Foundation for Chiropractic
Education and Research
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Response to Meta-Analysis Published By Assendelft Et Al
Anthony L. Rosner, Ph.D., LL.D. (Hon.)
June 25, 2003
The recent meta-analysis by Assendelft et al., published in the
June 3, 2003 edition of the Annals of Internal Medicine 
is a troubling example of how clinical data is to be interpreted and
presented for public consumption and policy development. In addition to
raising numerous issues as to the clinical applicability of meta-analyses,
it may even belie its basic premises as will be pointed out below. In
reviewing this document, one must remain vigilant as to how the rowdy
qualities of human bias, subjectivity, and disagreement extend well into
the rarefied atmospheres of randomized clinical trials, meta-analyses, and
actual clinical guidelines.
The overall conclusion of this report—that there is no evidence that
spinal manipulation therapy is superior to either standard treatments for
patients with acute or chronic low back pain—can be interpreted in the
same breath to indicate that, in terms of the pain or disability outcomes
scales evaluated, it is neither inferior. Before one analyzes the
methodological issues of the report itself, one is entirely justified to
ask whether the treatments are truly equivalent.
1. Comparative Side Effects and Relative Safety:
For spinal manipulation, the occurrence of major complications
(regardless of the region of the spine manipulated) has generally been
shown to be less than one per million. [2-5] Even transient, minor
side-effects have been estimated to occur at 1 per 120,000 cervical
manipulations.  These figures pale when compared to an
extensive body of literature describing as many as 220,000 deaths and
other complications produced in the United States each year by medications
in general [7-14] or the 10,000-20,000 fatalities and multiple
organ systems adversely affected by NSAIDs. [15-23] Even what has
been regarded as the more relatively benign COX-2 inhibitors [24-27]
and acetaminophen medications  have been described to generate
serious GI, cardiovascular, and hepatic problems at rates orders of
magnitude greater than side-effects attributed to spinal manipulation. The
overall picture comparing spinal manipulation to the commonly used
treatment alternatives of either direct analgesic ingestion or visits to
the general practitioner (80% resulting in analgesic use by the authors’
own citation [1,29] ) should be one of relative clarity to the
patient: In one instance there is an option with a low rate of lasting
side-effects and in the other a treatment regimen with severe and
sometimes fatal complications that are inexplicably deemed to be
2. Mix of Clinical Judgment with Data from the Literature:
The authors strongly imply that this study is intended to be more
rigorous than the systematic reviews and meta-analyses that preceded it.
Yet their admission to the effect that the comparison of spinal
manipulative therapy with each different treatment alternative for each
outcome for each back pain stratum "was not possible because the data
were sparse" raises one’s suspicion that this particular review may
not have been as "systematic" as first presumed. These fears are
confirmed in the very next sentence which informs the reader that the
clinical judgment of effectiveness benchmarks from members of the
Cochrane Editorial Board was used to fill in the gaps of experimental
data, undermining the very process championed in this study. Indeed, the
noted epidemiologist David Sackett applauds the use of clinical expertise
as well as experimental outcomes data to build a truly effective evidence
base for optimum patient care,  a sentiment echoed elsewhere
as well.  But this undercuts the very process that the authors
suggest that they are undertaking in pursuit of the most definitive
experimental data available. In other words, how much adulteration of this
"systematic review" has taken place?
3. Inadmissible Criterion of Quality:
One of the criteria for methodologic quality of RCTs by the Cochrane
Group—the blinding of the care provider (V3)—is impossible in the
administration of manual therapy, particularly high-velocity spinal
manipulation. Accordingly, its inclusion by the authors as a determinant
of inclusion or rejection of RCTs is without justification. As many as 11
studies have erroneously reported double-blinding in the chiropractic
experimental literature; the nonfeasibility of blinding the practitioner
in numerous modalities of alternative medicine has been extensively
discussed elsewhere and needs to be duly noted. 
4. Guideline Rationale:
As part of their rationale for embarking upon this investigation,
Assendelft et al. bemoan the disparity of recommendations for spinal
manipulative therapy from different countries, citing in particular the
dissension expressed in the guidelines from Australia, Israel, and The
Netherlands. What the authors do not disclose is the preponderance of
support for spinal manipulation expressed in 8 out of a total of 11 such
guidelines, with perhaps an additional half thrown in for The Netherlands
(which found sufficient justification for treating acute but not chronic
back pain by spinal manipulation,  an oddity since van Tulder
[who is Dutch] decisively supported the chronic over the acute evidence in
a recent systematic review).  Furthermore, in the comparison
of guidelines cited by the authors, there was concordance among all
11 nations (United States, United Kingdom, The Netherlands, Israel, New
Zealand, Finland, Australia, Switzerland, Germany, Denmark, and Sweden) in
six aspects of healthcare: (i) diagnostic triage, history taking, and
physical examination; (ii) their conclusion that radiographs were not
useful for managing nonspecific low back pain; (iii) their recognition of
the importance of psychosocial factors; (iv) their discouragement of bed
rest; (v) certain stipulations regarding the prescription of medications;
and (vi) their concluding that the vast majority of low back pain cases
should be managed in a primary care setting. Other areas besides spinal
manipulation in which differences arose were (i) exercise therapy,
(ii) muscle relaxants, and (iii) patient information.
