Thank you for commenting on our article and pointing out the short
hand statement "consented"
Thank you for your comments and with your permission I will use them
as a teaching peice for my students.
Yours
Kwame McKenzie
Conflict of Interest:
author of the article
Peter GSainsbury
16 February, 2012
I enjoyed reading about this well conducted study that produced
interesting results. I do, however, wish to comment on one sentence:
[The participants] were then approached face to face by the
researchers and consented.
While I realise that word limits encourage authors to be parsimonious
and make stylistic compromises, to state that research participants are
'consented' is to imply that they are passiv...
I enjoyed reading about this well conducted study that produced
interesting results. I do, however, wish to comment on one sentence:
[The participants] were then approached face to face by the
researchers and consented.
While I realise that word limits encourage authors to be parsimonious
and make stylistic compromises, to state that research participants are
'consented' is to imply that they are passive players in the act,
comparable perhaps to a patient being dressed (by a nurse) rather than a
patient dressing herself. Providing informed consent to participation in a
research project is an important aspect of the ethical conduct of research
and there are now well established processes to ensure that this occurs
properly. Crucially, there are two components of this: the seeking of
consent by the researcher and the decision to give or withhold consent by
the potential participant. A person who agrees to take part in the
research actively provides their consent, they are not passively consented
by another. This is so important that, to avoid slipping into sloppy
practices or teaching young researchers bad habits, it is essential that
researchers express it properly when they report research, in writing and
speech.
I should say that I note that a little later in the article the
authors express the matter more appropriately.
We thank Mayo-Wilson and colleagues for their comments(1). They have
used our paper on the effect of vitamin A campaigns on mortality(2) not to
question the paper itself, but to repeat a previous discussion(3, 4) about
whether new trials of vitamin A supplementation (VAS) are needed to
optimise the vitamin A policy. This is clearly a very important
discussion.
We think that new trials are needed. We have found i...
We thank Mayo-Wilson and colleagues for their comments(1). They have
used our paper on the effect of vitamin A campaigns on mortality(2) not to
question the paper itself, but to repeat a previous discussion(3, 4) about
whether new trials of vitamin A supplementation (VAS) are needed to
optimise the vitamin A policy. This is clearly a very important
discussion.
We think that new trials are needed. We have found in several studies
- including the present(2) - that VAS may interact negatively with routine
vaccinations producing no overall benefit of VAS on child survival or a
negative effect in some subgroups, e.g. children who have received
diphtheria-tetanus-pertussis vaccine (DTP) as their most recent
vaccination(5-7). We have emphasised that the randomised trials of VAS
showing a beneficial effect - as summarised in a recent meta-analysis by
Mayo-Wilson and colleagues(8) are from the 1980s and early 1990s when
vaccination coverage was much lower(7) than today. More recent
observational studies(2, 5-7) and a few randomised trials(9, 10) have not
found a beneficial effect of VAS. This could be due to increasing DTP
coverage.
Mayo-Wilson and colleagues disagree(1). In their meta-analysis they
include 16 trials with 194,413 children. They conclude that vitamin A is
associated with a 24% reduction in overall mortality. In a sensitivity
analysis they also include a recent yet unpublished Indian trial (DEVTA)
of more than 1 mill children which showed no effect of vitamin A on
mortality(9). Including this trial they still find a 12% significant
reduction in overall mortality. They conclude that no further trials are
needed(1, 4, 8).
A 12% reduction in mortality is obviously important but the problem
is that by lumping inhomogeneous data, the authors discard the possibility
that the effect of VAS may have ceased to be beneficial and may be
negative in some situations(3).
Could the effect of VAS have ceased to be beneficial? Mayo-Wilson and
colleagues(1) assert as untrue our claim that the trials with a positive
effect are from the 1980s and early 1990s and that more recent data is not
supporting current policy: "In our analysis of mortality, we included 8
studies published after 1993. Two studies (reported in 1994 and 1995)
report no significant difference in mortality whilst six studies (reported
from 1994 to 2002) report larger than average reductions in mortality.
Contrary to what Fisker et al. imply, we also included the DEVTA trial in
an analysis of mortality, and the effect remained statistically and
clinically significant".
The 8 studies(11-20) published after 1993 (i.e. the time of the first
meta-analyses(21,22)) were all conducted before 1995: Dibley 1996 in 1989-
90(11), Barreto 1994 and Agarwal 1995 in 1990-91(12, 13), Pant 1996 in
1990-92(16), Venkatarao 1996 and Donnen 1998 in 1991-93(14, 15) and Benn
1997 in 1993-95(17). The last study (Chowdhury 2002)(18) had sub-studies
submitted by 1994(19) and 1995(20). Thus all trials were conducted in the
early 1990s. In contrast, DEVTA was conducted between 1999 and 2004(9). We
did not imply the DEVTA trial was not included in the analysis of
mortality but importantly that the trial was not included in the analysis
of a possible secular trend(3).
If DEVTA is included there is a significant secular trend; the 12%
significant reduction in overall mortality consists of 24% significant
reduction 15-25 years ago and an insignificant 4% reduction in the most
recent and largest trial ever(9). Hence, the data is compatible with the
notion that VAS was beneficial in the 1980s and early 1990s, but has
ceased to be beneficial. We have supported this notion with reference to a
VAS-placebo randomised trial conducted in Guinea-Bissau between 2007 and
2011 in which VAS had no effect on survival(10). The possibility of no
effect should be of real concern. Why waste millions and millions of
dollars on distributing 1.500.000.000 annual doses of VAS globally(23) if
it no longer has any effect on overall child survival?
