How to use Gradepro to conduct a GRADE based review

… in which I describe a basic tutorial

Introduction and some background

In this tutorial I am going to show you how you can use GRADEpro to conduct a simple evidence portfolio for a study. An evidence portfolio refers to the combination of a summary of findings from one or more studies on a defined outcome and a table that lays out the rationale of the decision on the quality of the evidence for that particular outcome. These two activities are based on the principle of GRADE (Grading of Recommendations, Assessment, Development and Evaluation) process. The Gradepro is a web based app, and you can download and automatically install this app on your chosen browser (Firefox or Chrome or Safari or Edge or another version). If you are familiar with the principle of GRADE and know how to use the Gradepro app, you will be able to develop a set of guidelines or construct the tables of evidence for a systematic review for your research. Let’s discuss briefly the principles of GRADE first and then show you how you can use Gradepro to develop tables for systematic review, health technology assessments and guidelines. This is a very simple introductory tutorial to get you started on using Gradepro, in subsequent tutorials I will show you how you can use it for health technology assessments or guidelines, or indeed other forms of evidence synthesis.

Principles of GRADE

GRADE is an acronym for “Grading of Recommendations, Assessment, Development, and Evaluations”. This grading refers to the quality of evidence presented for health care decision making and drafting of guidelines. GRADE is based on the following concepts:

  • First, in GRADE, the emphasis is on outcomes across studies. Think in contrast, in systematic reviews and meta analyses, the emphasis is usually placed on studies across outcomes. This is an interesting difference, as GRADE is used for developing treatment guidelines, rather than focusing on individual studies to study their merits on internal validity and abstraction of information from all outcomes.
    As a result, in GRADE, we can assess all kinds of outcomes. These outcomes can be beneficial as well as harmful outcomes. For example, consider medications and interventions for the relief of neck pain. While relief from neck pain is a beneficial or desirable outcome, side effects of medications such as peptic ulcer, or renal failure are adverse outcomes that must also be considered in the balance of benefits and harms if you want to develop guidances for clinicians and patient advocates as to what specific pain relieving agents a patient will need to use or a physician can prescribe. Hence, while studying effectiveness of efficacy of specific medications in a systematic review might consider only benefits (such as relief of neck pain) and underplay harm, in evaluating quality of evidence to develop real world advisory, both harms as well as benefits need to be mapped and as such these must be taken into consideration.

How studies are awarded high or low quality points in GRADE

In GRADE, quality of a body of evidence for a particular outcome with respect to an intervention (or an intervention-control pair) is based on four to one stars. These are as follows:

| Star Rating | What does that mean?                      |
|-------------|-------------------------------------------|
| Four Pluses | Very high No further evidence needed |
| Three pluses| High, further evidence unlikely to change |
| Two Pluses | Moderate, further evidence may be needed |
| One plus | Low, further evidence will be needed |

The basis therefore is, how much confidence shall we have on the existing set of evidence we have at hand? Shall we say that based on the available evidence, we can proceed with the stated effectiveness of the intervention (either it is effective or not) and that is the final verdict? Or shall we wait for more evidence to emerge so we shall modify our decision. This is a moot point in GRADE style quality appraisal so that our emphasis is on the use of this information. As evidence hierarchy states that meta analyses and randomized controlled trials are placed at the highest level, so we start with clinical trials and assign them four stars to start with. For that reason, we assign one score lower to observational study designs (that is all studies that are not experimental study designs). Then, after we have done so, we upgrade and downgrade studies based on the following eight points.

What decisions or points do we consider for downgrading evidence?

  1. Risk of Bias. — On careful review of the body of the evidence, what biases could account for the findings? If you are reviewing meta analyses and RCTs, check for blindings and intention to treat analyses. Read the study designs and methods carefully for observational study designs. In particular check if there were important differences between the comparison groups that were not accounted for. If you suspect risks of bias, downgrade. If the risks of bias were not serious, deduct one point, else if the risks of biases are high, deduct a maximum of two points.