The reason this census of nations regarding guideline and medical
practices has been taken is to point out that the reported concordances
and discordances do not appear to correlate with the amount, design, and
quality of randomized clinical trials or systematic literature reviews
that have been published. Rather, there appear to be human and cultural
values at work here that I would maintain have not necessarily been
eliminated in the study currently under discussion. This leads directly to
our next point of critique.
5. Meta-Analyses Themselves Are Subject to Bias and Omissions:
Regarding their clinical relevance, the very basis of meta-analyses
(including the report of Assendelft et al.) has to be closely scrutinized.
One report has gone so far as to compare meta-analyses to statistical
alchemy, due to their intrinsic nature:
"...the removal and destruction of the scientific requirements
that have been so carefully developed and established during the 19th
and 20th centuries. In the mixtures formed for most statistical
meta-analyses, we lose or eliminate the elemental scientific
requirements for reproducibility and precision, for suitable
extrapolation, and even sometimes for fair comparison." 
Specifically, Feinstein raises the following deficiencies of meta-analyses, most having to do with the sloughing of
important clinical information:
i. Disparate groups of
patients of varying homogeneity across different studies are thrown
into one analysis, often called a "mixed salad";
ii. The weighting of
studies of different quality may be inaccurate or absent altogether;
iii. One needs to know
about the real-world effects in the presentation and treatment of
patients; in particular
(a) the severity of the illness,
(c) pertinent co-therapies, and
(d) clinically relevant and meaningful outcomes;
statistical techniques pertaining to increments, effect size,
correlation coefficients, and relative risk and odds ratios;
v. Omission of the
reference denominator; and
vi. The fact that the odds ratio inflates the
true value of the relative risk under certain conditions.
In any event, the numbers of patients needed to treat must be
reported in order to observe a true difference in treatment groups, a
practice often overlooked in meta-analyses.  To make matters
worse, a recent report involving four medical areas (cardiovascular
disease, infectious disease, pediatrics, and surgery) indicates that
individual quality measures were not reliably associated with the strength
of the treatment effect in 276 RCTs analyzed in 26 meta-analyses. 
The fact that arbitrariness and bias can not only creep into but
actually dominate in meta-analyses is both convincingly and
dramatically demonstrated in a recent publication in the Journal of the
American Medical Association. In their efforts to compare two
different preparations of heparin for their respective abilities to
prevent post-operative thrombosis, Juni and his colleagues have revealed
that diametrically opposing results can be obtained in different
meta-analyses, depending upon which of 25 scales is used to distinguish
between high- and low-quality RCTs. The root of the problem is evident
from the variability of weights given to three prominent features of RCTs
(randomization, blinding, and withdrawals) by the 25 studies which have
compared the two therapeutic agents. In one investigation, for example, a
third of the total weighting of the quality of the trial is afforded to
both randomization and blinding, whereas in another, none of the
quality scoring is derived from these two features. Widely skewed
intermediate values for the three aspects of RCTs under discussion are
apparent from the 23 other scales presented. The astute reader will
immediately suspect that sharply conflicting conclusions might be drawn
from these different studies—and these fears are amply borne out by the
forest plot presented in the study. Here each of the meta-analyses listed
resolve the studies they have reviewed into high- and low-quality strata,
based upon each of their scoring systems. It can be seen that ten of the
studies selected show a statistically superior effect of one heparin
preparation over the other, but only for the low-quality studies.