Could the effect of vitamin A be negative in some situations? In 2003
we hypothesised that vitamin A amplifies the non-specific effect of
vaccines and that VAS therefore would be beneficial when given with
measles vaccine or BCG but potentially negative when given with DTP(24).
It is this hypothesis which we have pursued and found supported in the
present paper(2), in the Ghana VAST reanalysis(7), in observational
studies of campaign VAS co-delivered with vaccines(5) and in trials of
neonatal VAS(6, 25). We have repeatedly found that the combination of VAS
and DTP has negative effects. Such consistent findings are unlikely to be
"chance findings"(1). The findings could explain why the effect of VAS is
no longer beneficial as DTP coverage has increased significantly since the
first VAS trials were conducted. Importantly, they are not refuted by the
Mayo-Wilson meta-analysis since no analysis by vaccination status has been
carried out(8).
In a world that increasingly demands evidence-based preventive
policies it is embarrassing that our evidence for the VAS policy is more
than 15 years old and contradicted by all recent studies. While it is true
that VAS is inexpensive, we can no longer be sure that it is safe and
beneficial. In such a situation randomised trials are needed.
References
1. Mayo-Wilson E, Imdad A, Herzer K, Bhutta ZA. There is no need for
further placebo-controlled trials. BMJ open 2012;2:e000448.
2. Fisker AB, Aaby P, Bale C, Balde I, Biering-Sorensen S, Agergaard J, et
al. Does the effect of vitamin A supplements depend on vaccination status?
An observational study from Guinea-Bissau. BMJ open 2012;2(1):e000448.
3. Benn CS, Fisker AB, Aaby P. With heterogeneous and potentially harmful
effects in existing trials it would be unethical not to conduct further
studies of the effect of vitamin A supplementation. BMJ 2011;343:d5094.
4. Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Response to
Benn et al. BMJ 2011;343:d5094.
5. Benn CS, Martins C, Rodrigues A, Ravn H, Fisker AB, Christoffersen D,
et al. The effect of vitamin A supplementation administered with missing
vaccines during national immunization days in Guinea-Bissau. International
journal of epidemiology 2009;38(1):304-11.
6. Benn CS, Rodrigues A, Yazdanbakhsh M, Fisker AB, Ravn H, Whittle H, et
al. The effect of high-dose vitamin A supplementation administered with
BCG vaccine at birth may be modified by subsequent DTP vaccination.
Vaccine 2009;27(21):2891-98.
7. Benn CS, Aaby P, Nielsen J, Binka FN, Ross DA. Does vitamin A
supplementation interact with routine vaccinations? An analysis of the
Ghana Vitamin A Supplementation Trial. Am J Clin Nutr 2009;90(3):629-39.
8. Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A
supplements for preventing mortality, illness, and blindness in children
aged under 5: systematic review and meta-analysis. BMJ 2011;343:d5094.
9. Awasthi S, Peto R, Read S, Bundy D. Six-monthly Augmented Vitamin A
Supplementation from 1 to 6 Years of Age: Block Randomized Trial in One
Million Children in Northern India. Available at:
www.ctsu.ox.ac.uk/projects/devta/istanbul-vit-alecture. Presented at
Micronutrient Forum; 2007; Istanbul.
10. Fisker AB. Evaluation of the WHO vitamin A supplementation policy in
Guinea-Bissau. [PhD Thesis]. University of Aarhus, 2011.
11. Dibley MJ, Sadjimin T, Kjolhede CL, Moulton LH. Vitamin A
supplementation fails to reduce incidence of acute respiratory illness and
diarrhea in preschool-age Indonesian children. J Nutr 1996;126(2):434-42.
12. Barreto ML, Santos LM, Assis AM, Araujo MP, Farenzena GG, Santos PA,
et al. Effect of vitamin A supplementation on diarrhoea and acute lower-
respiratory-tract infections in young children in Brazil. Lancet
1994;344(8917):228-31.
13. Agarwal DK, Pandey CM, Agarwal KN. Vitamin A administration and
preschol child mortality. Nutr Res 1995;15(5):669-80.
14. Venkatarao T, Ramakrishnan R, Nair NG, Radhakrishnan S, Sundaramoorthy
L, Koya PK, et al. Effect of vitamin A supplementation to mother and
infant on morbidity in infancy. Indian Pediatr 1996;33(4):279-86.
15. Donnen P, Brasseur D, Dramaix M, Vertongen F, Zihindula M, Muhamiriza
M, et al. Vitamin A supplementation but not deworming improves growth of
malnourished preschool children in eastern Zaire. J Nutr 1998;128(8):1320-
27.
16. Pant CR, Pokharel GP, Curtale F, Pokhrel RP, Grosse RN, Lepkowski J,
et al. Impact of nutrition education and mega-dose vitamin A
supplementation on the health of children in Nepal. Bull World Health
Organ 1996;74(5):533-45.
17. Benn CS, Aaby P, Bale C, Olsen J, Michaelsen KF, George E, et al.
Randomised trial of effect of vitamin A supplementation on antibody
response to measles vaccine in Guinea-Bissau, West Africa. Lancet
1997;350(9071):101-05.
18. Chowdhury S, Kumar R, Ganguly NK, Kumar L, Walia BN. Effect of vitamin
A supplementation on childhood morbidity and mortality. Indian journal of
medical sciences 2002;56(6):259-64.
