19. Protocol registration

What to write

Provide a statement indicating whether a protocol (including the research question, key design features, and analysis plan) was prepared before the study, and if and where this protocol was registered.

Explanation

Akin to the approach taken for clinical trials, protocol registration has emerged as a mechanism that is likely to improve the transparency of animal research1–3. Registering a protocol before the start of the experiment enables researchers to demonstrate that the hypothesis, approach, and analysis were planned in advance and not shaped by data as they emerged; it enhances scientific rigour and protects the researcher against concerns about selective reporting of results4,5. A protocol should consist of (1) the question being addressed and the key features of the research that is proposed, such as the hypothesis being tested, the primary outcome measure (if applicable), and the statistical analysis plan; and (2) the laboratory procedures to be used to perform the planned experiment.

Protocols may be registered with different levels of completeness. For example, in the Registered Report format offered by an increasing number of journals, protocols undergo peer review, and if accepted, the journal commits to publishing the completed research regardless of the results obtained2.

Other online resources include the Open Science Framework6, which is suitable to deposit PHISPS (Population; Hypothesis; Intervention; Statistical Analysis Plan; Primary; Outcome Measure; Sample Size Calculation) protocols7 and provide researchers with the flexibility to embargo the preregistration, keep it from public view until the research is published, and selectively share it with reviewers and editors. The EDA can also be used to generate a time-stamped PDF, which sets out key elements of the experimental design8. This can be used to demonstrate that the study conduct, analysis, and reporting were not unduly driven by emerging data. As a minimum, we recommend registering protocols containing all PHISPS components as outlined above.

Provide a statement indicating whether or not any protocol was prepared before the study, and if applicable, provide the time-stamped protocol or the location of its registration. When there have been deviations from the protocol, describe the rationale for these changes in the publication so that readers can take this into account when assessing the findings.

Examples

‘A detailed description of all protocols can be found in the Registered Report (Kandela et al., 2015). Additional detailed experimental notes, data, and analysis are available on the Open Science Framework (OSF) (RRID: SCR_003238) (https://osf.io/xu1g2/)’9.

‘To maximize the objectivity of the presented research, we preregistered this study with its 2 hypotheses, its planned methods, and its complete plan of data analysis before the start of data collection (https://osf.io/eb8ua/register/565fb3678c5e4a66b5582f67, accessed 29 December 2017). We closely adhered to our plan…. All statistical analyses closely followed our preregistered analysis plan (https://osf.io/eb8ua/)’10.

‘We preregistered our analyses with the Open Science Framework which facilitates reproducibility and open collaboration in science research…. Our preregistration: Sheldon and Griffith (2017), was carried out to limit the number of analyses conducted and to validate our commitment to testing a limited number of a priori hypotheses. Our methods are consistent with this preregistration …’11.

Training

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References

1.
Chalmers I, Bracken MB, Djulbegovic B, et al. How to increase value and reduce waste when research priorities are set. The Lancet. 2014;383(9912):156-165. doi:10.1016/s0140-6736(13)62229-1
2.
D. Chambers C, Feredoes E, D. Muthukumaraswamy S, J. Etchells P. Instead of “playing the game” it is time to change the rules: Registered reports at <em>AIMS neuroscience</em> and beyond. AIMS Neuroscience. 2014;1(1):4-17. doi:10.3934/neuroscience.2014.1.4
3.
Nosek BA, Lakens D. Registered reports: A method to increase the credibility of published results. Social Psychology. 2014;45(3):137-141. doi:10.1027/1864-9335/a000192
4.
Kaplan RM, Irvin VL. Likelihood of null effects of large NHLBI clinical trials has increased over time. Garattini S, ed. PLOS ONE. 2015;10(8):e0132382. doi:10.1371/journal.pone.0132382
5.
Allen C. Published online 2018.
6.
Nosek BA, Ebersole CR, DeHaven AC, Mellor DT. The preregistration revolution. Proceedings of the National Academy of Sciences. 2018;115(11):2600-2606. doi:10.1073/pnas.1708274114
7.
Macleod M, Howells D. Protocols for laboratory research. Evidence-based Preclinical Medicine. 2016;3(2):28-29. doi:10.1002/ebm2.21
8.
Percie du Sert N, Bamsey I, Bate ST, et al. The experimental design assistant. PLOS Biology. 2017;15(9):e2003779. doi:10.1371/journal.pbio.2003779
9.
Mantis C, Kandela I, Aird F. Replication study: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. eLife. 2017;6. doi:10.7554/elife.17584
10.
Jerónimo S, Khadraoui M, Wang D, et al. Plumage color manipulation has no effect on social dominance or fitness in zebra finches. Langmore N, ed. Behavioral Ecology. 2018;29(2):459-467. doi:10.1093/beheco/arx195
11.
Sheldon EL, Griffith SC. Embryonic heart rate predicts prenatal development rate, but is not related to post‐natal growth rate or activity level in the zebra finch (taeniopygia guttata). Fusani L, ed. Ethology. 2018;124(11):829-837. doi:10.1111/eth.12817

