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Levels of evidence and study designs: A brief introduction to dermato-

epidemiologic research methodology

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DOI: 10.4103/ds.DS-D-23-00159

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Levels of evidence and study designs: A brief introduction to

dermato-epidemiologic research methodology
Yen‑Ning Chen1, Ching‑Chi Chi2,3*
1
Department of Medical Education, Chang Gung Memorial Hospital, Linkou Main Branch, Taoyuan, Taiwan, 2School of Medicine, College of Medicine, Chang Gung
University, Taoyuan, Taiwan, 3Department of Dermatology, Chang Gung Memorial Hospital, Linkou Main Branch, Taoyuan, Taiwan
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Abstract
Levels of evidence (LOE), also known as hierarchies of evidence, are determined primarily by the inherent bias and validity of the study
designs. Understanding LOE is a crucial preliminary step in practicing evidence‑based medicine (EBM) or evidence-based dermatology. These
hierarchies facilitate the efficient acquisition of the best available evidence for clinicians in decision‑making, as well as guiding researchers
in conducting new studies with appropriate designs while considering the next higher LOE necessary to improve the quality of currently
available evidence. This article provides a concise overview of LOE and study designs based on the 2011 Oxford Centre for Evidence‑Based
Medicine LOE for treatment benefits. We utilize examples from medical literature to elucidate the strengths and limitations of various study
designs. Furthermore, we shed light on the key concepts of the updated evidence pyramid and how the EBM research roadmap functions to
bridge the gap between current best evidence and clinical practice.

Key words: Evidence pyramid, evidence-based dermatology, evidence‑based medicine, level of evidence, study design

Introduction design, considering the types of questions being addressed

Evidence‑based medicine (EBM) refers to the conscientious,
explicit, and judicious integration of the current best research
evidence, together with the clinician’s expertise and the
patient’s values, to guide clinical decision‑making.[1] When
applied in dermatology, the term ‘evidence-based dermatology’
is used.[2] Understanding the levels of evidence (LOE), also
known as hierarchies of evidence, is an essential preliminary
step in practicing EBM. These hierarchies provide a framework
for clinicians and researchers to efficiently acquire the best
available evidence by prioritizing the highest level of study
design during literature searches.[3] LOE and study designs also
assist researchers in conducting new studies with appropriate
Submitted: 15‑Aug‑2023 Revised: 02‑Nov‑2023 Accepted: 03‑Nov‑2023
Published: 15-Dec-2023
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and the next higher LOE required to enhance the quality of
currently available evidence.
Several versions of LOE pyramids have been proposed,
with most starting from bench research and expert opinions
as the lowest level, progressing through descriptive case
reports or case series, analytic observational designs such as
case–control and cohort studies, experimental randomized
controlled trials (RCTs), and finally culminating in systematic
Address for correspondence: Prof. Ching‑Chi Chi,
Department of Dermatology, Chang Gung Memorial Hospital, Linkou Main
Branch, No. 5, Fuxing St., Guishan Dist., Taoyuan 333423, Taiwan.
E‑mail: prof.chi.work@gmail.com
This is an open access journal, and articles are distributed under the terms of the Creative
Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to
remix, tweak, and build upon the work non‑commercially, as long as appropriate credit
is given and the new creations are licensed under the identical terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com

DOI: How to cite this article: Chen YN, Chi CC. Levels of evidence and
10.4103/ds.DS-D-23-00159 study designs: A brief introduction to dermato-epidemiologic research
methodology. Dermatol Sin 2023;41:199-205.