19. Chowdhury S, Kumar R, Ganguly NK, Kumar L, Nain CK, Walia BN.
Conjunctival impression cytology with transfer (CICT) to detect pre-
clinical vitamin A deficiency among slum children in India. The British
journal of nutrition 1996;75(5):785-90.
20. Chowdhury S, Kumar R, Ganguly NK, Kumar L, Verma M, Walia BN. Dynamics
of conjunctival impression cytologic changes after vitamin A
supplementation. The British journal of nutrition 1997;77(6):863-9.
21. Beaton GH, Martorell R, McCabe G, L'abb? KA, Edmonston B, Ross AC.
Effectiveness of vitamin A supplementation in the control of young child
morbidity and mortality in developing countries: United Nations
Administrative Committee on Coordination/Sub-Committee on Nutrition, 1993.
22. Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A
supplementation and child mortality. A meta-analysis. JAMA 1993;269(7):898
-903.
23. Wieringa FT, Dijkhuizen MA, Berger J. Vitamin A supplementation in
children and hearing loss. BMJ 2012;344:d7603.
24. Benn CS, Bale C, Sommerfelt H, Friis H, Aaby P. Hypothesis: Vitamin A
supplementation and childhood mortality: amplification of the non-specific
effects of vaccines? Int.J.Epidemiol. 2003;32(5):822-28.
25. Benn CS, Fisker AB, Napirna BM, Roth A, Diness BR, Lausch KR, et al.
Vitamin A supplementation and BCG vaccination at birth in low birthweight
neonates: two by two factorial randomised controlled trial. BMJ
2010;340:c1101.
We thank Drs Cherrie and MacCalman for their thoughtful comments.
However the first step in any analysis is exploring the variables.
When examining the distribution of women use of vaginal barriers world-
wide, one notices that no country reports more than 5% of woman using
this mode of contraception, and only 9 countries have over 1% use of
vaginal barriers. Clearly this variable cannot be entered at face value.
When w...
We thank Drs Cherrie and MacCalman for their thoughtful comments.
However the first step in any analysis is exploring the variables.
When examining the distribution of women use of vaginal barriers world-
wide, one notices that no country reports more than 5% of woman using
this mode of contraception, and only 9 countries have over 1% use of
vaginal barriers. Clearly this variable cannot be entered at face value.
When we apply a very conservative restriction, and include only countries
with over 0.2% of woman use vaginal barriers (n=45) the univariable
correlation with PCa incidence (r=0.19, p=0.23) and mortality (r=0.2,
p=0.23) are both insignificant.If we apply the same restriction to oral
contraceptive use the correlation remains the same.
We are now left with 3 modes of contraception: IUD, condoms and oral
contraceptives. On univariable analysis the correlation of IUD with PCa
incidence (r=-0.011, p=0.893) and mortality (r=-0.19, p=0.02) is
inconsistent. It is however correlated with mortality and as we stressed
earlier this is supportive of our hypothesis.
Now let's consider the differences between oral contraceptives and condoms
correlation with PCa incidence and mortality. On univariable analysis oral
contraceptives demonstrate a higher Pearson correlation for both PCa
incidence ( r= 0.5, p<0.001 vs. r=0.4, p<0.001) and mortality (r=
0.17, p=0.036 vs r=0.13 p=0.1). On multivariable analysis they are both
similar for both outcomes.
In summary, oral contraceptives are the only mode of contraception that on
univariable analysis correlates with both PCa incidence and mortality, and
remain significantly correlated on multivariable analysis with PCa
incidence. We therefore still believe our hypothesis is valid. We stress
again that we did not prove a causal relationship- but generated a valid
hypothesis worth further exploration. This theme has guided us when we
wrote the manuscript and every time we addressed it.
We again thank Drs Cherrie and MacCalmans for their comments; we believe
our hypothesis is valid however future studies are needed to provide
definitive proof.
We concur with Fisker et al. that factors moderating and mediating
the effect of vitamin A supplementation on mortality are not fully
understood.[1] Further observational studies could elucidate this
relationship. New trials might examine the impact of delivering vitamin A
at different times of year or with different doses and frequencies;
however, we disagree with Fisker et al. that further tri...
We concur with Fisker et al. that factors moderating and mediating
the effect of vitamin A supplementation on mortality are not fully
understood.[1] Further observational studies could elucidate this
relationship. New trials might examine the impact of delivering vitamin A
at different times of year or with different doses and frequencies;
however, we disagree with Fisker et al. that further trials in children
should use placebo controls.
In a systematic review,[2] we analysed 44 randomised controlled
trials including the large Indian trial they reference.[3] We found that
over 1.2 million children have already been randomised to receive vitamin
A or placebo. Taken together, these trials demonstrate that vitamin A is
important for normal functioning of several systems. In addition to
reducing mortality, randomised trials show that vitamin A supplementation
reduces diarrhoea, measles, and blindness. Another trial in a population
at risk of vitamin A deficiency would add little to what we know, and it
would deny some children an intervention that reduces illness, death, and
disability. Under these circumstances, a placebo-controlled trial would
be unethical.
