Rossouw et al. addressed only the comparisons of results from
randomized controlled trials (RCTs) and observational studies (OSs). They
did not consider analyses that compared outcomes of participants who had
the same treatment but were in different studies. These analyses found
that adjusting for the WHI risk factors was not sufficient to account for
unmeasured risk differences between subjects in different studies. T...
Rossouw et al. addressed only the comparisons of results from
randomized controlled trials (RCTs) and observational studies (OSs). They
did not consider analyses that compared outcomes of participants who had
the same treatment but were in different studies. These analyses found
that adjusting for the WHI risk factors was not sufficient to account for
unmeasured risk differences between subjects in different studies. The
differences between studies due to unexplained confounding were sometimes
larger then the effects of HT on either MI or stroke in the RCTs. For
example, after adjusting for risk factors measured by the WHI,
participants in the RCT of E-alone had a 37% higher rate of an MI
(p<0.0001) than participants in the WHI OS if both sets of participants
were not taking any HT and a 44% higher rate of an MI (p<0.0001) if
both sets of participants were taking E-alone. Explanations other than
unmeasured confounders are unlikely to account for differences in outcomes
among the studies.
These findings are important because comparisons of subjects in
different studies are closely related to OS comparisons of subjects on
different treatments. It is therefore likely that unmeasured confounders
may in some cases greatly distort apparent treatment effects in OSs even
after adjusting for WHI variables.
Below we summarized and responded to the Rossouw et al. critiques of
our OS/RCT comparisons.
1. THE DIFFERENCES BETWEEN OBSERVATIONAL STUDIES (OSS) AND RANDOMIZED
CONTROLLED TRIALS (RCTS) IN THE WHI CAN BE EXPLAINED BY TAKING INTO
ACCOUNT TIME SINCE INITIATION OF CURRENT REGIMEN OF HORMONE THERAPY (HT)
AND TIME SINCE MENOPAUSE.
This explanation depends on two beliefs: a) HT increases adverse
outcomes soon after it is initiated, and this effect disappears after two
years of continuing HT; b) HT increases adverse outcomes more for persons
who are older or more years past menopause. If these beliefs are true,
then associations between HT and adverse outcomes will be weaker for OS
participants because they have been on HT for considerable time before the
study and will be stronger for RCT participants who are older at the time
they are put on HT. The first belief was supported by our analysis of
the RCT of estrogen plus progestin (E+P). This analysis found HT
increased the MI rate during the first three years of the study but not
subsequently. However, the following findings from our analysis
challenged these beliefs.
a. In the RCT of estrogen alone (E-alone) there was no evidence that
HT increased the risk of MI either soon after beginning HT or
subsequently.
b. In the RCTs of E+P and of E-alone the associations between HT and
stroke remained constant over time, i.e., there was no effect of time
since initiation of therapy.
c. In the OSs there was a protective effect of HT for MI and no
effect of HT on stroke. Regardless of time since initiation the RCTs
never show a protective effect of HT and always showed an effect of HT on
stroke . In other words, time since initiation does not seem to account
for the differences between the OS and RCTs.
d. OS participants who began HT after the start date of the OS should show
increased risk according to the Rossouw et al. explanation, but instead
there was a statistically significant protective effect of HT.
e. In contrast to the Rossouw et al. analysis, neither years since
menopause nor age at study baseline significantly modulated the effect of
HT on outcome in any of numerous analyses (some reported and most not
reported) in the present study. It is possible that Rossouw et al. had a
particularly fortuitous way of analyzing the data and slight changes in
their analysis might give results that do not show that the HT effect was
significantly altered by effects of age or years since menopause.
2. RESULTS FROM THE PRESENT STUDY WERE INVALID BECAUSE WE USED THE
WRONG FOLLOW-UP MEASURES AND USED MI INSTEAD OF CHD AS AN OUTCOME MEASURE.
We have two responses to this criticism. The first is that it was
irrelevant to our research question, i.e., to determine whether OS results
were reliably valid. It has already been well established that OS and RCT
results can be similar. It makes no difference whether OS and RCT results
are similar for some follow-up times and some outcomes. If OS results are
reliably valid, they should be reliably valid for all modifications of the
research question. Our second response is that all analyses reported were
also performed for different follow-up periods and definitions of CHD as
close as we could make it to the Rossouw definition. These additional
results were not reported, but they were qualitatively the same as those
we did report.
