SPINE Volume 38, Number 9, pp 762-769
Spine
LITERATURE REVIEW
Systematic Review of Randomized Controlled
Trials of Clinical Prediction Rules for Physical
Therapy in Low Back Pain
Shilpa Patel, C. Psychol/Tim Friede, PhD,t Robert Froud, PhD,i§ David W. Evans, PhD,* and
Martin Underwood, MD*
Study Design. Systematic review.
Objective. To evaluate randomized controlled trials validating the
effects of a clinical prediction rulefor patients with non-specific low
back pain (LBP). The outcomes of interest were any back pain or
pain-related measures.
Summary of Background Data. LBP is a common and costly
condition. Interventions for back pain seem to have, at best, small to
moderate mean beneficial effects. Identifying subgroups of patients
who may respond better to certain treatments may help to improve
clinical outcomes in back pain. The development of clinical
prediction rules is an attempt to determine who will respond best to
certain treatments.
Methods. We conducted electronic searches of MEDLINE (1980-
2009), EMBASE (1980-2009), PsyclNFO (1980-2009), Allied and
Complementary Medicine (1980-2009), PubMed (1980-2009),
ISI Web of Knowledge (1980-2009), and the Cochrane Library
(1980-2009). The reference lists of relevant articles were searched
for further references.
Results. We identified 1821 potential citations; 3 articles were
included. The results from the available data do not support the use
of clinical prediction rules in the management of non-specific LBP.
From the *University of Warwick, Warwick Clinical Trials Unit, Warwick
Medical School, Coventry, United Kingdom; tDepartment of Medical
Statistics, University Medical Centre Cöttingen, Cöttingen, Germany;
íCentre for Primary Care and Public Health, Barts and The London School of
Medicine and Dentistry, Queen Mary University of London, London, United
Kingdom; and §University College of Health Sciences, Campus Kristiania,
Oslo, Norway.
Acknowledgment date: May 9, 2012. First revision date: October 24, 2012.
Acceptance date: October 25, 2012.
The manuscript submitted does not contain information about medical
device(s)/drug(s).
This project benefited from facilities funded through Birmingham Science City
Translational Medicine Clinical Research and infrastructure Trials platform,
with support from Advantage West Midlands.
Relevant financial activities outside the submitted work: consultancy, stock/
stock options, travel/accommodations/meeting expenses.
Address correspondence and reprint requests to Shilpa Patel, University of
Warwick, Clinical Trials Unit, Warwick Medical School, Gibbet Hill Road,
Coventry, CV4 7AL, West Midlands, United Kingdom; E-mail: shilpa.patel®
warwick.ac.uk
DOI: 10.1097/BRS.ObOI 3e31827b158f
762 www.spinejournal.com
©2013, Lippincott Williams & Wilkins
Conclusion. There isa lackofgood quality randomized controlled
trials validating the effects of a clinical prediction rule for LBP
Furthermore, there is no agreement on appropriate methodology
for the validation and impact analysis. The evidence for, and
development of, the existing prediction rules is generally weak.
Key words: clinical prediction rules, back pain, subgroups,
predictors of response to treatment, systematic review. Spine
2013;38:762-769
Level of Evidence: 1
L
ow back pain (LBP) is a common and costly condi-
tion."'^ Effective interventions for LBP have, at best,
small to moderate effects, when averaged over popula-
tions.^"^ The true potential value of these interventions might
have been underestimated because most trials encompass all
people with non-specific LBP as a single group, assuming
homogeneity.^""
The identification of subgroups is an important research
priority.^''^''^ There is growing interest in the development and
use of clinical prediction rules (CPRs) in the physical ther-
apy literature, where focus has been on using such rules to
determine who will best respond to a given intervention.'**"'*
It is likely that outcomes will be improved if subgroups of
patients with LBP could be identified and better matched to
Clinical prediction rules are defined as:
... the process by which combinations of clinical
findings that have been statistically demonstrated to
be meaningful predictors of a condition or outcome of
interest are used to categorize a heterogeneous group of
patients into subgroups based on a shared likelihood of
the presence of that condition or outcome.^
CPRs can be useful in determining prognosis, assessing the
likelihood of the presence or absence of a condition, and to
help classify patients into groups more likely to benefit from
treatment. Strictly speaking the latter is not covered by the
definition given above, but for the purpose of this review we
take a wider view. They can help with screening patients to
decide when further investigations are likely or unlikely to
yield meaningful findings.^'""
April 2013
Spine LITERATURE REVIEW Systematic Review of RCTs • Patel et al