Fisker et al. make claims that are too strong based on evidence that
demonstrates great uncertainty.[1] They report that vitamin A
supplementation was not significantly associated with mortality in an
observational study, but they observed only 64 events (deaths) across all
groups. Despite showing no main effect, the authors then conducted a
series of subgroup analyses that include only 58 events. Split by vitamin
A group and most recent vaccination, only one subgroup included more than
10 events. The results have very wide confidence intervals and could be
explained by chance. Fisker et al. bolster their argument by citing a
previous paper about the possible interaction of sex and vaccination
status,[4] an analysis they conducted sixteen years after the results of
the original trial were published.[5] In that trial, vitamin A
supplementation was associated with a 19% reduction in mortality, which
was similar across sexes. Across eight groups (split by vitamin A group,
sex, and health card), there were 173 events. The absolute difference in
mortality between girls with and without a health card (a proxy for
vaccination status) was 0.7%. Again, these differences could be explained
by chance, particularly if the reported analyses are a subset of the post-
hoc tests they conducted.
Fisker et al. err in privileging the results of these studies over
meta-analyses of much larger randomised controlled trials. We conducted an
analysis including all randomised controlled trials reporting separate
effects of vitamin A supplementation for boys and girls. Results from
trials with 107,474 children suggest that the effect of vitamin A
supplementation is not moderated by sex. Whilst some individual study
results were not significant, all of the effects for girls favour vitamin
A supplementation over placebo.[2]
In their discussion, Fisker et al. reiterate a claim that Benn made
in response to our systematic review, that our meta-analysis was
"essentially based on trials from the late 1980s and early 1990s". They
also assert "The only recent trials are the mega-trial from India showing
no effect and a placebo-controlled trial of VAS administered with vaccines
in Guinea-Bissau..." Neither claim is true. In our analysis of
mortality, we included 8 studies published after 1993. Two studies
(reported in 1994 and 1995) report no significant difference in mortality
whilst six studies (reported from 1994 to 2002) report larger than average
reductions in mortality. Both of the negative trials referenced by Fisker
et al. remain unpublished and unavailable for full scrutiny. Contrary to
what Fisker et al. imply, we also included the DEVTA trial in an analysis
of mortality, and the effect remained statistically and clinically
significant.
We concur with colleagues who explain that further work is needed to
refine supplementation programmes and to increase their coverage,[6] but
further placebo controlled trials would cause more harm than good. The
WHO reports that 190 million children remain vitamin A deficient, and
widespread deficiency persists among millions of women.[7] Evidence from
clinical trials shows that supplementation benefits boys and girls alike.
We can no longer claim equipoise. Remaining questions about vitamin A
supplementation must be answered using existing datasets or through
studies that do not deny children an intervention that is safe,
beneficial, and inexpensive.
References
1. Fisker AB, Aaby P, Bale C, et al. Does the effect of vitamin A
supplements depend on vaccination status? An observational study from
Guinea-Bissau. BMJ Open. 2012;2:e000448.
2. Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A
supplements for preventing mortality, illness, and blindness in children
aged under 5: systematic review and meta-analysis. BMJ. 2011;343:d5094.
3. Awasthi S, Peto R, Read S, Bundy D. Six-monthly vitamin A from 1
to 6 years of age. DEVTA: cluster randomised trial in 1 million children
in North India. www.ctsu.ox.ac.uk/projects/devta/istanbul-vit-alecture.
2008.
4. Benn CS, Aaby P, Nielsen J, Binka FN, Ross DA. Does vitamin A
supplementation interact with routine vaccinations? An analysis of the
Ghana Vitamin A Supplementation Trial. Am J Clin Nutr. 2009;90:629-639.
5. Vitamin A supplementation in northern Ghana: effects on clinic
attendances, hospital admissions, and child mortality. Ghana VAST Study
Team. Lancet. 1993;342:7-12.
6. Thorne-Lyman A, Fawzi WW. Improving child survival through vitamin
A supplementation. BMJ. 2011;343:d5294.
7. WHO. Guideline: Vitamin A supplementation in infants and children
6-59 months of age. Geneva: World Health Organization; 2011.
we appreciate the effort of the authors in looking into the 30-year
mortality outcomes of their initial cohorts, who were stratified into
different occupational work demands, adjusted for some co-morbidities,
risk factors and social classes. It was reassuring that the established
cardiovascular risk factors of smoking and hypertension were indeed true
much earlier than we aware. However...
we appreciate the effort of the authors in looking into the 30-year
mortality outcomes of their initial cohorts, who were stratified into
different occupational work demands, adjusted for some co-morbidities,
risk factors and social classes. It was reassuring that the established
cardiovascular risk factors of smoking and hypertension were indeed true
much earlier than we aware. However, we are perplexed with the conclusion
of men who were in profession of low physical work demand (such as
physicians and academic like us) was not protected by (and thus
discouraged from) physical activity or exercise that should be regular and
good enough to lead to physical fitness. We believe this conclusion is
misleading although it was well stated by the authors in the paper that
there were absence of intermediary or repeated measures of the cohorts
profession, physical activity and fitness. These aspects of life could
change, even among the people of 40-60 years of age, and this effect of
this change over the span of 30-year would have remarkable health
influence upon the study cohorts. Therefore, this paper is good at re-
emphasizing the detrimental effects of smoking behaviour and uncontrolled
hypertension but not the aforementioned conclusion when physicians and
doctors are as much predisposed to the risk factor of sedentary lifestyle-
obesity-cardiometabolic diseases.
We are pleased that Margel and Fleshner recognize the data errors in
their original manuscript [1], which have a dramatic impact on the outcome
of the ecological analysis [2]. Using the correct dataset and extending
the analysis to include all countries, which we agree is appropriate, the
authors report that the correlation between oral contraceptive use and
prostate cancer mortality was much reduced (Pearson correlation...
