Explanation of statistics in “Clinical outcomes” paper

Recently I had posted about this O’Sullivan “Clinical outcomes” paper.  And I had asked if anyone knew statistics and could understand what “older age of onset” means (the abstract indicates in MSA “older age of onset” is a factor “predicting shorter disease duration until death”) and what “early autonomic dysfunction” means (in MSA “early autonomic dysfunction” is a factor predicting shorter survival).

Well….local support group member Ted is a biostatistician!  He has answered these two questions in addition to providing a useful (and short) summary and some interesting comments about what is statistically significant.  Here’s Ted’s email below.  It’s just in time for the support group meeting tomorrow:  I know some of you MSA caregivers are really interested in this article!  Thanks Ted!



From Ted, local Brain Support Network group member

This is a complicated paper, so I’ll try just to summarize the parts I think are interesting, without adding very many thoughts of my own.

First, the very short version: MSA tends to start at a younger age than PSP.  Survival after getting the disease averages about 8 years for both diseases.

If you have PSP, you will tend to live longer if your early symptoms are more like typical Parkinson’s, if you are younger when you get the disease (though the difference isn’t large), if you are female, or if it is a comparatively long time before you hit your first “clinical milestone”, a list of bad things that happen as the disease progresses (I have a list below).

If you have MSA, you will tend to live longer if you are admitted to residential care at some point, if you do not have early autonomic dysfunction (various symptoms related to urination, digestion, sweating, blood pressure, and sexual function, within the first two years after onset; list below), if you are younger when you get the disease (again, not a big difference), if you are male (but this is a little complicated, as I explain below), and if it is a comparatively long time before you reach your first clinical milestone.

For both diseases, the degree of response to L-dopa does not appear to be associated with survival, at least in this study.

In this paper, the diagnosis of PSP or MSA is based on autopsy results.  The authors note that the accuracy of diagnosis during the patients’ lifetimes was less than 100%, and that PSP and MSA are often hard to distinguish during the patient’s lifetime.   All the conclusions presented were based on a set of 110 PSP patients and 83 MSA patients who had sought treatment and permitted autopsies at the Queen’s Square Brain Bank for Neurological Disorders.  This group of patients may not be exactly comparable to our own group of family members with PSP and MSA.

Now the less short version, in answer to your two questions:

Older age of onset:  First, “age of onset” means the age at which the first symptom attributable to PSP or MSA appeared in the patient’s medical record.  This is usually earlier than age at diagnosis (by 3-4 years on average; table 1).  “Older age of onset” does not refer to any specific cutoff age, but instead to the authors’ finding that patients who are older at onset tend not to live as long as patients who are younger at onset.  The “hazard ratio” for age of onset increases at 5% per year for both MSA and PSP (table 2).  The “hazard” is the rate at which patients die, so it would be measured in units like 10 deaths per year per 100 patients.   So, for example, patients with age of onset 64 would have a hazard approximately 20% higher (hazard ratio 1.2) than that of otherwise comparable patients with an age of onset of 60 (4 years younger at onset times 5% per year).

This is a small effect compared to some of the others shown in the table.  As an example, for PSP patients, male gender has a hazard ratio of 1.7 (meaning men have a 70% higher hazard than comparable women), which is equivalent to about an 11-year age difference at onset (the actual calculation is somewhat more complicated than just multiplying number of years times 5%).  So for PSP patients, a male with onset at 60 would have about the same hazard as an otherwise similar female with onset at 71.  Age isn’t in the same league as the big hazard ratios in the table, such as early autonomic dysfunction for MSA patients (hazard ratio 6.0).   I don’t think it’s clear from the paper how much of the age effect is due to differences in the progression of the disease versus just the increased hazard you would see in any comparison of older people versus younger.

