Participant Guide

Clinical Research Methodology

In Collaboration with the Egyptian Knowledge Bank

Nature Research Academies – Author Academy

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Skills and Careers Forum for Researchers
A84563
Workshop Overview
___________________________________________________________________________________

The Nature Research Academies virtual workshops are designed to offer accessible training
for busy journal editors. Through a combination of interactive group webinars and self-study
exercises led by a Nature Research trainer, the workshop will help you to succeed in today’s
competitive academic landscape.
The goal of clinical research is to improve patient care and management; however, this can
only be done if you have a robust and rigorous clinical study design. These webinars provide
practical insights and strategies to help you achieve this goal.
Participants who complete the workshop will be awarded a Certificate of Completion.

Objectives for this virtual workshop:

• Formulate a concise and impactful research question
• Choose the best study design according to your study aim
• Use appropriate sampling to improve the relevance to the clinical community
• Design robust protocols that minimize biases

Preparation for the workshop

To prepare for the virtual workshop, please read through the key points of the workshop
along with the activities, which should take you less than an hour. These exercises have been
designed to help you to get the most out of the workshop. By reviewing them ahead of time,
the trainer can focus on teaching and leading the activities more effectively during the
sessions. We encourage you to try to answer the activities before the webinar, and then you
can revise your answers during the webinar if necessary.
You will also need to have access to this Participant Guide during the webinars. The Nature
Research Academies team recommends that you either print or display it on a separate
device to the one you are using to access the webinars.

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Agenda
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Webinar 1 – Planning Before You Begin

Identifying an important research question
Session 1 This section discusses how to define a research question that will address an important
problem in the field, and then how to decide the best aims to address this question.

Deciding the appropriate outcomes

Session 2 This section reviews the variety of outcomes that can be evaluated and how to choose
which ones are most appropriate based on the aims that have been decided.

10 minutes Break

15 minutes Q&A

Choosing the best study design

Session 3 This section discusses different study designs along with their level of evidence,
strengths & weakness, as well as associated biases that need to be taken into
consideration during planning.

15 minutes Final Q&A

Webinar 2 – Conducting Robust Clinical Research

Session 1 Sampling methodologies
This section highlights the importance of using appropriate sampling to ensure that the
study is sufficiently powered as well as best represents the clinical population.

10 minutes Break

15 minutes Q&A

Session 2 Avoiding common biases

This section reviews a number of common biases that affect the quality and relevance of
clinical research, as well as strategies to avoid them.

Session 3 Effective analyses

This section discusses how to properly evaluate your obtained data, such as intention-to-
treat and per protocol as well as subgroup and sensitivity analyses.

15 minutes Final Q&A

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Key Points from this Workshop
___________________________________________________________________________________

Webinar 1 – Planning Before You Begin

Defining your research question

Formulate your research question using:

● the P–I–C–O approach, identifying:
o the Population studied
o the Intervention of interest
o the Comparison
o the Outcome(s) measured
● The F–I–N–E–R criteria; i.e., your study should be:
o Feasible: Do you have the expertise, resources and budget to complete your
study on time?
o Interesting: Does research question address an important topic in your field?
o Novel: Does the study generate novel information about this topic?
o Ethical: Are you respecting international guidelines related to human research?
Did you obtain approval by a research ethics committee?
o Relevant: What is the clinical relevance of your study?

