Estimating typical MS disability progression speed.....

[MSUK]

Estimating typical Multiple Sclerosis disability progression speed from clinical observations

Murray G. Brown, Mark Asbridge, Vern Hicks, Sarah Kirby, Thomas J. Murray, Pantelis Andreou, Dong Lin

Abstract

Introduction

Multiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods.

Methods

Our Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R-MS) natural history patients with 18,078 Expanded Disability Status Scale (EDSS) clinical observations in study period 1979–2010. Progression speed is measured by rate-of-change in range EDSS 0–6 and by survival time at irreversible endpoints EDSS 1–9. Midpoint censoring-bias-reduction methods are applied to clinical observations.

Findings

Typical EDSS increase per year in range EDSS 0–6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed.

Conclusions

Estimates of typical disease progression speed from 1979–2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts’ survival time assumptions. Censoring-bias-adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable within and across study groups and time periods, than unadjusted estimates, and are, arguably, more relevant for various stakeholders. The application of censoring-bias-reduction methods to other multiple sclerosis clinical databases may reduce variability in estimates of disability progression speed worldwide.

Full Article http://www.plosone.org/article/info%3Ad ... ne.0105123

Source: PLOS © 2014 Brown et al (20/10/14) http://www.ms-uk.org/qol

[ElliotB]

Am I reading this correctly that the EDSS yearly increase is higher for those taking DMDs than those that are not?

[DrGeoff]

I thought the same thing as ElliotB. So I read some more, and it looked worse. This could be:
a - It's coming up to tenure renewal time - better get a publication out fast.
b - There is something in this data - better get a publication out fast before someone else does.

The paper is proving really hard to download - I keep getting a "page reset".
Saying that the same unique case could be in more than one section, does make me wonder if the data was massaged to fit a theory.
Some of the figures would not download for me.
I did not find it clear how the "mid-point" was calculated.
I wondered why a EDSS of 6.0 was chosen as the upper limit of disability. Starting from EDSS 1.0 I can understand. Stopping at 6.0 rather than 6.5 or 7 does look like being selective with the data.
It has what is probably the worst abstract I have ever seen. And, moreover:
The sentence in the "Findings" section of the abstract has the statement pointed out by Elliot, followes by a sentence that appears to say exactly the opposite.

Not really a lot of use to anyone interested in the actual progression of MS (either their own, or another person's.

Geoff

[Kronk]

The goal of the study was to see if censoring-bias and analysts’ survival time assumptions affected the progression rates. It was not to determine what the progression rates are. I can only assume the data they are showing is not referring specifically to progression rates, but instead to the subgoups of data that they are examining as shown on the charts.

If we are to ignore that it makes absolutely no sense as Dr. Geoff pointed out they have conflicting statements. All conclusions drawn from the info would be speculation as we don’t know what they are referring to due to a really poorly written abstract.

The date range is very unusual as well as many of the DMDs offered today were not available for much of the patient data they are collecting. Again I think that without knowing what the data is referring to we cannot draw any conclusions from it… The title of this topic is also very misleading as the intentions of the study do not appear to be the determination of progression rates. Altogether WEIRD

[David1949]

I agree with the earlier posters; The report is poorly written and confusing. And interestingly it says that people who took the DMDs got worse faster than those who did not:

Findings

Typical EDSS increase per year in range EDSS 0–6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients.

As noted before the report is confusing so maybe it doesn't actually mean what it says. But if the findings are correct then one of the things you get for paying $20,000-$40,000 per year for DMDs is you get worse faster than if you didn't take the drugs. What a deal.

[Kronk]

That is a point that stands out... but it flies in the face of every other study prior to this and it is contradicted by the very next statement in the abstract...

"...Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients..."

[David1949]

That is a point that stands out... but it flies in the face of every other study prior to this and it is contradicted by the very next statement in the abstract...

"...Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients..."

Kronk
This is another area where the report is unclear. What does the quoted sentence mean? Anyway if you look at the bar chart in the report titled
"Survival time assumed in range EDSS 0-3 ' it is clear that the yearly increase in EDSS is less for people who didn't take the drugs than for people who did. This is true for both the midpoint and the maximum. Same situation for the bar chart titled "Survival time assumed in range EDSS 0-6".

Also I have not seen studies that show delayed progression of disability for people who take the DMDs. If you have a link to such a study I would like to see it. I think there are studies that show fewer relapses for people who take the DMDs and also less scarring. But I haven't seen any that show delayed progression of disability. I'm not saying they don't exist, just that I am not aware of any.