© 2023 Dermatologica Sinica | Published by Wolters Kluwer ‑ Medknow 199

 Chen and Chi: LOE and study designs
reviews (SRs) and meta‑analyses (MAs) at the pinnacle of the
pyramids as the highest LOE.[3] The LOE in medical research
is primarily determined by the inherent bias and validity of the
study designs. LOE can be further upgraded or downgraded
based on the quality of evidence after critical appraisal.[4]
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This article offers a succinct overview of LOE and study
designs based on the 2011 Oxford Centre for Evidence‑Based
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Medicine LOE for treatment benefits [Figure 1].[5‑7] We
employ the examples from medical literature to explicate
the strengths and limitations of various study designs. In
addition, we elaborate on the key concepts of the new
evidence pyramid and how the EBM research roadmap
serves as a bridge between current evidence and clinical
practice.
Five Levels of Evidence and Study designs
Level 5 evidence: Mechanism‑based reasoning
Mechanism‑based reasoning refers to the process of inferring
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from mechanisms to claims that an intervention produces a
patient‑relevant clinical outcome. This approach involves a
variety of study designs, including bench research utilizing
cell culture or animal models to investigate biochemistry,
pathophysiology, and pharmacokinetics. However, one major
limitation of level 5 evidence is its low external validity for
application to human.
Example
According to research conducted in vitro, ivermectin, an
antiparasitic agent, demonstrated inhibitory effects on the
replication of severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) during the early stages of infection.[8]
However, a recent Cochrane review of RCTs indicated no
beneficial effect of ivermectin for patients with SARS-
CoV-2 in neither outpatient nor inpatient settings.[9] Also,
there is no evidence on the use of ivermectin for preventing
SARS-CoV-2 infection in individuals following high‑risk
exposure.[9]
Figure 1: Levels of evidence pyramid and study designs for treatment benefits.
200
Level 4 evidence: Case series and case‑control study
Case series
A case series is a type of descriptive study reporting
observations on a series of individuals who have typically
undergone the same intervention without a control group. This
study design is often utilized to demonstrate novel or unusual
characteristics observed in patients in clinical practice, which
may prompt further investigation. The primary advantage of
a case series lies in its feasibility, as it requires less time and
financial resources than other study designs. However, a major
limitation of a case series is its susceptibility to selection bias,
which may limit its generalizability to larger populations of
patients.
Example
The initial documented evidence of the potential teratogenic
effects of thalidomide is a case series that reported a higher
incidence of the same type of birth defect (phocomelia)
in babies born to women who received thalidomide as an
antiemetic during pregnancy, reaching 20% compared to
the usual incidence of birth defects of 1.5% among general
newborns. As formal epidemiologic research would have taken
years and led to further fetal harm, this safety signal from level
4 evidence alone led to the withdrawal of thalidomide from
the market.[10]
Case‑control study
A case–control study is a retrospective observational study
that compares people with a prespecified disease or outcome
of interest (case group) to people without that disease or
outcome (control group) from the same population. The
primary function of case–control studies is to identify the
associations between the outcome and prior exposure to
specific risk factors [Figure 2]. This type of study is particularly
beneficial in situations where the outcome is rare and the past
exposure can be reliably measured. The major limitation of
this study design is its vulnerability to recall bias and selection
bias. Moreover, a case–control study can only infer correlations
Dermatologica Sinica ¦ Volume 41 ¦ Issue 4 ¦ October-December 2023
 Chen and Chi: LOE and study designs
rather than causal relationships between risk factors and
outcomes.
Example
A seminal case–control study conducted by Sir Richard
Doll and Sir Austin Bradford Hill in 1950 demonstrated the
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association between smoking and lung cancer. This case–
control study reported that smoking, particularly in the form
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of long‑term heavy use, was far more common among lung
cancer patients compared to noncancer control patients.[11]
Level 3 evidence: Nonrandomized controlled cohort/
follow‑up study
A nonrandomized controlled cohort (or follow‑up) study is
a longitudinal observational study, in which a defined group
of people (the cohort) is followed over time. The outcomes
of people in subsets of this cohort are compared, to examine
people who have been exposed or not exposed (or exposed at
different levels) to a particular intervention or other factors
of interest [Figure 3]. Since the exposure is identified before
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the outcome, cohort studies provide a temporal framework
to assess causality. Causality can be further evaluated by
Hill’s criteria for causation, which includes parameters for
strength, consistency, specificity, temporality, biological
gradient, plausibility, coherence, experiment, and analogy.[12,13]
Nevertheless, a major limitation of cohort studies is the potential
for selection bias due to loss of follow‑up. Furthermore,