Seven other studies reveal precisely the opposite effect, in which
the high- but not the low-quality studies display a statistically
significant superiority of low-molecular weight heparin. Depending upon
which scale one uses, therefore, one can either demonstrate or refute the
clinical superiority of one clinical treatment over the other. In this
manner, therefore, all the rigor and labor-intensive elements of the RCT
and its interpretation by the meta-analysis are simply reduced to the
subjective and undoubtedly capricious human element of value judgment
through the arbitrary assignment of numbers in the weighting of
experimental quality.  Reduced to lay terms often used to
describe the limits of computer capabilities, one might summarize this
undertaking as an apt demonstration of the principle, "Garbage in,
6. Contradictions in Design:
There appear to be contradictions in the
design in the authors’ comparison of spinal manipulative therapy to 7
other treatment therapies (sham, conventional general practitioner,
analgesics, physical therapy, exercises, back school, or collection of
therapies judged to be ineffective or even harmful [traction, corset, bed
rest, home care, topical gel, no treatment, diathermy, or minimal
a. Conventional general
practitioner and analgesic use is considered to be synonymous,
based upon a single reference which suggests that 80% of visits to the
general practitioner result in a prescription for using an analgesic.
Why then, should analgesic use then be presented in the report as a
b. Physical therapy is stated to
include exercise in amounts up to 100%. Again, why should exercise
then be presented elsewhere as a separate intervention?
7. Contradictions in Evaluating Statistical and Clinical Significance:
One especially troubling situation arises with the authors’
interpretation of the forest plots comparing spinal manipulative and sham
therapies. In one instance (Figure 3), spinal manipulative therapy is
shown to have "clinically important" short-term improvements in
pain and disability; however, these differences are deemed to have
"failed to reach a conventional level of statistical
significance." In comparing spinal manipulative therapy to the group
of treatments deemed ineffective, however, we now find a statistically
significant advantage for the former intervention. It is perplexing indeed
to then find the authors stating that "the clinical significance
of this finding is questionable (italics mine)."  In
the very simplest of terms, one cannot have it both ways. It would almost
seem as if there were a deliberate effort to minimize a treatment effect
of potential interpret pertaining to spinal manipulation.
8. Data are Not Shown in Areas of Interest:
Given the aforementioned arbitrary characteristics of meta-analyses and
perhaps of the authors’ presentation as well, one has every reason to
wish for the opportunity to examine the data which support the authors’
contention that "our sensitivity analyses supported the robustness of
our results with respect to the type of manipulative therapy, profession
of the manipulator, and the quality of the studies included." 
However, none pertaining to these critical areas were presented in the
body of the paper. The issue is particularly important with regard to the
skill and training of the manipulator, who at times has been
misrepresented in the scientific literature. [39,40] It is
questionable how effectively the authors were able to draw comparisons of
different chiropractic techniques, as they overlooked the most recent and
arguably comprehensive attempts to do so from both the points of view of
clinical effectiveness  and a literature review. 
9. Clinical as Opposed to Fastidious Treatments:
Some treatments (traction, diathermy, minimal massage) have been deemed
by the authors to lack sufficient evidence for their effectiveness as
stand-alone applications, and as such have been rejected from
consideration in this investigation. What is not clear, however, is
whether they are effective in a synergistic manner as ancillary
treatments and whether they have been excluded as potentially helpful
adjuncts to manual therapy. This was alluded to in Feinstein’s
discussion of meta-analyses presented above (critique #5). 
10. Lack of Long-Term Followup:
Followups for back pain outcome assessments are limited in this study
to 6 months. However, numerous studies cite recurrences of low back pain
for up to 1 year. [43-45] This not only makes the definition of an
episode problematical,  but it demands that follow-up times
for at least a year be observed in order to assess a more durable and
perhaps economical treatment effect. Indeed, the longevity of treatment
effects of spinal manipulation in managing back pain for 12 months [47-49]
to 3 years  have been amply demonstrated. In comparison to
medications for the treatment of headaches, it has been shown to be
markedly superior. [51,52] As in several aforementioned areas of
this study, this particular aspect for comparing treatments might be
expected to diminish the actual capacity of spinal manipulation to display
its full benefits.
From a variety of perspectives, this meta-analyses appears to be both
flawed and to have either obscured or overlooked the maximal clinical
benefits that might be expected to have been conferred upon patients by
spinal manipulation, particularly as performed by a chiropractor. The
patient response to intervention is far more complex than the dimensions
offered by the authors in their discussion. Tonelli points out, for
example, that there will always be a region in which discrete differences
between individuals cannot be made explicit and quantified, called an
epistemological zone.  This degree of sophistication is best
summarized by Horwitz, who points out that to assume that the entire range
of clinical treatment in any modality has been successfully captured by
the precision of existing analytical methods in the scientific literature
"would be like saying that a medical librarian who has access to
systematic reviews, meta-analyses, Medline, and practice guidelines
provides the same quality of healthcare as an experienced physician." 
Hopefully, these shortcomings in the current meta-analyses can be
appreciated by the public and addressed more meaningfully in future
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