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LITERATURE REVIEW
L
prediction rules is an attempt to determine who will respond best to ow back pain (LBP) is a common and costly condi-
certain treatments. tion."'^ Effective interventions for LBP have, at best,
Methods. We conducted electronic searches of MEDLINE (1980- small to moderate effects, when averaged over popula-
2009), EMBASE (1980-2009), PsyclNFO (1980-2009), Allied and tions.^"^ The true potential value of these interventions might
Complementary Medicine (1980-2009), PubMed (1980-2009), have been underestimated because most trials encompass all
ISI Web of Knowledge (1980-2009), and the Cochrane Library people with non-specific LBP as a single group, assuming
(1980-2009). The reference lists of relevant articles were searched homogeneity.^""
for further references. The identification of subgroups is an important research
Results. We identified 1821 potential citations; 3 articles were priority.^''^''^ There is growing interest in the development and
included. The results from the available data do not support the use use of clinical prediction rules (CPRs) in the physical ther-
of clinical prediction rules in the management of non-specific LBP. 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
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; Clinical prediction rules are defined as:
íCentre for Primary Care and Public Health, Barts and The London School of
Medicine and Dentistry, Queen Mary University of London, London, United ... the process by which combinations of clinical
Kingdom; and §University College of Health Sciences, Campus Kristiania, findings that have been statistically demonstrated to
Oslo, Norway.
be meaningful predictors of a condition or outcome of
Acknowledgment date: May 9, 2012. First revision date: October 24, 2012.
Acceptance date: October 25, 2012. interest are used to categorize a heterogeneous group of
The manuscript submitted does not contain information about medical patients into subgroups based on a shared likelihood of
device(s)/drug(s). the presence of that condition or outcome.^
This project benefited from facilities funded through Birmingham Science City
Translational Medicine Clinical Research and infrastructure Trials platform, CPRs can be useful in determining prognosis, assessing the
with support from Advantage West Midlands. likelihood of the presence or absence of a condition, and to
Relevant financial activities outside the submitted work: consultancy, stock/ help classify patients into groups more likely to benefit from
stock options, travel/accommodations/meeting expenses. treatment. Strictly speaking the latter is not covered by the
Address correspondence and reprint requests to Shilpa Patel, University of definition given above, but for the purpose of this review we
Warwick, Clinical Trials Unit, Warwick Medical School, Gibbet Hill Road,
Coventry, CV4 7AL, West Midlands, United Kingdom; E-mail: shilpa.patel® take a wider view. They can help with screening patients to
warwick.ac.uk decide when further investigations are likely or unlikely to
DOI: 10.1097/BRS.ObOI 3e31827b158f yield meaningful findings.^'""
762 www.spinejournal.com April 2013
Spine LITERATURE REVIEW Systematic Review of RCTs • Patel et al
exploratory evidence. All other studies were classified as pro- a preplanned analysis of data from an attention-controlled
viding insufficient evidence (Table 2). trial of spinal manipulation therapy. After collection of base-
line data, participants were randomized to one of 4 groups.
RESULTS Participants were assessed on the 5 criteria to determine sta-
We identified 1821 citations for possible inclusion from bib- tus on the prediction rule. A researcher who was blinded to
liographic searches. We obtained 35 full texts for detailed allocation collected data on 2 of the 5 criteria, the treating
inspection. Following examination and discussion, 32 articles physiotherapist collected data on the remaining 3 criteria. The
were excluded, 27 articles were not validating the effects of authors conducted a 3-way interaction between a patient's
a prediction rule, 3 presented results from mixed samples, 1 status on the rule, treatment group, and time, which was not
study was not randomized, and 1 study recruited some partic- statistically significant at the 5% level. The authors concluded
ipants under the age of 18 years. Subsequently, 3 studies were no clinically worthwhile interaction effects between treatment
included in this systematic review (Table 1). Statistical pooling group and status on the rule for either pain or disability at any
of the data was not performed because of the small number time point.
of studies found as well as heterogeneity in the interventions
applied, outcome measures collected, and populations from Critique of Included Articles
which samples were drawn. Brennan et aP^ adopted a pragmatic approach to treatment
Brennan et aP^ reported a 3-armed trial of manipulation, progression, patients moved to the second subacute stage if
stabilization, and exercise. The CPR used was on the basis they achieved a predefined reduction in their Oswestry Dis-
of work by Fritz et al?^ They examined the inter-rater reli- ability Index score. For these patients the therapist could
ability of individual examination items for a classification select only those treatments permitted based on the patient's
decision-making algorithm. At baseline history and physical original treatment group. Therapists were permitted to use
examination, data were collected before randomizing patients their own clinical judgment to determine exercise dosage for
to one of the 3 treatments. After completion of the study, the individual patients. Although this is more representative of
baseline signs and symptoms were used by 2 physical thera- normal clinical practice, it is difficult to determine confound-
pists to decide which subgroup the patient fitted and a third ing factors that may have an effect on response to treatment.