because subjects in a cohort study are not randomly allocated
to different interventions or other exposures, adjusted analysis
is usually necessary to control confounders. The design of
Figure 2: The study design of a case–control study.
Figure 3: The study design of a cohort study. COPD, chronic obstructive pulmonary disease; MI, myocardial infarction.
Dermatologica Sinica ¦ Volume 41 ¦ Issue 4 ¦ October-December 2023
a cohort study can be either prospective or retrospective,
depending on whether the data related to the exposure and the
outcome have already been collected.
Prospective cohort study
A prospective cohort study assembles participants and follows
them up. While this study design boasts superior accuracy in
data collection, it comes at the expense of reduced efficiency
due to its high cost and prolonged follow‑up period. As a result,
this study design is less suitable for investigating diseases
characterized by long latency periods and is susceptible to a
high rate of loss to follow‑up.
Example
After conducting a case–control study that established an
association between smoking and lung cancer, Sir Richard
Doll further launched the British Doctors’ Study, which tracked
a cohort of 34,439 male British doctors from 1951 to 2001.
This 50‑year prospective cohort study showed an increased
risk of mortality associated with neoplastic, respiratory, and
vascular diseases among smokers compared to nonsmokers.
These findings confirmed the causal effects of smoking on
lung cancer, thus providing crucial evidence to support the
detrimental health effects of smoking.[14‑20]
Retrospective (or historical) cohort study
A retrospective (or historical) cohort study identifies subjects
from past records and follows them from the time of those
records to the present. This study design offers the advantage
of reduced time and expense compared to prospective cohort
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 Chen and Chi: LOE and study designs
studies, owing to the immediate access to previously collected
data. However, the utilization of preexisting data that may be
incomplete or inaccurate impedes the investigators’ ability
to ensure data quality during collection and to mitigate
confounders and bias.
/Vda7SEXw52SzNkuAYA9HX/dDkLNRKffkwnZieKTaFmLvWzffg+WZd4Va4SIjdqyEP9EqgXFG9X3IZk2Dw5pXwMMzaHO31gjw4h7
Example
A nationwide cohort study conducted in Taiwan retrospectively
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evaluated the risk of incident uveitis among 147954 psoriatic
patients and an equal number of nonpsoriatic controls identified
in the National Health Insurance Research Database from 2000
to 2012. The study revealed that patients with severe psoriasis
and/or psoriatic arthritis exhibited a higher risk of incident
uveitis than nonpsoriatic controls.[21]
Level 2 evidence: Randomized controlled trial or
observational study with dramatic effect
Randomized controlled trial
A RCT is an interventional experimental study, in which two
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or more interventions, possibly including a control intervention
or no interventions, are compared by being randomly allocated
to participants [Figure 4]. Randomization balances known
and unknown confounders between the experimental and
control groups. Evidence from RCTs is more reliable than
those from other study designs. However, RCTs only serve as
approximations of real‑world clinical practice, hence why they
are called experiments. The inclusion and exclusion criteria
of RCTs may limit their external validity. In addition, some
research questions may be unsuitable for investigation through
randomization due to ethical considerations.
Example
In the VOYAGE 1 trial, a phase III, double‑blinded,
placebo‑  and active comparator‑controlled study, patients
diagnosed with moderate‑to‑severe psoriasis were randomized
into three groups: guselkumab, adalimumab, and placebo, and
were continuously treated for 1 year to evaluate the safety and
efficacy of guselkumab for the treatment of psoriasis. The study
findings demonstrated that guselkumab, an anti‑interleukin‑23
monoclonal antibody, was more effective than adalimumab,
a widely used tumor necrosis factor‑α inhibitor, with similar
Figure 4: The study design of a randomized controlled trial. EGFR-TKI, epidermal growth factor receptor-tyrosine kinase inhibitor.
202
safety profiles, as measured by both physician‑reported and
patient‑reported outcomes.[22]
Observational study with dramatic effect
Observational studies that are well‑designed and exhibit
dramatic effects, such as cohort studies with markedly high
or low hazard ratio, incidence rate ratio, or risk ratio, as well
as case–control studies with notably high or low odds ratio,
may also be classified as level 2 evidence.
Example
Based on a nationwide retrospective cohort study conducted
in Korea, current heavy smokers with more than 22.5
pack‑years of cigarette smoking had significantly higher
risks of developing lung cancer than never smokers. The risk
estimates were remarkably elevated, ranging from 11.1 to
13.5 times higher, varied according to gender and histological
type, including squamous cell carcinoma and small cell
carcinoma.[23]
Level 1 evidence: Systematic review of randomized
controlled trials or n‑of‑1 trials
Either n‑of‑1 trials or SRs and MAs of RCTs are regarded as
the highest LOE, as they can provide a more robust and reliable
conclusion than any individual study could offer.
Systematic review of randomized controlled trials
A SR is a rigorous and thorough examination of all relevant
studies on a specific topic, conducted using a systematic approach
that involves a comprehensive search, selection, critical appraisal,