So these are the five points on the basis of which you can downgrade the quality of the the evidence you appraise for a particular outcome. You can also upgrade the quality of evidence if you find information that fulfil the following three criteria:

  1. Large effect size. — This is particularly true for observational studies. If you find that the effect measure reported in the study is of the order of say something like a relative risk estimate of 3.0 or higher, this will qualify for a large effect size. Then increase the quality score.

So you see that based on these three plus and five minus points, take different combinations of outcomes and interventions and draw up a series of tables. How to construct those tables of evidence in the form of summary of findings and construct evidence portfolio is provided below.

Figure 1. Screenshot of the Gradepro

Log in first or create an account and log in

When you log in, you get to see this:

Figure 2. How gradepro appears in 2017 April once you log in

Gradepro runs on the basis of projects. Each study you’d do in Gradepro is a project. A project can contain many questions that are put together to synthesise the evidence. So, we start with a new project, and let’s call it “Neck Pain Project”. In this project we shall create an evidence profile of all interventions that relate to the relief of neck pain in individuals and study different outcomes (neck pain relief, adverse effects) and in the process we shall examine what evidence exists in terms of what health technology (drug, device, procedures) work best for relief of neck pain and what can be done

So, click on “New Project”, this will bring you up to the following window:

Figure 3. Project window

See the fields are all filled up. The Name is the name of the project. Here, we shall create an evidence profile; you could also create just a summary findings table, or an Evidence to Decision Framework or a Guideline from Scratch. We will explore each type of projects below.

Once you hit “Create Project”, it will result in the following window where we have now activated all modules.

Figure 4. Create Project Window

Right now, we are interested to only conduct comparisons of different interventions. In a future tutorial, I will show you that you can actually create a full guideline from scratch or you can create your own guideline for practice based on available evidence. As this is a team work (although you can work on your own), you can set tasks for teams, etc. This way it becomes a complete tool for you to develop guidelines for your own use and practice. Here, we shall keep things simple and click “Comparisons”, and then choose between whether we want to add diagnostic or whether we want to add management question. Here, we are interested to add management question, as we would like to know what treatment would best help in relief of neck pain.

then we add a management question as follows:

Figure 5. Management Question Window

At this stage, let’s grab the PDF copy of the systematic review and meta analysis of an article that looked at low level laser therapy for neck pain. You can find the paper here, and we will use this paper to extract data and fill in the form. As we do so, I will explain the various terms and the different concepts. In real life, we will use similar systematic reviews and meta analyses but we will also find our own primary studies, review the reference lists of these reviews and identify newer studies, and add/edit the study lists to develop our own guidelines or advisory. Here, for the sake of learning how to use Gradepro, we will use just this systematic review to learn about the process of Gradepro. You can work on other meta analyses and systematic reviews to produce your own evidence portfolio for other study questions.

Step 1: First, get or download the article from here

Step 2: Open the article and follow along

Here are the sixteen studies they covered in this systematic review and meta analyses on which we will also work. You can do additional meta analyses on your own if you like.

Figure 6. Our Meta analysis on the basis of which we run this dummy Gradepro exercise

Once you will save the above image in Figure 6, it will bring you to a window which will look like as follows:

Figure 7. How to fill in the Evidence Portfolio by filling in the Quality Assessment and Summary of Findings Table

Now we will add the outcome that we are interested in. In real life, you will be adding many outcomes. Some of these outcomes will be beneficial outcomes, others will be harm related outcomes. A beneficial outcome in this case is ‘relief from neck pain”, a harmful outcome might be “nausea”, or “increased pain”. In this review, the authors did not report harms as they failed to identify harm related studies or the studies they selected for this review did not contain any reference to harms. Hence, we are somewhat limited in the number of outcomes we can cover here. In real life, you will create a guideline only when you have information on both harms as well as benefits. Here, we shall only cover chronic neck pain relief and we will test if based on this article alone, what can we say.