Early autonomic dysfunction:  The autonomic nervous system regulates bodily functions like heart rate, respiration, digestion, salivation, urination, and sexual arousal.   For the purposes of the paper, autonomic dysfunction was defined to mean either an abnormal autonomic function test result, or (and I think this was what was used for the vast majority of cases) having two or more of the following set of symptoms, as reported by the patient:

  1. Frequent or urgent need to urinate, or “nocturia without hesitancy”, which sounds like it might mean either bedwetting or urgently needing to get up during the night to urinate; I’m not sure of the exact medical usage;
  2. Chronic constipation;
  3. Postural hypotension, presenting either as a complaint from the patient or just from observing a sufficient difference between sitting and standing blood pressure in the doctor’s office;
  4. Sweating abnormalities; and
  5. Erectile dysfunction.

Autonomic dysfunction was classified as early if it appeared within 2 years of onset (as defined above, first attributable symptom in the medical record).  The presence of erectile dysfunction on the list is a complicating factor, because it is a symptom that only men can experience, which means it is easier for a male patient to be classified as having early autonomic dysfunction than a female patient.  The authors mention this, and note that, as one would expect, a higher proportion of male patients had early autonomic dysfunction.  I’ll say a bit more about this later.

Finally, some unsolicited bonus commentary:

If you read the paper yourself, the word “significant”, or “statistically significant”  is used in a technical sense different from the everyday meaning.  A statistically significant effect is one for which the evidence is strong.  The effect itself may be rather weak (or it may not be).  So, for example, in table 2 the effect of age of onset is statistically significant, but it doesn’t have a very large effect on the hazard ratio compared with, say, the RS phenotype for PSP.

OK, then going over table 2, the biggest effect for PSP seems to be the RS phenotype.  This means that time to survival is shorter for patients whose main symptoms during the first two years are falls, cognitive dysfunction, supranuclear gaze palsy, abnormal saccadic (quick) eye movements, and postural instability.  PSP-P patients, whose first two years are more along the lines of typical Parkinson’s, with slow movement, tremor, some response to L-dopa, asymmetric onset and limb stiffness, tend to survive longer.  The hazard ratio is 2.37.   There were some patients for whom it was not clear which group they fell into, and they were excluded from the analysis.  Male gender is associated with shorter survival (hazard ratio 1.7), as is older age of onset, but for age it’s not a big difference.  Finally, patients who reach their first clinical milestone later tend to survive longer.  This is another per-year effect, with each year of delay for the first milestone reducing hazard by 20%.  On average, PSP patients’ time to first milestone varies by two or three years (bottom rows of table 3, showing a standard deviation of 2.7 years for PSP), so at 20% per year this is a pretty big effect.

For MSA, the big effects, which are really big, are early autonomic dysfunction (hazard ratio 6.0), and female gender (hazard ratio 3.0).  Both of these shorten survival, and I think they have to be viewed as a unit because of the erectile dysfunction symptom, which makes it easier for men to be classified as having early autonomic dysfunction.  It seems to me the high estimated hazard ratio for the female group may partly be explained as a “penalty” the female group pays for the greater proportion of undiagnosed early autonomic dysfunction in that group (this is my opinion, not the authors’, and I could be wrong).  Again for MSA patients, age of onset and interval to first milestone show up, with similar results.  Finally, not being admitted to residential care has an estimated hazard ratio of 2.8, so (perhaps surprisingly) residential care seems to increase survival for MSA.

The clinical milestones are a list of seven bad things that may happen to patients between disease onset and death: (1) frequent falls (2/year or more); (2) dependency on a wheelchair; (3) unintelligible speech; (4) severe dysphagia (difficulty swallowing); (5) use of a urinary catheter; (6) cognitive impairment; and (7) entering residential care.  Most patients experience at least a few of these (figure 2), but very few experience all seven.  Table 3 is a big summary of roughly when each milestone tends to occur (among patients that experience it), and a comparison of frequency of milestones between the disease groups.  Figure 4 plots the average times at which milestones occur, relative to the disease course, for Parkinson’s, PSP, and MSA.  The figure also shows time of diagnosis.  I’m a little dismayed to see how MSA patients seem to have a pileup of milestones at the end of life (although again, most patients don’t experience all milestones, and the times shown are the average for patients that do experience it).   I like the way the figure displays the average age of onset and duration for the three diseases.