3. THE INCLUSION OF HYSTERECTOMY STATUS WAS UNCLEAR. All of our
analyses were done for three data sets: the RCT of E+P (given only to
participants without a hysterectomy), the RCT of E-alone (given only to
participants with a hysterectomy), and the combined RCT data sets. All
three results were report for MI, but only the combined results were
reported for stroke because E+P and E-alone results were similar for
stroke, the confidence intervals for hazard ratios for stroke were very
wide in the individual RCTS, and the estimate for the combined dataset was
essentially the average of the estimates in the individual RCTs. OS
participants taking HT were also divided into those taking E+P and those
taking E-alone. OS participants not taking HT were not divided into those
who had or didn't have a hysterectomy because hysterectomy status was
unrelated to either subsequent MI or stroke after adjusting for the other
risk factors considered. It is unclear how we could have done a better
job managing hysterectomy status.
4. THE RCT DATA SHOULD HAVE BEEN DICHOTOMIZED BY A 2 YEAR INSTEAD OF
A 3 YEAR PERIOD SINCE ENROLLMENT.
We found no evidence that third year RCT results differed from second
year RCT results, and results based on our dichotomization were similar to
studies that dichotomized at 2 years. In addition, after delaying follow
-up for three years, the RCT results should have looked like the OS
results (i.e., HT should have been protective), but they did not.
5. WE WOULD HAVE BEEN WISE TO REQUEST THAT THE ANALYTIC PLAN BE
REVIEWED THROUGH THE USUAL WHI PUBLICATIONS PROCESS.
I do not know what the usual WHI publication process is. However,
many requests to WHI investigators and even a Nurses' Study Investigator
to collaborate on manuscripts, review manuscripts, or allow presentations
of this study were declined. I do not know how we could have obtained a
review.
With the currently available evidence it is premature to conclude
that the WHI data set was adequate to remove confounding. This is not a
criticism of the WHI data set, which is universally considered to be
outstanding. It is a criticism of the repeated claims that differences
between OS and RCT results of HT studies have been resolved. I wish this
were the case and that we could be confident of results in well done OSs.
Unfortunately, reliably valid OSs are still awaiting methodological
improvements.
I wish to formally submit this manuscript as a Letter to the Editors
but I found there is no facility to do so under the BMJ Open ScholarOne
portal.
I read with interest the research and conclusion presented by Dahlen
et al; their key message that "For low-risk women, care in a private
hospital, which includes higher rates of intervention, appears to be
associated with higher rates of mor...
I wish to formally submit this manuscript as a Letter to the Editors
but I found there is no facility to do so under the BMJ Open ScholarOne
portal.
I read with interest the research and conclusion presented by Dahlen
et al; their key message that "For low-risk women, care in a private
hospital, which includes higher rates of intervention, appears to be
associated with higher rates of morbidity seen in the neonate and no
evidence of a reduction in perinatal mortality" has been reported in
various international news outlets.
The statistics they presented is indeed sobering; many would conclude
that obstetric care in private setting in New South Wales, Australia is
associated with complications without overall reduction in neonate
mortality.
However I would like to offer a second look to the part of the
statistics involved; I accept the fact that instrumented delivery are more
likely to occur in private hospital setting in low risk birth, and that
most birth trauma is attributable to instrumented delivery.
On the assumption that all incidents of birth trauma are related to
instrumented delivery (forcep and vacuum), I looked at the estimated
proportion of instrumented delivery (8.0% of 28703 multiparous, 30.4%
29597 primiparous women in the private care, 2.8% of 99212 and 19.6% of
79792 in public setting respectively) that has resulted in birth trauma
(2948 vs 6447 or 2922 vs 6492 based on Table 5 or 7 respectively) in the
same period.
As a result the recalculated statistics suggest that birth trauma
from instrumented delivery occur in higher proportion at public hospital
(35.0 or 35.2%, Table 5 or 7) as compared to private setting (26.1 or
25.9%). My interpretation of this is that delivery requiring
instrumentation at private hospital is associated with fewer birth trauma
as compared to public hospital.
There is no doubt that there is a disproportionate trend of medical
intervention in child birth in low-risk women between public and private
setting and we should look into this matter in factors involved in
decision making, including surgeon's clinical judgement and patient's
preference.
However the conclusion by the authors of this article is at risk of
suggesting that instrumented deliveries in private hospitals are
associated with more birth trauma than public setting. I am concerned that
the less discerning readers amongst us may make further (unfounded)
conclusions from a complex situation.