So, go ahead, and click “Add Outcome”. Here, we are going to add pain relief and after we

Figure 8. How to fill in the Outcome window

Now we fill in the details of the studies. We will use 14 studies as in Figure 4 of the paper. See:

Figure 9. This is the Forest Plot of the Meta Analysis we are about to investigate

In order to fill in these boxes, not only do we need to access the meta analysis, but we will also need to conduct where needed our own analyses, and access the original RCTs to read more about them. This is a must. So, for this particular outcome, after we fill in the details, this is how the boxes are going to look like:

Figure 10. The window after adding the outcome and other points

As can be seen in the above figure, based on the description in the article, we have added the following information:

  1. The number of studies. — We kept at 14, because these were the number of studies where they measured the relief from neck pain as an outcome
Figure 11. Funnel Plot of the effect size and the sample size of the studies included in the meta analysis

The plot above is referred to as “funnel plot”. This graph plots on the x-axis the effect size and the sample size of the included studies on the y-axis. In an ideal world where no publication bias exists, the studies (dots in the graph) will look like an inverted funnel. There would be one or two studies at the top that would have large sample and they would also report an effect size close to the summary estimate; there would be increased number of studies down the bottom but evenly scattered with respect to the effect estimate and spread apart. The largest spread will be somewhere in the bottom. This would suggest that while there have been many studies reported, some of those studies would capture the true figure and others would not, but everyone had a fair go and got represented. If any “gradient” would be missed, that would suggest that there is a publication bias to consider.
With this in mind, check this plot. We see a few studies at the top of this graph, a lot of studies at the bottom and that there is no set pattern and we cannot find if any quadrant is missing. It does not look like the authors did not include studies with low sample size and negative or equivocal effect estimate. Hence on the basis of this meta analysis and this set of studies, we can not comment on any evidence of publication bias. We therefore will mark this as “not serious” for publication bias.

Next we add outcome to the or click “Add Outcome” and add an outcome. In our case the outcome was “relief of chronic neck pain” and we fill in the boxes. It now looks like as below:

Figure 12. Summary of Findings and summary assesment

A few things to note here:

  1. Gradepro automatically selects that it is not going to report Relative Risk estimate as you have specified that your outcome variable is measured in scale measures or continuous outcome measures. So, you can see that little dash mark in the corresponding box next to “Relative Risk” that is greyed out.

This completes your evidence portfolio for this outcome for the set of studies you checked. Let’s summarise the key points with respect to the summary of findings table and the evidence portfolio:

  1. Your outcome for this study or this problem was “relief from chronic neck pain”.

Remember that this is just for one outcome and for one specific intervention. Even if we keep the intervention same, we will now need to search for other outcomes and other sets of studies. Other outcomes can also come from the same set of studies. What is important here is not what set of studies we look for but what outcome we study, how critical is it, and what is the quality of the overall evidence we are presented with. Then, we make a call as to whether on the basis of the evidence presented to us, if we are confident enough to recommend this particular intervention for a particular set of outcomes that are achievable. This is based on the strength of the recommendations. As you can see, this strength will be derived from the following:

  1. The summary effect measure, its magnitude, and its precision

You will in real life need to go over a list of defined outcomes for an intervention and construct an evidence portfolio before you can come to a conclusion about the usability of this information. In this eample however, we have worked on only one outcome for which we identified a set of studies. The goal of this lesson was just to show you what you can do with Gradepro, not so much as to work through a real world exercise.

If we were to form an advisory only on this outcome and intervention, we would see that low intensity laser therapy for chronic neck pain may be justified as it has moderate quality of evidence, we consider chronic neck pain relief as critical as an outcome, and we also see that it leads to an overall 19 point drop on a 100 point scale of pain reporting. In real life however, we would consider more outcomes. Some of these outcomes will be beneficial outcomes, and others would be harmful oucomes. Finally, after we would have exhaused the list of outcomes and the rank order of those outcomes we will take a stock of the situation to test if we have sufficient stength in the evidence we have obtained. On this basis, we would have to conclude as to the real world effectiveness of an intervention for a family of outcomes or a health problem or an issue.