Developing a CPR should be a 3-step process of deriva- Electronic searches in MEDLINE,

tion, validation, and impact analysis.^"*"^* During the deriva- EMBASE, PsycINFO, AMED,
tion stage, it is important to identify known individual predic- PubMed, ISI Web of
tors of response to treatment. For validation, external validity Knowledge and the Cochrane
Library (1980-2009)
should be examined by applying the rule to different settings,
patients, and clinicians before generalizing.^*"^^ Unfortunately,
validation studies are rarely reported in the literature.-^* If
these tools are well-designed and validated in appropriate N=2853 citations identified
populations, they will have the potential to identify those from electronic searches
patients most likely to benefit from a particular treatment,
which in turn will help improve clinical decision making and N=1032 duplicates removed
practice.^' There is currently considerable interest in review-
ing the literature on CPRs for back pain. This largely focuses N= 1821 titles and abstracts
on synthesizing the outcomes of the original studies. If, how- screened independently by two
ever, the underpinning research methods used are not robust, reviewers
little weight can be given to the conclusions. Here, we report N=1786 citations excluded
a systematic review evaluating validation studies of CPRs for based on titles and abstracts
patients with LBP using randomized controlled trials (RCTs).
Our outcomes of interest were any back pain or pain-related N=35 full texts obtained for
measures. We provide a methodological and statistical cri- detailed evaluation N=32 papers excluded after
tique of the included articles, different to articles already pub- full review (27 not
validating a CPR; 3 mixed
lished in this area. patient populations; 1 not
RCT; 1 patient not all over
MATERIALS AND METHODS N=3 papers included in the 18 yr
systematic review
Inclusion Criteria Figure 1. Describes the study selection process for the systematic
We included RCTs that vaUdated the effects of a CPR. We review.
defined a CPR as any clinical tool with various components
drawn from the history, examination, and laboratory tests
used to inform treatment choices. We included studies of the management of LBP were assessed for inclusion in this
non-specific LBP, that is, we excluded studies concerned with review.
30

diagnosis and management of malignancy, infection, fracture,

or inflammatory disorders (e.g., ankylosing spondylitis). Tri-
als were of interventions to treat LBP of any duration with
outcomes of pain, disabiÜty, and psychological distress. The
age of participants in trials was restricted to adults (18 yr
or older). Only articles published in English were included.
Studies described as RCTs that did not allow the performance
of the CPR to be assessed using random allocation were
excluded. We excluded studies of surgical techniques and der-
ivation studies (studies prospectively examining the predictive
ability of selected variables for a CPR).
Search Strategy
We searched the following electronic databases from 1980 to
2009: MEDLINE, EMBASE, PsycINFO, AMED, PubMed,
ISI Web of Knowledge, and the Cochrane Library. We used
MeSH (Medical Subject Heading) terms to identify articles
containing material relevant to "back pain" and "low back
pain." We combined these using Boolean operators with key-
word terms "subgroup" or "subgroups" or "classification"
or "criteria" or "diagnostic criteria" or "rule" or "rules"
or "decision rules" or "prediction rule" or "clinical predic-
tors." Databases were limited to RCTs. We also searched
reference lists of relevant articles for further citations. The
validation studies included in a recent review of CPRs for
Inclusion Process
Two reviewers independently reviewed titles and abstracts
of citations identified from the electronic searches (Eigure 1).
We found that the inter-observer rehability for screening titles
and abstracts was poor; we therefore used a third reviewer
to screen all titles and abstracts. The third reviewer screened
the titles and abstracts and developed a list of the potentially
included articles. These were compared with those selected
by reviewers 1 and 2. Those that matched were included and
those that did not were discussed by all 3 reviewers to reach
a consensus. The agreed upon full articles were obtained and
reviewed by 2 reviewers. SP and RE independently extracted
data and assessed the quality of each article. We extracted
data on the derivation and composition of the CPR tested, the
treatments being compared, and the study design (Table 1).
All disagreements over data extraction and quality assessment
were resolved by means of discussion.
Quality Assessment
We used the Pincus^' quality assessment tool for studies of
treatment moderators. Each study was assessed for quahty
independently by 2 reviewers. Studies that met all 5 criteria
were classified as providing confirmatory evidence, those
complying with criteria 3,4, and 5 were classified as providing