PS Ashton Embry reviewed three recent studies which looked at the effectiveness of the CRAB drugs in delaying progression of disability. He concluded that the drugs are not effective in that regard. http://www.direct-ms.org/sites/default/ ... 7%2010.pdf

PS2 Here is an article in the New York Times discussing another recent study which showed that interferon -beta does not delay progression of disability.
http://www.nytimes.com/2012/07/18/healt ... html?_r=5&

[cheerleader]

I was able to read the full paper, online here:
http://www.plosone.org/article/fetchObj ... tation=PDF

The paper effectively explained censoring bias and differences in observing and monitoring disease progression in treated and treatment naive patients, as stated in the conclusion of the abstract.

from the paper:

Estimates of disease progression speed from unadjusted clinical observations implicitly assume maximum survival time – that each patient’s disease does not progress (as measured at their previous clinic visit) until immediately before their next clinic visit. In fact, only rarely do patients experience maximum survival times. In reality, their disease may progress at any point during the interval. Assuming maximal survival times will underestimate disease progression speed. The longer the interval is between observations, the larger the interval censoring bias and the larger the underestimation. Missing (censored) information between exper-imental study observations collected prospectively at frequent andregular intervals over short study periods is typically small, by design.

Estimates of disability progression speed from clinical observations which assume midpoint survival time are significantly faster than estimates which assume maximum survival time. These results suggest that, at least for observations collected at Dalhousie Multiple Sclerosis Research Unit (DMSRU) clinics from 1979– 2010, the missing (censored) information between clinical observations is too large and variable to ignore.

Clinical assessments per patient per year were initially infrequent, increased gradually over time, varied greatly within and across study groups, and increased abruptly if patients began disease-modifying-drug treatment. It is therefore not surprising that estimates of progression speed from unadjusted clinical observations, which implicitly assume maximum survival time, vary greatly across study groups and study periods, or that censoring-bias-adjusted estimates, which assume midpoint survival time, are faster and more stable.

What are the implications for effectiveness studies of treatments expected to slow disease progression? To minimize bias in treatment effect estimates that is attributable to censoring-bias, the censoring-bias in treatment-group observations should be as similar as possible to that in natural history comparator-group observations. Treatment effect estimates will be downward-biased, to some degree, whenever censoring-bias in comparator-group observations is greater than in treatment-group observations.

Dr. Helen Tremlett of UBC has published on how the growing lack of treatment naive patients is changing our understanding of natural MS disease progression. How can we say that the DMDs are slowing MS disease progression, if we are not using consistent assessments? Or if we do not fully understand natural MS disease progression? Tremlett has been very vocal about this problem, and how DMDs are overstating their benefits. http://news.ubc.ca/2012/10/17/some-ms-p ... -research/

cheer

[David1949]

Thanks for the info Cheer. That explains the meaning of maximum and midpoint as used in this study.

[Kronk]

Thanks Cheer, that definitely adds some insight into the study.

Also I have not seen studies that show delayed progression of disability for people who take the DMDs. If you have a link to such a study I would like to see it.

David the studies on progression are typically not encouraging but 2 seem to show a slowing of disability...

TECFIDERA -
https://www.insightsinms.com/the-mystiq ... ra-part-2/

...the study revealed Tecfidera treatments were able to slow disability progression by approximately 38%...

COPAXONE
http://www.drugs.com/clinical_trials/lo ... -2226.html

...The majority of patients (84.8 percent) in the ongoing cohort (n=112), who continuously received COPAXONE(R) showed either unchanged or improved disability scores, as measured by Expanded Disability Status Scale (EDSS)...

I personally don't put a ton of faith in the study on Copaxone as it was not done in a blinded study. But was performed in Latin America vs. Israel where the manufacturer is based.

[cheerleader]

Hey Kronk--
Those 2 drug studies kind of prove the point of the paper we're discussing on this thread----they use shorter time periods than the duration of those followed who are treatment naive, and evaluations are much more frequent than in treatment naive patients. (In the Tecfidera study, patients who received treatment were only followed 2 yrs. And although there was a treatment naive cohort in the Copaxone study, they were not followed as long as those who stayed on Copaxone. And for the patient group who discontinued use, we need to understand why they stopped. Was their disease more aggressive? Is the success of the Copaxone group due to a naturally milder disease course? Lots of questions which make interpretation of success rates difficult to intuit.)

What the authors of the new paper conclude is that this shortened and heightened time frame gives a censoring bias to the drug studies, which needs to be mathematically adjusted in order to understand true disability progression in MS.

cheer