Measurements

The most common epidemiological measures are:

● Frequency measures:
o The prevalence is a frequency measure of the existing cases of a disease over
a given time period
o The incidence is a frequency measure of the number of new cases of a
disease over a given time period
● Mortality measures:
o The mortality rate reflects the frequency of deaths in a population for a given
time period
o The case-fatality risk reflects the proportion of patients with a condition who
die from that condition
● Association measures:
o The risk ratio (or relative risk; RR) is the probability of events in the
exposed/treated group divided by the probability of events in the control
group
o The odds ratio (OR) is the odds of events in the exposed/treated group
divided by the odds in the control group

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Study design
The most common study designs are listed by decreasing order of clinical relevance and
should be chosen according to the study’s aim:
● A meta-analysis is a type of systematic review that uses a statistical approach to
summarize empirical evidences from published and unpublished studies
● A systematic review uses a narrative approach to synthesis empirical evidences from
published and unpublished studies
● A randomized controlled trial (RCT) is a special type of experimental cohort study
whereby the investigator randomizes participants suffering from a disease into >2
groups, assigns them to different treatments (e.g., a drug and a placebo) and follows
them prospectively while comparing the treatment’s effect
● In an observational cohort study, the investigator identifies a cohort of interest
exposed to a risk factor or a treatment and chooses a control group with a different
exposure. These groups are then followed prospectively while comparing the long-
term consequences of the exposures. They are particularly relevant for evaluating risk
factors of the disease, the prognosis, the incidence and/or risk ratio
● In a case-control study, the investigator first identifies patients or “cases” afflicted by
a disease of interest and then finds a matching control group without the disease. The
exposures in each group are then compared retrospectively. They are relevant to
identify potential risk factors of the disease and the odds ratio
● In a cross-sectional study, the investigator measures both the exposure and disease
prevalence at a single time point. They are appropriate to generate hypotheses on the
cause of disease or to evaluate the odds ratio
● In a case series, the investigator describes several (>3–4) patients with unique
clinical presentation that have a high educational value
● In a case report, the investigator describes 1–3 patients with very unique clinical
presentation that has a high educational value

Webinar 2 – Conducting Robust Clinical Research

Participants
Before recruiting participants, you should ask yourself:
● How many to recruit?
o A power calculation should always be done to determine the number of
participants needed for a study and ensure that the study is not
underpowered.
o The sample size varies with the significance level (alpha), power (1-beta),
expected variability (standard deviation) and effect size (delta)
o You should always recruit more participants than what the power calculation
indicates to compensate for participants who do not complete the study or are
lost to follow up
● Who?
o Exclusion and inclusion criteria should always be defined and justified before
selecting participants
● How?
o Probability sampling methods use are more robust because they use random
selection of participants

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 o Non-probability sampling methods (e.g., convenience or judgmental)
introduce selection bias which reduces the external validity of the results
o The internal validity questions whether a study is done right
o The external validity addresses whether the study results found in the sample
can be generalized to the population

Avoiding common biases

Here are some strategies to avoid common biases in clinical research:

● Selection bias: Participants included in the study sample fail to represent the
population of interest
o Use a probability sampling method
o Randomize participants individually or by cluster
o Use a cross-over design where the same participants are exposed to the two
conditions and the order of condition is randomized between groups.
o Match participants with similar characteristics (e.g., gender, age) either by
group or by individual
● Measurement bias: The quality, validity and/or availability of the data is compromised.
o Calibrate and test your equipment and record their precision and accuracy
o Run a pilot study to test your methodology
o Train your research staff to homogenize the procedures
o Blinding: keep some information secret from patient/investigator
o Concealment: Ensure that blinding is maintained throughout the study.
● Attrition bias: Participants discontinue their enrollment during the study leading to
missing data. Remember that participants are always free to withdraw at any time
during a study.
o Consider a run-in period to screen for participants with high attrition risk and
exclude them from your sample
o Maximize patients’ benefits (e.g. match doctor’s visit with follow-up)
o Be efficient, collect only what is necessary to answer your research question
o Be patient-friendly, convenient and flexible
o Identify locators (patient’s friend or family) who can contact the participant in
case you fail to
o Maintain regular contact
● Recall bias: Participants recall better their exposure if it is associated with a certain
outcome.
o Optimize data gathering such that information is obtained at time of exposure
and outcome
o Choose a control group with similar recall bias
● Publication bias: Positive results are more likely to get published than inconclusive
results.
o Consider submitting to a journal that only evaluates scientific rigor, not
perceived impact, of a study (e.g., Scientific Reports, BMC Research Notes,
or PLoS ONE)
o Make your research available and citable in a public repository (e.g. FigShare)
or preprint server (e.g., BioRxiv or MedRxiv)
o Register your RCT (e.g. ClinicalTrials.gov) or systematic review (e.g.,
PROSPERO) before you begin