and summary of the evidence to minimize biases and random
errors. A MA utilizes quantitative statistical analysis to combine
results from independent studies, aiming to produce a single
estimate of a treatment effect [Figure 5].[24] A SR may or may
not include a MA [Figure 6].
Example
A SR and MA of 16 RCTs involving 2076 patients with
moderate‑to‑severe hidradenitis suppurativa (HS) revealed
that among 9 biologics and 3 small‑molecule inhibitors which
have been tested for the treatment of HS, only adalimumab
and bimekizumab demonstrated significant improvement in
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Figure 5: The study design of a systematic review and meta‑analysis.
Figure 6: The differences between systematic review and meta‑analysis.
HS clinical response without an associated increase in serious
adverse events. Based on the findings of this latest SR and
MA, adalimumab and bimekizumab were recommended for
the management of moderate‑to‑severe HS when conventional
first‑line therapies with systemic antibiotics had proven
ineffective.[25]
n‑of‑1 trials
An n‑of‑1 trial is a type of RCT that assigns a sequence
of alternative treatment regimens to a single patient in a
randomized manner, followed by comparing the outcomes
of each regimen to determine the optimal treatment for the
individual patient.[26]
Example
While the results of RCTs and MAs provide valuable insights
into establishing and forecasting the average clinical response
to gabapentin on a population scale, they encompass a broad
spectrum of individual responses, which are inherently
challenging to predict. As a response to this challenge, a
series of n‑of‑1 trials was conducted within a hospital setting,
comparing gabapentin to placebo in patients suffering from
chronic neuropathic pain. The objective was to evaluate the
Dermatologica Sinica ¦ Volume 41 ¦ Issue 4 ¦ October-December 2023
efficacy of gabapentin at the individual level, and subsequently,
at the population level through a MA of completed trials. This
comprehensive study revealed that only 29% of participants
exhibited a positive response to gabapentin. The outcomes
of these individual trials had a substantial influence on the
subsequent posttrial prescribing practices of gabapentin for
individual patients.[27]
Discussion
The new evidence pyramid
The new evidence pyramid proposed in 2016 had two
modifications to the traditional pyramid. [28] The first
modification was to change the straight lines separating study
designs in the pyramid into wavy lines to reflect the Grading of
Recommendations Assessment, Development, and Evaluation
(GRADE) approach of downgrading and upgrading the quality
of evidence based on an assessment of the overall risk of bias,
inconsistency, indirectness, imprecision, publication bias,
effect size, dose–response relationship, and opposing plausible
residual confounding.[29,30] In other words, well‑designed and
conducted studies from a lower level of the pyramid may be
considered higher quality of evidence compared to poorly
designed studies from a higher level of the pyramid. The
second modification was to remove SRs and MAs from the
top of the pyramid and instead use them as a lens through
which evidence should be appraised and applied. This updated
pyramid enhanced the methodology of evaluating evidence and
aligned with contemporary best practices in evidence‑based
decision‑making.
Evidence‑based medicine research roadmap
The EBM research roadmap involves a structured
approach to guide the process of evidence‑based clinical
decision‑making. It commences with identifying and
203
 Chen and Chi: LOE and study designs
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Figure 7: The evidence‑based medicine research roadmap.
formulating pertinent questions from patient encounters
in clinical practice. Subsequently, a comprehensive and
updated SR is conducted to acquire the current best evidence.
Once we identify the knowledge gap between the existing
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evidence and clinical practice, we undertake new studies
with appropriate study designs depending on the types of
questions being addressed, such as diagnosis, prognosis,
screening, or treatment, to bridge the knowledge gap. With
sufficient evidence, clinical practice guidelines can be
established and ultimately applied to patients in clinical
practice. This approach ensures the incorporation of the
latest evidence into clinical decision‑making and enhances
patient care [Figure 7].
Conclusions
The LOE plays a pivotal role as a preliminary step in the
practice of EBM by ranking study designs based on their
inherent bias and validity. This ranking system enables
clinicians to acquire the best available evidence efficiently
during clinical decision‑making and aids researchers
in designing new studies to improve the quality of
existing evidence. However, the lower LOE should not
be overlooked or disregarded. Critical appraisal of the
certainty of evidence according to how well studies are
designed and implemented is more important than merely
the LOE. Well‑conducted studies at lower LOE are valuable
for generating hypotheses and serve as stepping stones for
higher LOE. Various LOE and study designs work in tandem
to ensure the incorporation of the current best evidence into
clinical practice.
Data availability statement
Data sharing not applicable to this article as no datasets were
generated or analyzed during the current study.
Financial support and sponsorship
Nil.
Conflicts of interest
Dr. Yen‑Ning Chen declared none. Prof. Ching‑Chi Chi, the
Editor‑in‑Chief of Dermatologica Sinica, had no role in the
peer review process of or decision to publish this article.
204
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