Spine www.spinejournal.com 763

Spine LITERATURE REVIEW
exploratory evidence. All other studies were classified as pro-
viding insufficient evidence (Table 2).
RESULTS
We identified 1821 citations for possible inclusion from bib-
liographic searches. We obtained 35 full texts for detailed
inspection. Following examination and discussion, 32 articles
were excluded, 27 articles were not validating the effects of
a prediction rule, 3 presented results from mixed samples, 1
study was not randomized, and 1 study recruited some partic-
ipants under the age of 18 years. Subsequently, 3 studies were
included in this systematic review (Table 1). Statistical pooling
of the data was not performed because of the small number
of studies found as well as heterogeneity in the interventions
applied, outcome measures collected, and populations from
which samples were drawn.
Brennan et aP^ reported a 3-armed trial of manipulation,
stabilization, and exercise. The CPR used was on the basis
of work by Fritz et al?^ They examined the inter-rater reli-
ability of individual examination items for a classification
decision-making algorithm. At baseline history and physical
examination, data were collected before randomizing patients
to one of the 3 treatments. After completion of the study, the
baseline signs and symptoms were used by 2 physical thera-
pists to decide which subgroup the patient fitted and a third
therapist was consulted if agreement could not be reached.
Patients were then classified as "matched" (if they received
the treatment that matched their subgroup classification) or
"unmatched" (if they received a treatment different to their
subgroup classification). The results were analyzed using a
3-way interaction between randomized treatment, classifi-
cation, and time that was found to be significant, whereas
both the 2-way interaction between randomized treatment
and time and that between classification subgroup and time
were not statistically significant. The authors reported greater
change in the Oswestry Disability Questionnaire for matched
subjects than unmatched both at 4-week and 1-year follow-
up.
Childs etaV^ used a CPR in a 2-arm trial of spinal manipu-
lation and exercise. The rule had previously been developed in
a prospective cohort study with a small sample of participants
from an army medical center.'^ The prediction rule identified
patients with LBP who had a good prognosis when treated
with spinal manipulation, based on 5 clinical factors. Data on
these 5 factors were collected at baseline by a physica! therapist
blind to the participant's treatment group. Those participants
who met 4 or more of the 5 criteria were classified as posi-
tive and therefore likely to respond to manipulation. Those
classified with 3 or fewer positive criteria were classified as
negative. The authors tested for a 3-way interaction between
patients' status on the rule, treatment group, and time. The
authors concluded that those positive on the prediction rule
that received a form of lumbosacral spinal manipulation had
the greatest treatment benefit at 4- and 6-month follow-up.
Hancock etaP"^ evaluated the spinal manipulation rule used
by Childs et aV^ to assess generalizibility of setting and sample
of patients receiving spinal manipulation. They carried out
764 www.spinejournal.com
Systematic Review of RCTs • Patel et a\
a preplanned analysis of data from an attention-controlled
trial of spinal manipulation therapy. After collection of base-
line data, participants were randomized to one of 4 groups.
Participants were assessed on the 5 criteria to determine sta-
tus on the prediction rule. A researcher who was blinded to
allocation collected data on 2 of the 5 criteria, the treating
physiotherapist collected data on the remaining 3 criteria. The
authors conducted a 3-way interaction between a patient's
status on the rule, treatment group, and time, which was not
statistically significant at the 5% level. The authors concluded
no clinically worthwhile interaction effects between treatment
group and status on the rule for either pain or disability at any
time point.
Critique of Included Articles
Brennan et aP^ adopted a pragmatic approach to treatment
progression, patients moved to the second subacute stage if
they achieved a predefined reduction in their Oswestry Dis-
ability Index score. For these patients the therapist could
select only those treatments permitted based on the patient's
original treatment group. Therapists were permitted to use
their own clinical judgment to determine exercise dosage for
individual patients. Although this is more representative of
normal clinical practice, it is difficult to determine confound-
ing factors that may have an effect on response to treatment.
Statistically, comparing those that are classified as matched
with those that are unmatched is likely to produce larger
effects than if comparing those randomized with the different
treatments because some participants will receive the correct
treatment by chance. A closer inspection reveals that the sta-
tistical analysis used by Brennan seems not to have included
a test for an interaction between all subgroups and treatment,
making it difficult to conclude which subgroup of patients
would respond best to which treatment. In addition quality
assessment of this article provided inconclusive evidence.
In the analysis conducted by Childs et al,^'* the authors do
test for a 3-way interaction between CPR, treatment group,
and time and concluded a positive effective for the CPR.
However, the CPR has been criticized as comprising of items
that would ordinarily be associated with a favorable prog-
nosis,^^'^^ which challenges the usefulness of such a rule in
clinical practice. Despite their positive result we think that the
methods used to develop this rule are not robust and the items
included in the rule select those that would get better ordinar-
ily. The quality assessment of this article provided inconclu-
sive evidence.
Hancock etal,^"^ when independently assessing the findings
reported by Childs et al,^'* found no significant interactions
between the treatment group and status on the rule for either
pain or disability. They found that a positive status on the rule
predicted better prognosis regardless of treatment received for
pain and disability at 2 and 12 weeks. Importantly, because
Hancock et aP'* did not find a difference between interven-
tion and control treatments, it would be unlikely that there
would be an important interaction between CPR and treat-
ment group unless it was hypothesized the intervention was
harmful for at least some individuals. These results do not
April 2013
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765
Systematic Review of RCTs • Patel et al
Spine LITERATURE REVIEW Systematic Review of RCTs • Patel et al