Here’s the figure four of the O’Sullivan paper:

O’Sullivan et al, Fig. 4

Well, I think that’s all I have to say.  I hope it’s not too incomprehensible.  Please feel free to distribute this, or parts of it, to the group.



“Antipsychotics Dangerous for Elderly With Dementia”

This post will be of interest to those dealing antipsychotics (such as Haldol, Seroquel, or Risperdal) in the elderly with dementia.  Many with Lewy Body Dementia take this type of medication.  I have heard of a few people with Progressive Supranuclear Palsy, Corticobasal Degeneration, and even Multiple System Atrophy taking this type of medication.

HealthDay News (at everydayhealth.com) published a news article earlier this week on a new study showing that:

“Elderly people with dementia who are given antipsychotics, even for a very short period of time, are more likely to end up in the hospital or even die, new research shows.”

This is some follow-up to Canadian research published in June ’07 on the same subject (PubMed ID#17548409).  (Many of the researchers are the same on the two studies.)

The news article included reference to an Alzheimer’s Association (alz.org) publication on using antipsychotics in those with AD.  This publication is worth reading:


There is an FDA “black box” warning on the atypical antipsychotics.  You can find the April ’05 FDA warning on fda.gov at:


The HealthDay News article follows.  Below that is the abstract of the medical journal article.




Antipsychotics Dangerous for Elderly With Dementia
HealthDay News
Published: 05/27/08

MONDAY, May 26 (HealthDay News) — Elderly people with dementia who are given antipsychotics, even for a very short period of time, are more likely to end up in the hospital or even die, new research shows.

However, the problems underlying the need for such medications, behavioral problems such as aggression and agitation, are very real, and the alternatives to antipsychotics are limited, the researchers added.

“A misreading of the findings would be we don’t need to do something for these nursing home residents,” said study author Dr. Gary J. Kennedy, head of geriatric psychiatry for Montefiore Medical Center in New York City.

Many experts feel behavioral interventions should be tried first and antipsychotics used as a last resort, “when the behavior or the psychiatric symptoms are really out of control and causing complete distress not only for the person suffering from Alzheimer’s, but for caregivers all around them,” said Maria Carrillo, director of medical and scientific affairs at the Alzheimer’s Association in Chicago. “It’s important to work these things out with the physician and, of course, do follow-up very closely together, so you can make sure these antipsychotics are having the effect you want and, if not, discontinue them immediately.”

The findings were published in the May 26 issue of the Archives of Internal Medicine.

Antipsychotic drugs are commonly used to treat some of the behavioral complications of dementia, including delirium.

Newer antipsychotic medications such as Zyprexa (olanzapine) and Risperdal (risperidone) have been available for about a decade and have largely replaced their older counterparts.

Researchers from the Institute for Clinical Evaluative Sciences in Ontario, Canada, compared 20,682 older adults with dementia living in the community with 20,559 older adults with dementia living in a nursing home between April 1, 1997, and March 31, 2004.

Each group was divided into three subgroups: those not receiving any antipsychotics, those taking newer antipsychotics, and those taking older antipsychotics such as Haldol (haloperidol).

According to information gleaned from medical records, community-dwelling adults who had recently received a prescription for a newer antipsychotic medication were 3.2 times more likely than individuals who had received no antipsychotic therapy to be hospitalized or to die during 30 days of follow-up.

Those who received older antipsychotic therapy were 3.8 times more likely to have such an event, relative to their peers who had received no antipsychotic therapy.

A similar pattern, albeit less dramatic, emerged in the nursing home group. Individuals taking older antipsychotics were 2.4 times more likely to be hospitalized or die, while those taking newer drugs were 1.9 times more likely to die or be hospitalized during the 30 days of follow-up.