The Maori population of New Zealand was about 12% at the time of the
Vietnam war. The New Zealand Vietnam veterans have a Maori participation
of 30%+ over double the percentage of Maori in the general population.
Statistics NZ tell us that Maori males die at twice the rate of
Caucasians, mainly cancers, diabetes and heart attacks. By their late
fifties Maori male mortality is two and a half time...
The Maori population of New Zealand was about 12% at the time of the
Vietnam war. The New Zealand Vietnam veterans have a Maori participation
of 30%+ over double the percentage of Maori in the general population.
Statistics NZ tell us that Maori males die at twice the rate of
Caucasians, mainly cancers, diabetes and heart attacks. By their late
fifties Maori male mortality is two and a half times that of Caucasians so
using the general population to measure mortality or disease is as futile
as it is pointless.
Please note, the acknowledgements and funding should read as follows:
Acknowledgements: This article presents independent research funded by the
National Institute for Health Research (NIHR) under its Programme Grants
for Applied Research (PGfAR) Programme (Grant Reference Number RP-PG-0407-
10029). The views expressed are those of the author(s) and not necessarily
those of the NHS, the NIHR or the Department of Health. We t...
Please note, the acknowledgements and funding should read as follows:
Acknowledgements: This article presents independent research funded by the
National Institute for Health Research (NIHR) under its Programme Grants
for Applied Research (PGfAR) Programme (Grant Reference Number RP-PG-0407-
10029). The views expressed are those of the author(s) and not necessarily
those of the NHS, the NIHR or the Department of Health. We thank members
of The Infant Mortality and Morbidity Studies team (University of
Leicester) for helpful advice and comments throughout the study.
Funding: UK Department of Health, National Institute for Health Research
Roy,
If we saw worse mortality in this group, we would have a problem. We
don't, we see the 'healthy soldier' effect. This probably means that the
Maori men in our sample were as healthy as anyone else.
The paper by Dahlen et al has predictably generated a public v
private maternity care debate in the Australian media. Unfortunately the
data upon which the conclusion of higher morbidity of babies born in
private maternity units is compromised by the manner in which the data was
collected. Basing the public hospital morbidity data on the NSW Admitted
Patient Data Collection (APDC) will inevitably lead to under-reporting o...
The paper by Dahlen et al has predictably generated a public v
private maternity care debate in the Australian media. Unfortunately the
data upon which the conclusion of higher morbidity of babies born in
private maternity units is compromised by the manner in which the data was
collected. Basing the public hospital morbidity data on the NSW Admitted
Patient Data Collection (APDC) will inevitably lead to under-reporting of
diagnostic categories which the authors use as a proxy for neonatal
morbidity.
Numerous studies have shown that NSW Public Hospital Inpatient
Statistics consistently tend to under-report conditions (Hadfield RM,
Lain SJ, Cameron CA, Bell JC, Morris JM, Roberts CL. The prevalence of
maternal medical conditions during pregnancy and a validation of their
reporting in hospital discharge data. ANZ J Obstet Gynaecol 2008;48(1):78-
82.)
Why might this invalidate the authors conclusions? Private hospitals,
unlike public hospitals, are paid for care provided according to diagnosis
of conditions treated, so private hospital records on discharge are more
likely to record conditions presenting during the admission. Until 2013,
funding of public hospitals in NSW was based on annual budgets, and not
tied to recorded complexity/comorbidities. This has been acknowledged by
the significant resources currently allocated to more accurate inpatient
data collection with the move towards Activity Based Funding. It is likely
that the higher rate of conditions in private hospitals reported in the
study is at least partly due to under-reporting in the public hospitals
APDC.
It is clear private hospital maternity units have higher rates of
intervention than public hospital maternity units. The authors objective
of comparing neonatal outcomes between the two types of facility cannot be
achieved with the methods used.
Conflict of Interest:
I am an Obstetrician working in private and public practice
The use of complementary and alternative treatment in asthmatic
patients was very well described by Chen et al. It is indeed a good piece
of research wherein relationship of different types of CAM is done with
asthma severity and treatment by conventional medications. However, it is
also important to estimate the therapeutic-toxicologic safety profile
(risk-benefit ratio) of various CAM interventions for asthma 1. Also,...