We are pleased that Margel and Fleshner recognize the data errors in
their original manuscript [1], which have a dramatic impact on the outcome
of the ecological analysis [2]. Using the correct dataset and extending
the analysis to include all countries, which we agree is appropriate, the
authors report that the correlation between oral contraceptive use and
prostate cancer mortality was much reduced (Pearson correlation
coefficient r=0.17 compared with r=0.53 previously). It is worth noting
that this result is only marginally statistically significant and, if
real, suggests that something less than 3% of the variation in national
rates for prostate cancer mortality might be due to oral contraceptive
use. This correlation is only a little higher than that found for condom
use (r=0.13), which was dismissed as non-significant.
It is easy to explore the inter-relationships between contraception
and risk a little further. Using the full dataset we have undertaken a
more comprehensive multivariate regression analysis, as Margel and
Fleshner did on the sample in their original paper. i.e. using the four
forms of contraceptive use, country GDP and prostate cancer mortality.
This analysis showed that two forms of contraception were highly
significantly associated with mortality (IUD was negatively associated and
barrier methods positively associated), but use of oral contraceptives was
not statistically significant in the model. Carrying out the same
analysis on the incidence data we found that three of the four
contraception methods were significantly associated with prostate cancer
incidence (the use of the pill, vaginal barrier methods and condoms were
all positively associated).
This was a hypothesis-generating exercise and the univariate results
presented by Margel and Fleshner, along with the multivariate results
discussed here, suggest that any hypothesis on the relationship between
contraception use and prostate cancer mortality and incidence should not
be reduced to a simple hypothesis about oral contraception.
Our main concern about the Margel and Fleshner paper [1] stems from
the extensive coverage that it has received in the lay press and the
likelihood that the erroneous findings have been widely interpreted as
being causal. For example, we note that in the British Daily Mail
newspaper the study was reported with the headline 'Rise in prostate
cancer due to use of the Pill which increases men's exposure to oestrogen'
[3]. We accept that many research publications ultimately turn out to
present false conclusions [4]; that there is a need for researchers to
float interesting ideas; and that researchers are not responsible for over
-interpretation by the press. However, we believe that it is of prime
importance that scientists endeavor to frame their results and their
speculations in ways that limit the potential for misinterpretation.
Margel and Fleshner did not do this: the original data were wrong; the
authors' analysis and interpretation of the correct data remains
unconvincing; and the title of their paper is misleading.
We reiterate the point we made in our original letter [1], that there
is no evidence that oral contraceptive use is associated with prostate
cancer mortality and the evidence that it is associated with prostate
cancer incidence is weak. As a hypothesis generating exercise these data
suggest that there may be some relationships between contraception and
prostate cancer; that these are not simple and are not limited to one form
of contraception; and that, if real, they explain at most a small
proportion of differences between countries in risks of prostate cancer
mortality.
John W Cherrie
Laura MacCalman
References
1. Margel D, Fleshner NE. Re:Oral contraceptive use is not associated
with prostate cancer BMJ Open 2011; 1(2): e000311.
2. Margel D, Fleshner NE. Oral contraceptive use is associated with
prostate cancer: an ecological study. BMJ Open 2011; 1(2): e000311.
3. Rise in prostate cancer 'due to use of the Pill which increases
men's exposure to oestrogen'. Daily Mail, 16th November 2011.
(http://www.dailymail.co.uk/health/article-2061253/Birth-control-pills-
Prostate-cancer-rise-contraceptive-pill-mens-oestrogen-exposure.html).
4. Ioannidis, J.P.A., 2005. Why most published research findings are
false. PLoS Medicine, 2(8), p.e124.
References
'Chronic Fatigue syndrome affects 1 in 100 pupils'
This statement featured prominently on the BBC website and drew me
first to press article and then the study. It seemed like reasonable
research on first glance, it involved 2855 pupils and was published in a
BMJ journal. However on closer inspection, the study is flawed.
The authors present a clear agenda that they feel CFS/ME remains
undiagnosed an...
'Chronic Fatigue syndrome affects 1 in 100 pupils'
This statement featured prominently on the BBC website and drew me
first to press article and then the study. It seemed like reasonable
research on first glance, it involved 2855 pupils and was published in a
BMJ journal. However on closer inspection, the study is flawed.
The authors present a clear agenda that they feel CFS/ME remains
undiagnosed and untreated which biases the study. It is not designed as a
prevalence study of CFS/ME in secondary schools pupils; it is a
feasibility study for a regional service.
The methodology is poor. The authors fail to mention the socio-
economic mix of the schools and only mention that one school was an all
girls school in the discussion. Missing 20% of school sounds very
concerning but the time period used is relatively short and could equate
to only 6 days missed in 6 weeks. Treatment outcomes in the school and
service groups were not compared. We were not told how many children
benefitted from each treatment. Finally the study used time in education
as the sole marker for improvement which is not recommended by NICE
guidelines1, which suggest a more holistic approach.
The conclusion that 1% of enrolled children miss 20% of school due to
CFS/ME fits the authors' hypothesis that CFS/ME is under diagnosed and
under treated. Although they suggest that other psychological and medical
causes have a part to play their solutions only include CFS/ME.
It is possible to draw other headlines from the study of equal
validity.
* Depression and anxiety affects 1 in 200 pupils and mean they miss
more than 6 school days in 6 weeks.