support the wider use of the Childs rule and we agree that
this conclusion is supported by the analysis of results from"
the Hancock trial.
The differences in findings between Hancock et aP'^ and
Childs etfl/'**can be attributed to a variation on the type
c
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nal manipulation groups and placebo group, and these were
small and not statistically significant. Therefore, testing for an
O interaction effect may be misleading. This was the only trial
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providing exploratory evidence.

DISCUSSION
rt 3 In this review, we focused on evaluating validation studies of
0) ^ CPRs for LBP using RCTs. We have therefore not included
¿¿3 0 studies looking specifically at the derivation of rules. Two
systematic reviews, published after we had completed our
review, support our conclusions. The first, examined the
validity of CPRs and concluded that derivation studies were
O mainly of high quality, whereas the cross-sectional validation
studies were weak, limiting application of the rules in clinical
• •5 3 practice.^^ The second, a more recent review of CPRs for the
management of LBP conclude the current evidence does not
support the clinical application of these rules.^'* Our findings
add to this work by demonstrating that the evidence from ran-
rt domized trials validating CPRs for non-specific LBP is weak.
C Only 3 articles met our inclusion criteria, 2 of which were
small studies with a total sample of less than 150 patients.
In all cases, the prediction rule had been developed in small
5 o -o selected populations compromising external validity. Even the
•£ eo'îâ largest of these studies {Hancock et al^^^ n = 239) is likely
j i CÛ
to be too small to validate a CPR adequately, and thus their
negative findings are unlikely to be robust due to the possibil-
c ity of type II error; indeed one of the challenges to performing
c o interaction tests is having adequate statistical power.
•O ro '
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After completing the work for this review, the results of

0 TD -= s the STarT back trial,'a well conducted RCT of subgrouping
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2Í5 E u (N > ro u 1— u a positive result, were published.^^ This trial would not have
+