Citation

For attribution, please cite this work as:
Sert NP du, Hurst V, Ahluwalia A, et al. The ARRIVE reporting guideline for writing animal research articles. The EQUATOR Network guideline dissemination platform. doi:10.1234/equator/1010101

Reporting Guidelines are recommendations to help describe your work clearly

Your research will be used by people from different disciplines and backgrounds for decades to come. Reporting guidelines list the information you should describe so that everyone can understand, replicate, and synthesise your work.

Reporting guidelines do not prescribe how research should be designed or conducted. Rather, they help authors transparently describe what they did, why they did it, and what they found.

Reporting guidelines make writing research easier, and transparent research leads to better patient outcomes.

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Maximum impact

From nobel prizes to null results, articles have more impact when everyone can use them.

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Who reads research?

You work will be read by different people, for different reasons, around the world, and for decades to come. Reporting guidelines help you consider all of your potential audiences. For example, your research may be read by researchers from different fields, by clinicians, patients, evidence synthesisers, peer reviewers, or editors. Your readers will need information to understand, to replicate, apply, appraise, synthesise, and use your work.

Cohort studies

A cohort study is an observational study in which a group of people with a particular exposure (e.g. a putative risk factor or protective factor) and a group of people without this exposure are followed over time. The outcomes of the people in the exposed group are compared to the outcomes of the people in the unexposed group to see if the exposure is associated with particular outcomes (e.g. getting cancer or length of life).

Source.

Case-control studies

A case-control study is a research method used in healthcare to investigate potential risk factors for a specific disease. It involves comparing individuals who have been diagnosed with the disease (cases) to those who have not (controls). By analysing the differences between the two groups, researchers can identify factors that may contribute to the development of the disease.

An example would be when researchers conducted a case-control study examining whether exposure to diesel exhaust particles increases the risk of respiratory disease in underground miners. Cases included miners diagnosed with respiratory disease, while controls were miners without respiratory disease. Participants' past occupational exposures to diesel exhaust particles were evaluated to compare exposure rates between cases and controls.

Source.

Cross-sectional studies

A cross-sectional study (also sometimes called a "cross-sectional survey") serves as an observational tool, where researchers capture data from a cohort of participants at a singular point. This approach provides a 'snapshot'— a brief glimpse into the characteristics or outcomes prevalent within a designated population at that precise point in time. The primary aim here is not to track changes or developments over an extended period but to assess and quantify the current situation regarding specific variables or conditions. Such a methodology is instrumental in identifying patterns or correlations among various factors within the population, providing a basis for further, more detailed investigation.

Source

Systematic reviews

A systematic review is a comprehensive approach designed to identify, evaluate, and synthesise all available evidence relevant to a specific research question. In essence, it collects all possible studies related to a given topic and design, and reviews and analyses their results.

The process involves a highly sensitive search strategy to ensure that as much pertinent information as possible is gathered. Once collected, this evidence is often critically appraised to assess its quality and relevance, ensuring that conclusions drawn are based on robust data. Systematic reviews often involve defining inclusion and exclusion criteria, which help to focus the analysis on the most relevant studies, ultimately synthesising the findings into a coherent narrative or statistical synthesis. Some systematic reviews will include a meta-analysis.