therapist was consulted if agreement could not be reached. Statistically, comparing those that are classified as matched
Patients were then classified as "matched" (if they received with those that are unmatched is likely to produce larger
the treatment that matched their subgroup classification) or effects than if comparing those randomized with the different
"unmatched" (if they received a treatment different to their treatments because some participants will receive the correct
subgroup classification). The results were analyzed using a treatment by chance. A closer inspection reveals that the sta-
3-way interaction between randomized treatment, classifi- tistical analysis used by Brennan seems not to have included
cation, and time that was found to be significant, whereas a test for an interaction between all subgroups and treatment,
both the 2-way interaction between randomized treatment making it difficult to conclude which subgroup of patients
and time and that between classification subgroup and time would respond best to which treatment. In addition quality
were not statistically significant. The authors reported greater assessment of this article provided inconclusive evidence.
change in the Oswestry Disability Questionnaire for matched In the analysis conducted by Childs et al,^'* the authors do
subjects than unmatched both at 4-week and 1-year follow- test for a 3-way interaction between CPR, treatment group,
up. and time and concluded a positive effective for the CPR.
Childs etaV^ used a CPR in a 2-arm trial of spinal manipu- However, the CPR has been criticized as comprising of items
lation and exercise. The rule had previously been developed in that would ordinarily be associated with a favorable prog-
a prospective cohort study with a small sample of participants nosis,^^'^^ which challenges the usefulness of such a rule in
from an army medical center.'^ The prediction rule identified clinical practice. Despite their positive result we think that the
patients with LBP who had a good prognosis when treated methods used to develop this rule are not robust and the items
with spinal manipulation, based on 5 clinical factors. Data on included in the rule select those that would get better ordinar-
these 5 factors were collected at baseline by a physica! therapist ily. The quality assessment of this article provided inconclu-
blind to the participant's treatment group. Those participants sive evidence.
who met 4 or more of the 5 criteria were classified as posi- Hancock etal,^"^ when independently assessing the findings
tive and therefore likely to respond to manipulation. Those reported by Childs et al,^'* found no significant interactions
classified with 3 or fewer positive criteria were classified as between the treatment group and status on the rule for either
negative. The authors tested for a 3-way interaction between pain or disability. They found that a positive status on the rule
patients' status on the rule, treatment group, and time. The predicted better prognosis regardless of treatment received for
authors concluded that those positive on the prediction rule pain and disability at 2 and 12 weeks. Importantly, because
that received a form of lumbosacral spinal manipulation had Hancock et aP'* did not find a difference between interven-
the greatest treatment benefit at 4- and 6-month follow-up. tion and control treatments, it would be unlikely that there
Hancock etaP"^ evaluated the spinal manipulation rule used would be an important interaction between CPR and treat-
by Childs et aV^ to assess generalizibility of setting and sample ment group unless it was hypothesized the intervention was
of patients receiving spinal manipulation. They carried out harmful for at least some individuals. These results do not
764 www.spinejournal.com 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
o and application of spinal manipulation, the setting, and the
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— O reported baseline pain and disability scores between the spi-
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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.
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+
TABLE 2. fiinmTïTMîf!5sÎ](SïEffiï?OÎ?lMh^
Question Brennan Childs Hancock
1. Was the subgroup analysis specified a prioril Yes Yes Preplanned secondary analysis
2. Was the selection of subgroup factors for analysis Yes—based on work Yes—based on work Yes—independent evaluation of
theory/evidence driven? by Fritz et aP^ by Flynn ei a/'^ work by Childs et al" whose
rule was based on Flynn et aF
3. Were subgroup factors measured prior to Yes Yes Yes
randomization?