* Social and emotional problems affect 1 in 100 pupils and mean they
miss more than 6 school days in 6 weeks
* Recurrent headache, migraine, diarrhoea and vomiting or upper
respiratory tract infections affect 1 in 100 pupils and mean they miss
more than 6 school days in 6 weeks.
A more holistic approach exploring the bio-psycho-social health of
young people in order to tackle chronic school absence is more appropriate
and patient centred. Engaging with patients, listening, taking the
problems seriously and making patient centred action plans are encouraged
by the Royal College of General Practitioners in managing medically
unexplained symptoms2 and CFS/ME3. Good medicine involves putting aside
our prejudices and focusing on the patient. Good research should be
unbiased and based on robust methods.
1 NICE. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
(Encephalopathy); Diagnosis and Management. CG53. London: National
Institute for Clinical Excellence (NICE), 2007.
2 Chitnis A et al. Guidance for health professionals on medically
unexplained symptoms (MUS). Royal college of General Practitioners and
Royal College of Psychiatrists.
http://www.rcgp.org.uk/PDF/MUS_Guidance_A4_4pp_6.pdf Published January
2011.
3 Gibson J, Smith B, Ward C. Chronic fatigue syndrome. InnovAit
2011;4,:691-6.
This paper (1) includes data on two separate (but related) issues:
(i) the prevalence of diagnosed and undiagnosed Chronic Fatigue
Syndrome/Myalgic Encephalomyelitis ("CFS/ME") (NICE criteria (2)) in
children aged 11-16 and (ii) information on how they fared when they
received therapy at the CFS clinic. The relative rigour that is brought to
the first set of data may mean some may miss that many questions remain
about th...
This paper (1) includes data on two separate (but related) issues:
(i) the prevalence of diagnosed and undiagnosed Chronic Fatigue
Syndrome/Myalgic Encephalomyelitis ("CFS/ME") (NICE criteria (2)) in
children aged 11-16 and (ii) information on how they fared when they
received therapy at the CFS clinic. The relative rigour that is brought to
the first set of data may mean some may miss that many questions remain
about the therapeutic data, which I will now attempt to elucidate.
Ideally what one would want to know is whether there would have been
any difference in outcomes if the children had been neither diagnosed nor
treated. The criteria used, the NICE criteria (2), which require fatigue
and one other symptom for three months or more, are relatively broad -
most other criteria for ME and/or CFS are stricter i.e. they require more
symptoms (3-9). A systematic review looking at the prognosis of chronic
fatigue and chronic fatigue syndrome found that as the criteria got more
stringent, the prognosis worsened (10). A Dutch natural course study found
that less fatigue improved the prognosis of CFS (11). A US team noted that
CFS patients with higher levels of physical functioning were more likely
to report recovery at follow-up (12). This suggests the possibility that
the group diagnosed because of the surveillance, who had less severe
fatigue and better physical functioning, might have a better prognosis
than clinic attenders i.e. data from the latter should not necessarily be
extrapolated to the former without adjustment for their less severe
illness. The prognosis for many adolescents with CFS is good (13-14).
However, despite these difficulties in estimating the prognosis of
patients if they had been given neither a diagnosis nor treatment, I'm
inclined to think it is better to give a diagnosis based on existing data.
A Centers for Disease Control and Prevention (CDC) study suggested that a
delayed diagnosis appeared to be a risk factor for poor prognosis,
prompting them to launch a multi-million dollar awareness and education
campaign aimed at both clinicians and the general public (15). A study in
the UK found that a longer time to diagnosis significantly increased the
chances that a person would be severely affected [i.e. it compared those
who were mildly affected and those who were severely affected (omitting
those who could not easily be classified in either group) and found, even
after adjustments, that the time to diagnosis was greater for the severely
affected group than the more mildly affected group] (16).
So the more important question in my mind is the value, or otherwise,
of therapy received. Unfortunately we don't get that much quantitative
data on this. We are told information about children being "fully
recovered" without information about how this was defined or indeed who
decided they were fully recovered (e.g. clinician, parent, children or a
combination of individuals?). An important aspect of this is the number of
time points that were used. "CFS/ME" is well-known for often having a
relapsing and remitting course, something the CDC found in one of their
longitudinal studies (17). Another CDC CFS paper reported (in a study
where recovery was self-defined) "at 6 months from first reported
recovery, 57% (26/46) of these patients reported that they continued to
consider themselves recovered from their fatiguing illness, 28% (13/46)
reported a return of their fatigue, and 15% (7/46) had incomplete data on
fatigue status following their report of initial recovery" (18). A US
paediatrician followed some of his ME/CFS patients into adulthood. In one
study, ten persons who considered themselves "recovered" or "nearly
recovered" (at the time of the assessment) were given questionnaires to
assess health status and compared to healthy adults (19). Half of the
"recovered" subjects would be considered ill with CFS based upon the
disability requirements of the CDC empiric definition of CFS (a broad
definition) (20), and all "recovered" subjects had significant somatic
symptoms.