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Data collection & analysis

Here are some strategies to avoid common problems related to data:

● Missing data are handled differently according to their nature:
o Missing completely at random (MCAR):
▪ Listwise deletion: the entire case with missing data is deleted and the
analysis is done with the completed cases only
▪ Pairwise deletion: the case with missing data are kept intact and the
analysis is run with different number of participants for each variable
o Missing at random (MAR):
▪ Single imputation: each missing data is replaced by a single data (e.g.
mean)
▪ Last observation carried forward (LOCF): each missing data is
replaced by the last value
● The nature and cause for missing data should always be reported using a flowchart
(available at the equator network [www.equator-network.org])
● Multiple comparisons should be corrected statistically and be justified a priori
● Statistical significance does not equal clinical relevance
o When listing your results, always quantify your findings and provide a
confidence interval

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Activities
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Webinar 1 – Planning Your Clinical Study

Activity 1 – Identifying a valuable research question

Although PD-1 blockade has only shown limited efficacy in patients with glioblastoma,
preclinical studies have suggested that the PD-1-programmed death-ligand (PD-L1) axis is
immunologically relevant and that a therapeutic window exists for PD-1 blockade in at least
some glioblastoma patients. How might you address this issue in a study?

A. Investigate if combinatorial blockade of the Na/H exchanger isoform 1 and PD-1 more
strongly altered the functional immune landscape and extend the survival in
glioblastoma patients compared with PD-1 blockade alone.

B. Investigate if neoadjuvant PD-1 blockade altered the functional immune landscape

and extend survival in patients with recurrent, surgically resectable glioblastoma, who
were identified for susceptibility in a previous subgroup analysis.

C. Investigate if salvage therapy with PD-1 blocking antibodies improved the median
progression-free survival in patients with recurrent high-grade gliomas.

________________________________________________________________________________
________________________________________________________________________________

________________________________________________________________________________

Activity 2 – Study design

In your colleague’s multi-center RCT to compare the efficacy of a novel drug with liraglutide
for cardiovascular risk reduction in individuals with type 2 diabetes, they had all 750
participants submit a blood sample upon recruitment. During the study, they noted that 53 of
the participants developed colorectal cancer (not correlated to their intervention). You
suggested that they evaluate the donated blood samples from the beginning of the study for
carcinoembryonic antigen (CEA), a tumor marker for colorectal cancer, along with other
markers to see which were associated with increased risk among diabetic participants.
Which type of study design would you recommend they use to investigate this possibility?

A. Case-control study
B. Randomized control trial
C. Retrospective cohort study
D. Case series
E. Cross-sectional study

________________________________________________________________________________
________________________________________________________________________________

________________________________________________________________________________

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Webinar 2 – Conducting Robust Clinical Research

Activity 3 – Randomization and blinding

An investigator at a clinic in Cairo is designing a superiority trial to compare a new treatment
with the standard of care. She plans to do a single-center study with 112 participants. She
knows that gender is strongly related to the outcome measure and generates the following
treatment assignment schedules using permuted block randomization. The first 16
assignments for each gender are shown in the table below.
Women Men
Block Block Seq in Block Block Seq in
Seq Size Block Treatment Seq Size Block Treatment
1 4 1 New drug 1 2 1 Standard of care
1 4 2 Standard of care 1 2 2 New drug
1 4 3 New drug 2 4 1 Standard of care
1 4 4 Standard of care 2 4 2 New drug
2 4 1 Standard of care 2 4 3 New drug
2 4 2 Standard of care 2 4 4 Standard of care
2 4 3 New drug 3 2 1 New drug
2 4 4 New drug 3 2 2 Standard of care
3 2 1 Standard of care 4 4 1 Standard of care
3 2 2 New drug 4 4 2 New drug
4 2 1 New drug 4 4 3 New drug
4 2 2 Standard of care 4 4 4 Standard of care
5 4 1 New drug 5 4 1 Standard of care
5 4 2 New drug 5 4 2 New drug
5 4 3 Standard of care 5 4 3 Standard of care
5 4 4 Standard of care 5 4 4 New drug