The use of complementary and alternative treatment in asthmatic
patients was very well described by Chen et al. It is indeed a good piece
of research wherein relationship of different types of CAM is done with
asthma severity and treatment by conventional medications. However, it is
also important to estimate the therapeutic-toxicologic safety profile
(risk-benefit ratio) of various CAM interventions for asthma 1. Also, a
study done by Blanc et al revealed that there was increase incidence of
hospitalization with the use of herbal medicines, attributed to lack of
control of airway inflammation in herbal medicine 2.Similarly, Mizushima
and Kobayashi published a series of 24 cases of interstitial pneumonitis
induced by herbal remedies 3.Thus, it is important to assess via
questionnaire history of such episodes and the patients must be counseled
about potential benefits and harmful effects of the therapy they use.
Lastly, this study would have been more comprehensive if children were
also included in it.There has been tremendous rise in asthma in children
both in number and severity.This may be due to early exposure, immature
immunity or genetic factors 4. It is seen that many parents are opting for
CAM as a treatment modality for children due to concerns about the long
term treatment with conventional medicines 5.
This study indeed opens avenue for future investigators to look upon the
above mentioned factors for devising a better approach for preventing and
treating asthmatic patients.
REFERENCES:
1. L. Bielory, J. Russin, and G. B. Zuckerman, "Clinical efficacy,
mechanisms of action, and adverse effects of complementary and alternative
medicine therapies for asthma," Allergy and Asthma Proceedings, vol. 25,
no. 5, pp. 283-291, 2004
2. Marino LA, shen, Joannie. Characteristics of complementary and
alternative medicine use among adults with current asthma. Journal of
Asthma : 47;5; 2010: 521-525.
3. Sonibare MA, Gbile ZO. Ethnobotanical survey of anti- asthma plants in
south western Nigeria. Afr. J. trad. CAM 2008:5;340-345.
4. O'Connell EJ. The burden of atopy and asthma in children. Allergy. 2004
Aug;59 Suppl 78:7-11.
5. Helen Kopnina, "Alternative Treatment for Asthma: Case Study of Success
of Traditional Chinese Medicine Treatment of Children from Urban Areas
with Different Levels of Environmental Pollution,"ISRN Allergy, vol. 2012,
Article ID 547534, 6 pages, 2012.
Dahlen et al have published a paper looking at the rates of
intervention and morbidity in low risk women. Two valuable points are
made. Firstly that intervention rates in the private system remain higher
than those in the public system and secondly, though not a finding of this
study, that early term delivery may carry neonatal behavioural
consequences which warrant further consideration.
Dahlen et al have published a paper looking at the rates of
intervention and morbidity in low risk women. Two valuable points are
made. Firstly that intervention rates in the private system remain higher
than those in the public system and secondly, though not a finding of this
study, that early term delivery may carry neonatal behavioural
consequences which warrant further consideration.
However perhaps it would have been better if they had taken to heart
their own comment that their study protocol is limited by the "restricted
number of variables that are included (in routine data sets) and the
scarcity of specific information on potential influencing variables". It
is this scarcity of information that has led them to group variables "for
ease of analysis and interpretation" which lead to very misleading
conclusions.
Take the grouping together of Special Care Nursery admission with
Neonatal Intensive Care admission. These two events have such different
implications that grouping them together has the potential to hide
morbidity on one hand and to imply its presence incorrectly on the other.
Many private hospitals use their SCN as a neonatal general observation
area and in the past it was common for babies after Caesarean section to
spend time there while waiting for the mother to return to the ward. NICU
admissions on the other hand are reserved for babies who are very unwell.
In this study babies from public hospitals were 7 times more likely to be
transferred to another hospital and most of these will be for NICU
admission. In fact one in every 24 babies born to a low risk primigravid
woman in the public system had to be transferred to another hospital for
further care compared to 1:160 in the private. This is despite the fact
that all newborn intensive care units are in public hospitals, which means
that transfers to NICU within those hospitals are hidden (along with their
morbidity) whereas all private hospital babies needing NICU must be
transferred and therefore are identifiable.
This is also seen in the variable "requiring any resuscitation" which
includes any oxygen or suction. While it is valuable to point out to
practitioners that suction is rarely needed, it is not reasonable to
suggest that this implies that babies born in the private system are more
likely to need "resuscitation" which implies morbidity. There is no
evidence for this since Apgars < 7 were less likely in private
obstetrics and the need for transfer of a sick infant markedly less than
in public. Once again it is likely that variations in practice are wrongly
being interpreted as reflecting morbidity.