The question of whether patients should be treated, or whether simply
diagnosing at this time might be better, is important given the therapies
in question: Graded Exercise Therapy (GET) and Cognitive Behaviour Therapy
(CBT). I recently published a paper (21) looking at the reporting of harms
for GET and CBT (and in particular the form of CBT based on scheduling
graded activity, the form recommended by the NICE guidelines to which the
clinic adheres (22)). Reporting of harms in RCTs of these therapies has
been recognised as being poor by Cochrane Reviews on both therapies along
with the systematic review on which the NICE guidelines were based (22-
25). As they are non-pharmacological interventions, no yellow card
facility exists for reporting adverse events. In this scenario, data from
surveys may be particularly important: a review of 10 surveys I collated
found 51% of survey respondents (range 28-82%, n=4338, 8 surveys) reported
that GET worsened their health while 20% of respondents (range 7-38%,
n=1808, 5 surveys) reported similar results for CBT (21). This should
raise serious questions about the use of these therapies, particularly on
individuals who haven't presented themselves to their doctors but have
been picked up by surveillance.
As I said, the information on efficacy in this study (1) is far from
ideal given it's uncontrolled. The authors claim the "PACE trial provided
strong evidence that these treatments are moderately effective in adults"
(1,26). However, this statement is based on subjective outcome measures
and previous studies of therapies testing graded activity protocols for
CFS have shown that, despite reporting improvements over a control group
(27), or over time (28), individuals may not have improved when activity
(as measured by actometers) are used as the outcome measure. If one looks
at the most objective measure of functioning that has so far been reported
in the PACE Trial, the 6 minute walk test (6MWT), there was no difference
between the CBT and control group (26). Following adjustment, the GET
group did increase by 35 metres over the control group but a final result
of only 379m is more like the result of a spavined older adult than the
644m that population norms predict for the participants in the PACE Trial
(adults of average age 39 year old adults, 77% of whom are female)
(21,26).
So, in conclusion, I'm inclined to believe this study suggests the
need for a greater awareness of how prevalent "CFS/ME" can be amongst
adolescents. However, whether they should then routinely be treated with
CBT and/or GET is still open for debate.
References:
(1) Crawley EM, Emond AM, Sterne JA. Unidentified Chronic Fatigue
Syndrome/myalgic encephalomyelitis (CFS/ME) is a major cause of school
absence: surveillance outcomes from school-based clinics. BMJ Open. 2011
Dec 12;1(2):e000252. Print 2011.
(2) NICE. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or
Encephalopathy); Diagnosis and Management. CG53. London: National
Institute for Health and Clinical Excellence (NICE), 2007.
(3) Carruthers B, Jain A, de Meirleir K, Peterson D, Klimas N, Lemer
A, et al.: Myalgic encephalomyelitis/chronic fatigue syndrome: clinical
working case definition, diagnostic and treatment protocols. J Chronic
Fatigue Syndrome 2003;11(1):7-33
(4) Jason LA, Bell DS, Rowe K, Van Hoof ELS, Jordan K, Lapp C,
Gurwitt A, Miike T, Torres-Harding S, De Meirleir K. & IACFS. A
pediatric case definition for ME/CFS. J Chronic
Fatigue Syndr. 2006;13(2/3):1-44.
(5) Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A.
The chronic fatigue syndrome: A comprehensive approach to its definition
and study. Annals of Internal Medicine. 1994;121:953-959.
(6) Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome:
a working case definition. Ann Intern Med. 1988 Mar;108(3):387-9.
(7) Jason LA, Evans M, Porter N, et al. The development of a revised
Canadian Myalgic Encephalomyelitis-Chronic Fatigue Syndrome case
definition. American Journal of Biochemistry and Biotechnology. 2010:6;120
-135.
(8) Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG,
Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R,
Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J,
Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits
JA, Miwa K, Murovska M, Pall ML, Stevens S. Myalgic encephalomyelitis:
International Consensus Criteria. J Intern Med. 2011;270:327-38. doi:
10.1111/j.1365-2796.2011.02428.x. Epub 2011 Aug 22.
(9) Jason LA, Damrongvachiraphan D, Hunnell J, Bartgis L, Brown A,
Evans M, Brown M. Myalgic Encephalomyelitis: Case definitions. Autonomic
Control of Physiological State and Function. 2012. 1, 1-14.
doi:10.4303/acpsf/K11060. Available at:
http://www.ashdin.com/journals/ACPSF/K110601.pdf Accessed Dec. 30, 2011.
(10) Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue
and chronic fatigue syndrome: a systematic review. QJM. 1997 Mar;90(3):223
-33.
(11) Vercoulen JH, Swanink CM, Fennis JF, Galama JM, van der Meer JW,
Bleijenberg G. Prognosis in chronic fatigue syndrome: a prospective study
on the natural course. J Neurol Neurosurg Psychiatry. 1996 May;60(5):489-
94.
(12) Pheley AM, Melby D, Schenck C, Mandel J, Peterson PK: Can we
predict recovery in chronic fatigue syndrome? Minnesota Medicine 1999,
82(11):52-6.
(13) Rimes KA, Goodman R, Hotopf M, Wessely S, Meltzer H, Chalder T.
Incidence, prognosis, and risk factors for fatigue and chronic fatigue
syndrome in adolescents: a prospective community study. Pediatrics. 2007
Mar;119(3):e603-9.
(14) Katz BZ, Shiraishi Y, Mears CJ, Binns HJ, Taylor R. Chronic
fatigue syndrome after infectious mononucleosis in adolescents.
Pediatrics. 2009 Jul;124(1):189-93.
(15) Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B,
Stewart G, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC. Prevalence and
incidence of chronic fatigue syndrome in Wichita, Kansas. Archives of
Internal Medicine 2003;163:1530-1536.
(16) Pheby D, Saffron L. Risk Factors for Severe ME/CFS. Biology and
Medicine. 2009;1:50-74.