This was a quick tour of the core issues that you can use about GRADE as a decision making tool for your health problem. Below you will find more resources (some annotated) so that you can learn more about GRADE and use it to develop guidelines and resources for your health and healthcare related questions.

Additional Resources

The Gradepro Website & the Webapp

This is the tool that you will use on a daily basis. This is a web based tool and is frequently upgraded. Use it on any modern web browser (Safari, Edge, Google Chrome/Chromium, Vivaldi, Firefox and clones).

In subsequent tutorials, I shall get into the details of the different types of research questions and framing of guidelines from existing reviews.

Pertinent Literature

I have linked a set of 11 core articles from where you will learn more about the GRADE process.

Guyatt, G., Oxman, A. D., Akl, E. A., Kunz, R., Vist, G., Brozek, J., … & Rind, D. (2011). GRADE guidelines: 1. Introduction — GRADE evidence profiles and summary of findings tables. Journal of clinical epidemiology, 64(4), 383–394.

Guyatt, G. H., Oxman, A. D., Kunz, R., Atkins, D., Brozek, J., Vist, G., … & Schünemann, H. J. (2011). GRADE guidelines: 2. Framing the question and deciding on important outcomes. Journal of clinical epidemiology, 64(4), 395–400.

Balshem, H., Helfand, M., Schünemann, H. J., Oxman, A. D., Kunz, R., Brozek, J., … & Guyatt, G. H. (2011). GRADE guidelines: 3. Rating the quality of evidence. Journal of clinical epidemiology, 64(4), 401–406.

Guyatt, G. H., Oxman, A. D., Vist, G., Kunz, R., Brozek, J., Alonso-Coello, P., … & Norris, S. L. (2011). GRADE guidelines: 4. Rating the quality of evidence — study limitations (risk of bias). Journal of clinical epidemiology, 64(4), 407–415.

Guyatt, G. H., Oxman, A. D., Montori, V., Vist, G., Kunz, R., Brozek, J., … & Williams, J. W. (2011). GRADE guidelines: 5. Rating the quality of evidence — publication bias. Journal of clinical epidemiology, 64(12), 1277–1282.

Guyatt, G. H., Oxman, A. D., Kunz, R., Brozek, J., Alonso-Coello, P., Rind, D., … & Jaeschke, R. (2011). GRADE guidelines 6. Rating the quality of evidence — imprecision. Journal of clinical epidemiology, 64(12), 1283–1293.

Guyatt, G. H., Oxman, A. D., Kunz, R., Woodcock, J., Brozek, J., Helfand, M., … & Norris, S. (2011). GRADE guidelines: 7. Rating the quality of evidence — inconsistency. Journal of clinical epidemiology, 64(12), 1294–1302.

Guyatt, G. H., Oxman, A. D., Kunz, R., Woodcock, J., Brozek, J., Helfand, M., … & Akl, E. A. (2011). GRADE guidelines: 8. Rating the quality of evidence — indirectness. Journal of clinical epidemiology, 64(12), 1303–1310.

Guyatt, G. H., Oxman, A. D., Sultan, S., Glasziou, P., Akl, E. A., Alonso-Coello, P., … & Jaeschke, R. (2011). GRADE guidelines: 9. Rating up the quality of evidence. Journal of clinical epidemiology, 64(12), 1311–1316.

Brunetti, M., Shemilt, I., Pregno, S., Vale, L., Oxman, A. D., Lord, J., … & Jaeschke, R. (2013). GRADE guidelines: 10. Considering resource use and rating the quality of economic evidence. Journal of clinical epidemiology, 66(2), 140–150.

Guyatt, G., Oxman, A. D., Sultan, S., Brozek, J., Glasziou, P., Alonso-Coello, P., … & Rind, D. (2013). GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. Journal of clinical epidemiology, 66(2), 151–157.