The next obvious questionable grouping is "trauma". In this grouping
the authors have combined Erb's palsy, broken bones and CNS trauma with
scalp abrasions. All these have been called "major birth and readmission
morbidities". While no-one would deny that Erbs palsy and broken bones
(both more common in the public system) are major traumas, does anyone
really believe that scalp abrasion is in the same category?
Not only inappropriate grouping of variables to enable statistically
significant but often clinically insignificant variances to be
demonstrated but also misleading language is a feature of the paper and
detracts from its merit. In the abstract it states that neonates in
private hospitals were more likely "to be readmitted in the first 28 days
with birth trauma (5%) hypoxia (1.7%)...". One has to go a long way
through the text before it can be determined that this "major birth
morbidity" was a in fact a composite of the birth admission and
readmission within 28 days and that it mostly represented scalp abrasion.
Moreover far from being "admitted for" these conditions, as stated in the
text, most of these were incidental observations made during the birth
admission (in a ratio of 64:1 for scalp abrasion). Many of these
documented findings had no impact at all on the baby or its wellbeing. The
fact that benign flow murmers were more common in private babies suggests
that these babies were being more closely examined by more skilled
observers (consultants vs residents and registrars) and it is likely that
they also documented other minor variations more closely. The authors
state in the discussion that birth trauma is associated with a range of
adverse outcomes which is true. However to imply that minor scalp
abrasions are related to neurological morbidity equates to a degree of
dissembling that is not relieved by, in the last sentence of the
discussion, saying that they are not suggesting that this is causal.
In terms of readmission with feeding difficulties and settling
problems it needs to be remembered that it is much easier to gain
readmission to a private hospital for help in such circumstances than in
the public where beds are under far greater pressure. People in the
private are effectively choosing to pay for help in these areas, they are
buying services at their discretion. A similar point may be made about
circumcision. Women in public hospitals are often unable to access
circumcision in the hospital, it is not offered. In the private women and
families are able to exercise their choice in this area whilst still in
hospital, in the public system it is done after discharge in doctor's
rooms and thus escapes notice in this data set.
Finally a point is made about babies and mothers being separated
after caesarean section. However this really relates to outdated practice
and most hospitals, both public and private, have been practicing so
called "baby friendly Caesars" for some years where mother and baby are
kept together throughout the procedure and where skin to skin contact and
breast feeding taking place in recovery barely 30 minutes after the baby
is delivered.
The topics discussed in this paper are important and it is a shame
that they have been treated with less than rigorous intellectual vigor.
Misleading language and inappropriate clinical grouping have resulted in
conclusions, both stated and implied, which cannot be drawn from the data
available. One has to conclude that the authors went to the data to prove
a preconceived belief. Unfortunately we have seen many times in the
history of medicine when this approach is taken misleading conclusions are
drawn, because if you torture the data enough, it will confess.
The study by Bouwmans and colleagues seems to be well designed and
thoroughly executed [1], but the primary results are surprising regarding
both the transcranial sonography (TCS) and dopamine transporters - single-
photon emission computed tomography (DAT-SPECT) results. According to
large scale prospective studies, DAT-SPECT should have a specificity close
to 100% in differentiating neurodegenerative parkinsonian syndrom...
The study by Bouwmans and colleagues seems to be well designed and
thoroughly executed [1], but the primary results are surprising regarding
both the transcranial sonography (TCS) and dopamine transporters - single-
photon emission computed tomography (DAT-SPECT) results. According to
large scale prospective studies, DAT-SPECT should have a specificity close
to 100% in differentiating neurodegenerative parkinsonian syndromes such
as Parkinson's disease (PD) and atypical parkinsonian disorders (APD)
based on the underlying nigrostriatal dopaminergic depletion versus other
conditions without nigrostriatal denervation [2,3]. In this study
specificity for PD was 68% and if merging the conditions which should not
be associated with nigrostriatal denervation (i.e. the groups essential
tremor, vascular parkinsonism, drug induced parkinsonism, and no
parkinsonism) it still was only 84%. Sensitivity of DAT-SPECT to diagnose
neurodegenerative parkinsonism was 88% for PD and 84% for
neurodegenerative parkinsonism (i.e. merging the groups PD, multiple
system atrophy, progressive supranuclear palsy, dementia with Lewy bodies,
and corticobasal degeneration) which is the range of the reported
sensitivity in literature. However, considering that DAT-SPECT should
detect neurodegenerative parkinsonian disorders in general, the negative
predictive value was only 74% due the high false negative rate
misclassifying subjects with a neurodegenerative process as having one of
the other conditions. Such diagnostic accuracy data suggest not to use DAT
-SPECT in the diagnostic work-up of patients presenting with a
parkinsonian syndrome of recent onset which is against current
recommendations [4,5]. Similarly, the TCS data in this study have
determined suboptimal diagnostic accuracy in detecting PD. Up to now
several independent studies by various groups have detected substantia
nigra (SN) hyperechogenicity in 80-90% of patients with PD [6-13].