Source

Systematic review protocols

TODO

Meta analyses of Observational Studies

TODO

Randomised Trials

A randomised controlled trial (RCT) is a trial in which participants are randomly assigned to one of two or more groups: the experimental group or groups receive the intervention or interventions being tested; the comparison group (control group) receive usual care or no treatment or a placebo. The groups are then followed up to see if there are any differences between the results. This helps in assessing the effectiveness of the intervention.

Source

Randomised Trial Protocols

TODO

Qualitative research

Research that aims to gather and analyse non-numerical (descriptive) data in order to gain an understanding of individuals' social reality, including understanding their attitudes, beliefs, and motivation. This type of research typically involves in-depth interviews, focus groups, or field observations in order to collect data that is rich in detail and context. Qualitative research is often used to explore complex phenomena or to gain insight into people's experiences and perspectives on a particular topic. It is particularly useful when researchers want to understand the meaning that people attach to their experiences or when they want to uncover the underlying reasons for people's behavior. Qualitative methods include ethnography, grounded theory, discourse analysis, and interpretative phenomenological analysis.

Source

Case Reports

TODO

Diagnostic Test Accuracy Studies

Diagnostic accuracy studies focus on estimating the ability of the test(s) to correctly identify subjects with a predefined target condition, or the condition of interest (sensitivity) as well as to clearly identify those without the condition (specificity).

Prediction Models

Prediction model research is used to test the accurarcy of a model or test in estimating an outcome value or risk. Most models estimate the probability of the presence of a particular health condition (diagnostic) or whether a particular outcome will occur in the future (prognostic). Prediction models are used to support clinical decision making, such as whether to refer patients for further testing, monitor disease deterioration or treatment effects, or initiate treatment or lifestyle changes. Examples of well known prediction models include EuroSCORE II for cardiac surgery, the Gail model for breast cancer, the Framingham risk score for cardiovascular disease, IMPACT for traumatic brain injury, and FRAX for osteoporotic and hip fractures.

Source

Animal Research

TODO

Quality Improvement in Healthcare

Quality improvement research is about finding out how to improve and make changes in the most effective way. It is about systematically and rigourously exploring "what works" to improve quality in healthcare and the best ways to measure and disseminate this to ensure positive change. Most quality improvement effectiveness research is conducted in hospital settings, is focused on multiple quality improvement interventions, and uses process measures as outcomes. There is a great deal of variation in the research designs used to examine quality improvement effectiveness.

Source

Economic Evaluations in Healthcare

TODO

Meta Analyses

A meta-analysis is a statistical technique that amalgamates data from multiple studies to yield a single estimate of the effect size. This approach enhances precision and offers a more comprehensive understanding by integrating quantitative findings. Central to a meta-analysis is the evaluation of heterogeneity, which examines variations in study outcomes to ensure that differences in populations, interventions, or methodologies do not skew results. Techniques such as meta-regression or subgroup analysis are frequently employed to explore how various factors might influence the outcomes. This method is particularly effective when aiming to quantify the effect size, odds ratio, or risk ratio, providing a clearer numerical estimate that can significantly inform clinical or policy decisions.

How Meta-analyses and Systematic Reviews Work Together

Systematic reviews and meta-analyses function together, each complementing the other to provide a more robust understanding of research evidence. A systematic review meticulously gathers and evaluates all pertinent studies, establishing a solid foundation of qualitative and quantitative data. Within this framework, if the collected data exhibit sufficient homogeneity, a meta-analysis can be performed. This statistical synthesis allows for the integration of quantitative results from individual studies, producing a unified estimate of effect size. Techniques such as meta-regression or subgroup analysis may further refine these findings, elucidating how different variables impact the overall outcome. By combining these methodologies, researchers can achieve both a comprehensive narrative synthesis and a precise quantitative measure, enhancing the reliability and applicability of their conclusions. This integrated approach ensures that the findings are not only well-rounded but also statistically robust, providing greater confidence in the evidence base.

Why Don't All Systematic Reviews Use a Meta-Analysis?