met our inclusion criteria as the actual subgrouping too! was

not being tested but rather the targeted treatments were being
tested. To test the targeting tool the trial design would need,
to randomize patients to receive the "tool" versus "no tool,"
with those receiving the tool being allocated to treatment and
those without being randomly assigned to treatment. This
tí trial design would allow for the statistical comparison of tool
rt Ö
DO C versus no tool, giving a better indication of the tools ability to
C O
subgroup patients to targeted treatments.
A systematic review by Haskins et aP^ excluded the anicle
by Brennan et al,^^ in which a classification approach was
used. We have included this article in our review as we have
used a slightly different definition of CPRs that allows trials
using classification and categorization to be included. We have
excluded the article by Cleland'ei al,^^ which was included in
this recent review because the authors only included patients
766 www.spinejournal.com April 2013
Spine LITERATURE REVIEW
TABLE 2. fiinmTïTMîf!5sÎ](SïEffiï?OÎ?lMh^
Question Brennan
1. Was the subgroup analysis specified a prioril Yes
2. Was the selection of subgroup factors for analysis Yes—based on work
theory/evidence driven? by Fritz et aP^
3. Were subgroup factors measured prior to Yes
randomization?
4. Were subgroup factors measured by adequate Yes
(reliable and valid) measurements, appropriate
for the target population?
5. Does the analysis contain an explicit test of the No
interaction between moderator and treatment?
positive on the CPR, therefore not allowing for the rule to be
validated appropriately.
Kent et al'*° conclude that treatments targeted to subgroups
may be effective; however, the results of the studies need to be
interpreted with caution. In their review they include a trial by
Long et al,''^ which we have excluded from our review because
the authors include patients only with a directional preference
and exclude those without, therefore not allowing the clini-
cal prediction rule to be tested appropriately. The discussions
within the review by Kent et a/" focus on the effect sizes of the
included trials and significance of this. In our article we focus
on the authors ability to test a clinical prediction rule effec-
tively in a RCT. We present a methodological and statistical
critique, different than that presented by Kent et a/."
The development of the CPRs tested in these studies lacked
methodological rigor.^^ It remains unclear as to which candi-
date domains should be included in. a prediction rule for LBP.
It seems that identification of such domains, or indeed con-
cluding that such domains cannot be identified will require
a substantial study with an a priori design. To develop a
rule that enables clinicians to choose between interventions,
the developmental work of derivation and validation needs to
be thoroughly designed and systematically validated.
The methodology for quality assessing studies of CPRs
is poorly developed. We used a tool developed for a differ-
ent study of moderators.^' Based on these criteria only one
of the included studies provides exploratory evidence, none
fall within the remit of confirmatory evidence (Table 2). The
focus of this review was to critique the statistical methods
used for the testing of a CPR. Therefore, we did not provide
any extensive data on the quality of the underpinning trial.
If we had found an apparently robust evaluation of a CPR
on which changes in clinical practice might be based, then it
would be very important to know the quality of the trials by
conventional measures.
At present, we do not know if the disappointing perfor-
mance of CPRs in RCTs is because inappropriate rules have
been tested, the trials have been poorly designed, underpow-
ered, or indeed whether it is impossible to develop CPRs
that are fit for this purpose. Although most of the derivation
Spine
Systematic Review of RCTs • Patel et al
Childs Hancock
Yes Preplanned secondary analysis
Yes—based on work Yes—independent evaluation of
by Flynn ei a/'^ work by Childs et al" whose
rule was based on Flynn et aF
Yes Yes
Yes Yes
No • .Yes
Studies have been of high quality,^^ our review, as well as pre-
vious reviews, have found the quality of validation studies to
have been poor.^*'^^
In a perspective article, Hancock et ap^ make a number of
useful suggestions for future work on predictors of response
to treatment which could also be applied to validation of a
CPR. Alternatively, a CPR could be validated as the interven-
tion in a RCT. Any such trials are likely to need very large
numbers of subjects. The effect size for main treatment effects '
in current positive LBP pain trials are typically small to mod-
erate. Any interaction effect is unlikely to be greater than the
main treatment effect; indeed if it was, it would suggest that
for a substantial group of people the intervention was likely
to have no positive effect or for an identifiable group to make
their condition worse. Thus, as a rule of thumb, trials at least
4 times the size of current large trials of LBP treatments; per-
haps 2000 to 3000 participants will be needed to validate
CPRs satisfactorily.''^
Ideally, it would be better to have CPRs that can be applied
to a varied range of clinical décisions, but this is unlikely.
CPRs would be useful in LBP as the treatment effects cur-
rently seen in populations remain small; this is probably, at
least in part, due to the heterogeneity of the un-subgrouped
back pain population. In the physical therapy literature there
are currently 10 prediction rule derivation studies that have
not been validated.^* Notwithstanding this, authors continue
to cite the effective management of LBP using CPR.''^''*''
There is a need for future well-designed validation studies
of these rules to enable better matching of patients to treat-
ment that in turn may lead to better patient outcomes and
less health care usage and thus cost to the health care system.
The task of developing, validating, and testing such CPRs
should not be underestimated. It is difficult to justify the very
large cost entailed in taking one CPR through full testing
to inform just one treatment choice, therefore our research
efforts and our funders' resources may be better directed in
alternative directions. However, we warn against the applica-
tion of CPRs without sufficient evidence because patients in
need of treatment may be denied treatments that they might
have benefited from.
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Spine LITERATURE REVIEW
Key Points
Q Identifying subgroups of patients with LBP who can
be better matched to treatments might help to im-
prove clinical outcomes.
• The existing evidence for CPRs is weak. Despite this,
prediction rules are still being promoted in the physi-
cal therapy literature.
Q There is a need for well-designed validation studies
of CPRs to enable progression to clinical implementa-
tion.
Acknowledgment
The authors thank Professor Sallie Lamb for her contribution
in the early stage of this review.
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