The investigator stores the treatments in bins labeled A (for the new treatment) and B (for the
standard of care). After creating the treatment assignment list, she posts it on the clinic wall
so that it will be easy for clinic staff to give the correct treatment to a study participant once
he/she is randomized. She labels the assignments in the list with ‘A’ and ‘B’ to correspond to
bins A and B.

A. After the first 20 people are enrolled, what would be the overall treatment assignment
count if 75% of participants are women and 25% are men?
____________________________________________________________________________

B. Does the total in the “women” stratum meet the allocation ratio after 14 women are
enrolled? Why or why not?
____________________________________________________________________________

C. How does the investigator undermine the purpose of the randomization in this
example? What other simple methods could she have used that would preserve the
integrity of the randomization process?

____________________________________________________________________________
____________________________________________________________________________

Activity 4 – Identifying biases

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For each situation listed below, name the type of bias that is likely involved:

A. During an RCT, patients who found the clinic difficult to access decided to discontinue
their participation in the study.

_____________________________________________________________________________

B. A company encourages their scientists to publish studies demonstrating positive

effects of the drugs, but not inconclusive or non-significant studies.

_____________________________________________________________________________

C. The case-fatality risk of Ebola patients was evaluated in a male hospital in Nigeria where
the principal investigator works.

_____________________________________________________________________________

A. In an RCT, the authors measured the risk of mortality and efficacy (risk ratio) of a new
beta-blocker compared with that of statin for treatment of coronary heart disease. They
reported a significant RR of 0.85 (95% CI: 0.72–0.98) for efficacy, but not a non-
significant difference in risk of mortality.

_____________________________________________________________________________

E. In a case-controlled study, the researchers found limited risk factors that contributed
to the development of ischemic heart disease among residents in rural Egypt.

_____________________________________________________________________________

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Useful Resources
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Ethics
Declaration of Helsinki (https://www.wma.net/policies-post/wma-declaration-of-helsinki-
ethical-principles-for-medical-research-involving-human-subjects/)
Equator Network (www.equator-network.org)
Nature – Challenges in Irreproducible Research (www.nature.com/news/reproducibility-1.17552)
Nature – Life Sciences Reporting Summary
(www.nature.com/authors/policies/ReportingSummary.pdf)
Committee on Publication Ethics (publicationethics.org)
WHO Informed Consent Form Templates (www.who.int/rpc/research_ethics/informed_consent/en/)
ICMJE Conflicts of Interest Form (www.icmje.org/conflicts-of-interest)
ICMJE – Authorship (www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-
the-role-of-authors-and-contributors.html)
ORCiD – Unique identifier for researchers (www.orcid.org)

Clinical Trials
ICMJE – Clinical Trial Registration (www.icmje.org/recommendations/browse/publishing-and-
editorial-issues/clinical-trial-registration.html)
WHO – International Clinical Trials Registry Platform (www.who.int/ictrp/network/primary/en/)
Pan African Clinical Trial Registry (www.pactr.org)
ClinicalTrials.gov (www.clinicaltrials.gov)

Statistics
Nature – Statistics for Biologists (www.nature.com/collections/qghhqm)
BMJ – Statistics Notes (www.bmj.com/specialties/statistics-notes)

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FAQs
___________________________________________________________________________________

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This material is not to be used outside of the workshop without the consent of Springer Nature. ©2020 Springer Nature Limited

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