivity for Detecting Structural Disease in Patients with Antithyroglobulin Antibodies. Thyroid, 27(1), 74-80.
- Clarke, N.J. et al. (2012). A novel mass spectrometry-based assay for the accurate measurement of thyroglobulin from patient samples containing antithyroglobulin autoantibodies. J Investig Med, 60(8), 1157-63.
- Hoofnagle, A.N. et al. (2008). Quantification of thyroglobulin, a low-abundance serum protein, by immunoaffinity peptide enrichment and tandem mass spectrometry. Clin Chem, 54(11), 1796-804.
- Netzel, B.C. et al. (2015). First Steps toward Harmonization of LC-MS/MS Thyroglobulin Assays. Clin Chem, 62(1), 297-9.
- Netzel, B.C. et sl. (2015). Thyroglobulin (Tg) Testing Revisited: Tg Assays, TgAb Assays, and Correlation of Results With Clinical Outcomes. J Clin Endocrinol Metab, 100(8), E1074-83.
- Powers, J.L. et al. (2017). Thyroglobulin Antibody Screen Prior to Mass Spectrometry Provides Measurable Cost Savings and Optimal Laboratory Utilization. Am J Clin Pathol, 147(3), 309-314.
- Wheeler, S.E. et al. (2017). Clinical laboratory verification of thyroglobulin concentrations in the presence of autoantibodies to thyroglobulin: comparison of EIA, radioimmunoassay and LC MS/MS measurements in an Urban Hospital. BMC Res Notes, 10(1), 725.
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