(17) Nisenbaum R, Jones JF, Unger ER, Reyes M, Reeves WC. A
population-based study of the clinical course of chronic fatigue syndrome.
Health Qual Life Outcomes. 2003 Oct 3;1:49.
(18) Reyes M, Dobbin JG, Nisenbaum R, Subedar N, Randall B, Reeves
WC: Chronic fatigue syndrome progression and self-defined recovery:
evidence from CDC surveillance system.
Journal of Chronic Fatigue Syndrome 1999 5(1):17-27.
(19) Bell DS, Bell DE. Definition of recovery in Chronic Fatigue
Syndrome. The Journal of IiME. 2010. 4 (1) 23-27
(20) Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon
L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome-
-a clinically empirical approach to its definition and study. BMC Med.
2005;3:19.
(21) Kindlon T. Reporting of Harms Associated with Graded Exercise
Therapy and Cognitive Behavioural Therapy in Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME.
2011;19(2):59-111.
http://www.iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx
(22) NICE. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or
Encephalopathy); Diagnosis and Management. CG53. London: National
Institute for Health and Clinical Excellence (NICE), 2007.
(23) Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour
therapy for chronic fatigue syndrome in adults. Cochrane Database Syst
Rev. 2008;(3):CD001027.
(24) Edmonds M, McGuire H, Price J. Exercise therapy for chronic
fatigue syndrome. Cochrane Database Syst Rev. 2004;(3):CD003200.
(25) Chambers D, Bagnall AM, Hempel S, Forbes C. Interventions for
the treatment, management and rehabilitation of patients with chronic
fatigue syndrome/myalgic encephalomyelitis: an updated systematic review.
J R Soc Med. 2006;99:506-20. Review.
(26) White P, Goldsmith K, Johnson A, et al. Comparison of adaptive
pacing therapy, cognitive behaviour therapy, graded exercise therapy, and
specialist medical care for chronic fatigue syndrome (PACE): a randomised
trial. Lancet 2011;377:823e36.
(27) Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How
does cognitive behaviour therapy reduce fatigue in patients with chronic
fatigue syndrome? The role of physical activity. Psychol Med. 2010;40:1281
-1287.
(28) Friedberg F, Sohl S. Cognitive-behavior therapy in chronic
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Clin Psychol. 2009;65:423-42.
Conflict of Interest:
I am Information Officer of the Irish ME/CFS Association. All my work for the Association is voluntary (i.e. unpaid)
Thank you for commenting on our article and pointing out the short hand statement "consented"
Thank you for your comments and with your permission I will use them as a teaching peice for my students.
Yours
Kwame McKenzie
Conflict of Interest:
author of the article
I enjoyed reading about this well conducted study that produced interesting results. I do, however, wish to comment on one sentence:
[The participants] were then approached face to face by the researchers and consented.
While I realise that word limits encourage authors to be parsimonious and make stylistic compromises, to state that research participants are 'consented' is to imply that they are passiv...
We thank Mayo-Wilson and colleagues for their comments(1). They have used our paper on the effect of vitamin A campaigns on mortality(2) not to question the paper itself, but to repeat a previous discussion(3, 4) about whether new trials of vitamin A supplementation (VAS) are needed to optimise the vitamin A policy. This is clearly a very important discussion.
We think that new trials are needed. We have found i...
Author affiliation 3 should read NWORTH, Bangor University, Bangor, UK
We thank Drs Cherrie and MacCalman for their thoughtful comments. However the first step in any analysis is exploring the variables. When examining the distribution of women use of vaginal barriers world- wide, one notices that no country reports more than 5% of woman using this mode of contraception, and only 9 countries have over 1% use of vaginal barriers. Clearly this variable cannot be entered at face value. When w...
To the Editor:
We concur with Fisker et al. that factors moderating and mediating the effect of vitamin A supplementation on mortality are not fully understood.[1] Further observational studies could elucidate this relationship. New trials might examine the impact of delivering vitamin A at different times of year or with different doses and frequencies; however, we disagree with Fisker et al. that further tri...
Dear BMJ Open Editorial,
we appreciate the effort of the authors in looking into the 30-year mortality outcomes of their initial cohorts, who were stratified into different occupational work demands, adjusted for some co-morbidities, risk factors and social classes. It was reassuring that the established cardiovascular risk factors of smoking and hypertension were indeed true much earlier than we aware. However...
We are pleased that Margel and Fleshner recognize the data errors in their original manuscript [1], which have a dramatic impact on the outcome of the ecological analysis [2]. Using the correct dataset and extending the analysis to include all countries, which we agree is appropriate, the authors report that the correlation between oral contraceptive use and prostate cancer mortality was much reduced (Pearson correlation...
'Chronic Fatigue syndrome affects 1 in 100 pupils'
This statement featured prominently on the BBC website and drew me first to press article and then the study. It seemed like reasonable research on first glance, it involved 2855 pupils and was published in a BMJ journal. However on closer inspection, the study is flawed.
The authors present a clear agenda that they feel CFS/ME remains undiagnosed an...
This paper (1) includes data on two separate (but related) issues: (i) the prevalence of diagnosed and undiagnosed Chronic Fatigue Syndrome/Myalgic Encephalomyelitis ("CFS/ME") (NICE criteria (2)) in children aged 11-16 and (ii) information on how they fared when they received therapy at the CFS clinic. The relative rigour that is brought to the first set of data may mean some may miss that many questions remain about th...
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