Depending on the cut-off, approximately 10% of healthy adult controls and
patients with APDs and a slightly higher number of patients with ET have
been reported to show SN hyperechogenicity [6,14-17].
It is unclear, why both the TCS and DAT-SPECT results in this study were
surprisingly disappointing. Regarding the TCS data, one has to consider
that insufficient technical equipment may have played a role; the authors
used the Sonos 5500 Philips machine, which they had judged to be
insufficient to display SN- hyperechogenicity in an earlier analysis of
the baseline data ("Fourthly, the quality of the ultrasound system is a
non-neglectable variable, since in our pilot examinations, we found that
the newest ultrasound systems will reveal hyperechointensity of the SN in
more patients...") [18]. However, the Sonos 5500 Philips machine has also
been used by other groups, yielding useful images suitable for further
statistical analysis. It is well known that the way settings are adjusted
do play a major role for the visibility of structures under investigation.
It cannot be estimated why the authors had more problems in scanning with
this machine than other groups. Still, it needs to be acknowledged, that
they realized themselves, that they would have done better with another
device [18].
The main reason given by the authors for their discrepant results to the
literature is that they postulate that their study is the second
prospective after the study by Gaenslen et al. [20]. However, there are
several other prospective studies in this field, showing the diagnostic
utility of TCS in PD, APDs and essential tremor [6,17,22-24]and in the
assessment of PD risk in rapid eye movement sleep behaviour disorder
patients[25] as well as the general population [26]. Also recent
guidelines from the EFNS/MDS-ES recommend TCS for the differential
diagnosis of PD from APS and secondary parkinsonian syndromes, for the
early diagnosis of PD, and for the detection of subjects at risk for PD
[27]. As DAT-SPECT data are not in accordance with the clinical data,
clinical classification of the patients might have been suboptimal. Other
studies used DAT-imaging in addition to the clinical information to reach
a final diagnosis and it would be interesting to know the diagnostic
accuracy of TCS in the subjects, whose final clinical diagnosis was also
supported by their DAT-Scan.
Taken together, this study proves the importance of a good gold standard
for diagnosis of all disease entities investigated in studies trying to
validate other diagnostic instruments. Moreover, careful consideration
should be given to the devices used and to the way methods are applied and
data are analysed.
Affiliations:
Department of Neurology, Innsbruck Medical University (Philipp Mahlknecht
and Klaus Seppi)
Center of Neurology, Department of Neurodegeneration and Hertie Institute
for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany;
German Center for Neurodegenerative Diseases, University of Tuebingen,
Tuebingen, Germany (Daniela Berg)
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I read with interest the paper by Qina et al. which details by far
the largest experience of human prion disease associated with the V180I
variant of the prion protein gene. The term "genetic Creutzfeldt-Jakob
disease" will for many clinicians equate these patients with those
described in association with the highly penetrant E200K mutation of PRNP.
In my view however this would be misleading as carriers of V180I have a...
I read with interest the paper by Qina et al. which details by far
the largest experience of human prion disease associated with the V180I
variant of the prion protein gene. The term "genetic Creutzfeldt-Jakob
disease" will for many clinicians equate these patients with those
described in association with the highly penetrant E200K mutation of PRNP.
In my view however this would be misleading as carriers of V180I have a
very low lifetime risk of developing the disease.
We are fortunate in the last few years for the development of
databases describing the exome sequence of large series of healthy
individuals. One of these, the Human Genetic Variation Database, details
the variants found by exome sequencing of several thousand Japanese
individuals (http://www.genome.med.kyoto-u.ac.jp/SnpDB/about.html). At the
prion protein gene (PRNP), sequencing depth is good, and notably, V180I
was found in 18 samples from 2204 sequenced, implying a population carrier
frequency 0.008. http://www.genome.med.kyoto-u.ac.jp/SnpDB/cgi-
bin/frequency_plot.cgi?chr=chr20&range=4680404-4680404-437772&org_id=1.