positive on the CPR, therefore not allowing for the rule to be Studies have been of high quality,^^ our review, as well as pre-
validated appropriately. vious reviews, have found the quality of validation studies to
Kent et al'*° conclude that treatments targeted to subgroups have been poor.^*'^^
may be effective; however, the results of the studies need to be In a perspective article, Hancock et ap^ make a number of
interpreted with caution. In their review they include a trial by useful suggestions for future work on predictors of response
Long et al,''^ which we have excluded from our review because to treatment which could also be applied to validation of a
the authors include patients only with a directional preference CPR. Alternatively, a CPR could be validated as the interven-
and exclude those without, therefore not allowing the clini- tion in a RCT. Any such trials are likely to need very large
cal prediction rule to be tested appropriately. The discussions numbers of subjects. The effect size for main treatment effects '
within the review by Kent et a/" focus on the effect sizes of the in current positive LBP pain trials are typically small to mod-
included trials and significance of this. In our article we focus erate. Any interaction effect is unlikely to be greater than the
on the authors ability to test a clinical prediction rule effec- main treatment effect; indeed if it was, it would suggest that
tively in a RCT. We present a methodological and statistical for a substantial group of people the intervention was likely
critique, different than that presented by Kent et a/." to have no positive effect or for an identifiable group to make
The development of the CPRs tested in these studies lacked their condition worse. Thus, as a rule of thumb, trials at least
methodological rigor.^^ It remains unclear as to which candi- 4 times the size of current large trials of LBP treatments; per-
date domains should be included in. a prediction rule for LBP. haps 2000 to 3000 participants will be needed to validate
It seems that identification of such domains, or indeed con- CPRs satisfactorily.''^
cluding that such domains cannot be identified will require Ideally, it would be better to have CPRs that can be applied
a substantial study with an a priori design. To develop a to a varied range of clinical décisions, but this is unlikely.
rule that enables clinicians to choose between interventions, CPRs would be useful in LBP as the treatment effects cur-
the developmental work of derivation and validation needs to rently seen in populations remain small; this is probably, at
be thoroughly designed and systematically validated. least in part, due to the heterogeneity of the un-subgrouped
The methodology for quality assessing studies of CPRs back pain population. In the physical therapy literature there
is poorly developed. We used a tool developed for a differ- are currently 10 prediction rule derivation studies that have
ent study of moderators.^' Based on these criteria only one not been validated.^* Notwithstanding this, authors continue
of the included studies provides exploratory evidence, none to cite the effective management of LBP using CPR.''^''*''
fall within the remit of confirmatory evidence (Table 2). The There is a need for future well-designed validation studies
focus of this review was to critique the statistical methods of these rules to enable better matching of patients to treat-
used for the testing of a CPR. Therefore, we did not provide ment that in turn may lead to better patient outcomes and
any extensive data on the quality of the underpinning trial. less health care usage and thus cost to the health care system.
If we had found an apparently robust evaluation of a CPR The task of developing, validating, and testing such CPRs
on which changes in clinical practice might be based, then it should not be underestimated. It is difficult to justify the very
would be very important to know the quality of the trials by large cost entailed in taking one CPR through full testing
conventional measures. to inform just one treatment choice, therefore our research
At present, we do not know if the disappointing perfor- efforts and our funders' resources may be better directed in
mance of CPRs in RCTs is because inappropriate rules have alternative directions. However, we warn against the applica-
been tested, the trials have been poorly designed, underpow- tion of CPRs without sufficient evidence because patients in
ered, or indeed whether it is impossible to develop CPRs need of treatment may be denied treatments that they might
that are fit for this purpose. Although most of the derivation have benefited from.
Spine
www.spinejournal.com 767
Spine LITERATURE REVIEW Systematic Review of RCTs • Patel et al
39. Cleland JA, Fritz JM, Kulig K, et al. Comparison of the effective- 42. Brookes ST, Whitley E, Peters TJ, et al. Subgroup analyses in ran-
ness of three manual physical therapy techniques in a subgroup of domised controlled trials: quantifying the risks of false-positives
patients with low back pain who satisfy a clinical prediction rule. A and false-negatives. Health Technol Assess 2001;5:l-56.
randomized clinical trial. Spine 2009;34:2720-9. 43. Bialosky JE, Bishop MD, Robinson ME, et al. Spinal manipulative
40. Kent P, MJ0sund HL, Petersen DH. Does targeting manual therapy therapy has an immediate effect on thermal pain sensitivity in peo-
and/or exercise improve patient outcomes in non-specific low back ple with low back pain: a randomized controlled trial. Phys Ther
pain.' A systematic review. BMC Med 2010;8:22. 2009;89:1292-303.
41. Long A, Donelson R, Fung T. Does it matter which exercise? A 44. George SZ, Zeppieri G Jr, Cere AL, et al. A randomized trial of
randomized control trial of exercise for low back pain. Spine behavioral physical therapy interventions for acute and sub-acute
2004;29:2593-602. low back pain (NCT00373867). Pain 2008;140:145-57.