Systematic reviews do not always have meta-analyses, due to variations in the data. For a meta-analysis to be viable, the data from different studies must be sufficiently similar, or homogeneous, in terms of design, population, and interventions. When the data shows significant heterogeneity, meaning there are considerable differences among the studies, combining them could lead to skewed or misleading conclusions. Furthermore, the quality of the included studies is critical; if the studies are of low methodological quality, merging their results could obscure true effects rather than explain them.

Protocol

A plan or set of steps that defines how something will be done. Before carrying out a research study, for example, the research protocol sets out what question is to be answered and how information will be collected and analysed.

Source

Animal research

When ARRIVE refers to animal research it is referring to in vivo animal research. This is the use of non-human animals, sometimes known as model organisms, in experiments that seek to control the variables that affect the behavior or biological system under study. This approach can be contrasted with field studies in which animals are observed in their natural environments or habitats. Animal research varies on a continuum from pure research, focusing on developing fundamental knowledge of an organism, to applied research, which may focus on answering some questions of great practical importance, such as finding a cure for a disease. Source" The ARRIVE guidelines apply to all areas of bioscience research involving living animals. That includes mammalian species as well as model organisms such as Drosophila or Caenorhabditis elegans. Each item is equally relevant to manuscripts centred around a single animal study and broader-scope manuscripts describing in vivo observations along with other types of experiments. The exact type of detail to report, however, might vary between species and experimental setup; this is acknowledged in the guidance provided for each item. Source

Bias

The over- or underestimation of the true effect of an intervention. Bias is caused by inadequacies in the design, conduct, or analysis of an experiment, resulting in the introduction of error.\n\nSource

Descriptive and inferential statistics

Descriptive statistics are used to summarise the data. They generally include a measure of central tendency (e.g., mean or median) and a measure of spread (e.g., standard deviation or range). Inferential statistics are used to make generalisations about the population from which the samples are drawn. Hypothesis tests such as ANOVA, Mann-Whitney, or t tests are examples of inferential statistics.\n\nSource

Effect size

Quantitative measure of differences between groups, or strength of relationships between variables.\n\nSource

Experimental unit

Biological entity subjected to an intervention independently of all other units, such that it is possible to assign any two experimental units to different treatment groups. Sometimes known as unit of randomisation.\n\nSource

External validity

Extent to which the results of a given study enable application or generalisation to other studies, study conditions, animal strains/species, or humans.\n\nSource

False negative

Statistically nonsignificant result obtained when the alternative hypothesis (H~1~) is true. In statistics, it is known as the type II error.\n\nSource

False positive

Statistically significant result obtained when the null hypothesis (H~0~) is true. In statistics, it is known as the type I error.\n\nSource

Independent variable

Variable that either the researcher manipulates (treatment, condition, time) or is a property of the sample (sex) or a technical feature (batch, cage, sample collection) that can potentially affect the outcome measure. Independent variables can be scientifically interesting, or nuisance variables. Also known as predictor variable.\n\nSource

Internal validity

Extent to which the results of a given study can be attributed to the effects of the experimental intervention, rather than some other, unknown factor(s) (e.g., inadequacies in the design, conduct, or analysis of the study introducing bias).\n\nSource

Nuisance variable

Variables that are not of primary interest but should be considered in the experimental design or the analysis because they may affect the outcome measure and add variability. They become confounders if, in addition, they are correlated with an independent variable of interest, as this introduces bias. Nuisance variables should be considered in the design of the experiment (to prevent them from becoming confounders) and in the analysis (to account for the variability and sometimes to reduce bias). For example, nuisance variables can be used as blocking factors or covariates.\n\nSource

Null and alternative hypotheses

The null hypothesis (H~0~) is that there is no effect, such as a difference between groups or an association between variables. The alternative hypothesis (H~1~) postulates that an effect exists.\n\nSource

Outcome measure

Any variable recorded during a study to assess the effects of a treatment or experimental intervention. Also known as dependent variable, response variable.\n\nSource

Power

For a predefined, biologically meaningful effect size, the probability that the statistical test will detect the effect if it exists (i.e., the null hypothesis is rejected correctly).\n\nSource

Sample size

Number of experimental units per group, also referred to as n.\n\nSource