This finding is not statistically significantly different from the report
in the paper of zero V180I carriers in 466 healthy controls sequenced
(P>0.05, Fisher's Exact test). V180I is an uncommon polymorphism in
East Asia, but this conclusion should not come as a surprise as Moe Lee
and colleagues reported finding V180I in healthy controls in 2012 (Prion,
PMID: 22561193).
These allele frequency data suggest that there are over a million
carriers of V180I in the Japanese population. Clearly for a very rare
disease like CJD, these numbers put the risk conferred by the variant in
perspective. I don't dispute that V180I increases risk of CJD, however,
the lifetime risk for carriers is likely to be <1%, hence a marked
contrast to other variants associated with genetic CJD. Also, it is
possible that the clinical data are contaminated by non-prion cases with
other neurodegenerative disease who are incidental carriers of V180I. To
allow for formal calculations of odds ratio it would be useful to know (1)
how many suspect cases (positive and negative for V180I) were sequenced by
Qina and colleagues, and (2) how many cases would have been diagnosed as
probable or definite CJD by WHO criteria in exclusion of the genetic data.
This information is particularly important to inform the genetic
counselling of V180I family members and accurate genotype-phenotype
studies.
Rossouw et al. addressed only the comparisons of results from randomized controlled trials (RCTs) and observational studies (OSs). They did not consider analyses that compared outcomes of participants who had the same treatment but were in different studies. These analyses found that adjusting for the WHI risk factors was not sufficient to account for unmeasured risk differences between subjects in different studies. T...
Dear Editors
I wish to formally submit this manuscript as a Letter to the Editors but I found there is no facility to do so under the BMJ Open ScholarOne portal.
I read with interest the research and conclusion presented by Dahlen et al; their key message that "For low-risk women, care in a private hospital, which includes higher rates of intervention, appears to be associated with higher rates of mor...
Sir,
The Maori population of New Zealand was about 12% at the time of the Vietnam war. The New Zealand Vietnam veterans have a Maori participation of 30%+ over double the percentage of Maori in the general population.
Statistics NZ tell us that Maori males die at twice the rate of Caucasians, mainly cancers, diabetes and heart attacks. By their late fifties Maori male mortality is two and a half time...
Please note, the acknowledgements and funding should read as follows: Acknowledgements: This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research (PGfAR) Programme (Grant Reference Number RP-PG-0407- 10029). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We t...
Roy, If we saw worse mortality in this group, we would have a problem. We don't, we see the 'healthy soldier' effect. This probably means that the Maori men in our sample were as healthy as anyone else.
Conflict of Interest:
None declared
The paper by Dahlen et al has predictably generated a public v private maternity care debate in the Australian media. Unfortunately the data upon which the conclusion of higher morbidity of babies born in private maternity units is compromised by the manner in which the data was collected. Basing the public hospital morbidity data on the NSW Admitted Patient Data Collection (APDC) will inevitably lead to under-reporting o...
The use of complementary and alternative treatment in asthmatic patients was very well described by Chen et al. It is indeed a good piece of research wherein relationship of different types of CAM is done with asthma severity and treatment by conventional medications. However, it is also important to estimate the therapeutic-toxicologic safety profile (risk-benefit ratio) of various CAM interventions for asthma 1. Also,...
Dear Editors
Dahlen et al have published a paper looking at the rates of intervention and morbidity in low risk women. Two valuable points are made. Firstly that intervention rates in the private system remain higher than those in the public system and secondly, though not a finding of this study, that early term delivery may carry neonatal behavioural consequences which warrant further consideration.
...
The study by Bouwmans and colleagues seems to be well designed and thoroughly executed [1], but the primary results are surprising regarding both the transcranial sonography (TCS) and dopamine transporters - single- photon emission computed tomography (DAT-SPECT) results. According to large scale prospective studies, DAT-SPECT should have a specificity close to 100% in differentiating neurodegenerative parkinsonian syndrom...
I read with interest the paper by Qina et al. which details by far the largest experience of human prion disease associated with the V180I variant of the prion protein gene. The term "genetic Creutzfeldt-Jakob disease" will for many clinicians equate these patients with those described in association with the highly penetrant E200K mutation of PRNP. In my view however this would be misleading as carriers of V180I have a...
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