The study does, however, have its limitations. “It’s a carefully done study,” Kennedy said. “One flaw is that the [participants] weren’t randomly administered antipsychotics. There was some reason they were given an antipsychotic, such as aggression or agitation. It may have been done if they were recently admitted to the nursing home as part of the adjustment process.

Indeed, the authors acknowledged that about 17 percent of patients entering nursing homes start taking an antipsychotic within 100 days.

“For any of us, moving is like being sick. It takes a while to recover,” Kennedy said. “We need other sets of interventions besides medications. What that implies is more staffing and better training for staff, and that may not be a whole lot more expensive than medicines.”


Here’s the abstract of the medical journal article:

Archives of Internal Medicine. 2008 May 26;168(10):1090-6.

Antipsychotic therapy and short-term serious events in older adults with dementia.

Rochon PA, Normand SL, Gomes T, Gill SS, Anderson GM, Melo M, Sykora K, Lipscombe L, Bell CM, Gurwitz JH.
Department of Medicine, University of Toronto, Canada.

BACKGROUND: Antipsychotic therapy is widely used to treat behavioral problems in older adults with dementia. Cohort studies evaluating the safety of antipsychotic therapy generally focus on a single adverse event. We compared the rate of developing any serious event, a composite outcome defined as an event serious enough to lead to an acute care hospital admission or death within 30 days of initiating antipsychotic therapy, to better estimate the overall burden of short-term harm associated with these agents.

METHODS: In this population-based, retrospective cohort study, we identified 20 682 matched older adults with dementia living in the community and 20 559 matched individuals living in a nursing home between April 1, 1997, and March 31, 2004. Propensity-based matching was used to balance differences between the drug exposure groups in each setting. To examine the effects of antipsychotic drug use on the composite outcome of any serious event we used a conditional logistic regression model. We also estimated adjusted odds ratios using models that included all covariates with a standard difference greater than 0.10.

RESULTS: Relative to those who received no antipsychotic therapy, community-dwelling older adults newly dispensed an atypical antipsychotic therapy were 3.2 times more likely (95% confidence interval, 2.77-3.68) and those who received conventional antipsychotic therapy were 3.8 times more likely (95% confidence interval, 3.31-4.39) to develop any serious event during the 30 days of follow-up. The pattern of serious events was similar but less pronounced among older adults living in a nursing home.

CONCLUSIONS: Serious events, as indicated by a hospital admission or death, are frequent following the short-term use of antipsychotic drugs in older adults with dementia. Antipsychotic drugs should be used with caution even when short-term therapy is being prescribed.

PubMed ID#: 18504337  (see pubmed.gov for the abstract)

German CoQ10 study results published

This German CoQ10 study was announced a couple of years ago. Results have finally been published. Researchers “performed a double-blind, randomized, placebo-controlled, phase II trial, including 21 clinically probable PSP patients (stage </= III) to receive a liquid nanodispersion of CoQ(10) (5 mg/kg/day) or matching placebo. … CoQ(10) was safe and well tolerated. … Clinically, the PSP rating scale and the Frontal Assessment Battery improved slightly, but significantly, upon CoQ(10) treatment compared to placebo. Since CoQ(10) appears to improve cerebral energy metabolism in PSP, long-term treatment might have a disease-modifying, neuroprotective effect.”

I’m assuming that the “PSP rating scale” used is the rating scale developed by Dr. Golbe. You can find this online at:

Here’s the abstract of the article:

Movement Disorders. 2008 May 7 [Epub ahead of print]

Short-term effects of coenzyme Q(10) in progressive supranuclear palsy: A randomized, placebo-controlled trial.

Stamelou M, Reuss A, Pilatus U, Magerkurth J, Niklowitz P, Eggert KM, Krisp A, Menke T, Schade-Brittinger C, Oertel WH, Höglinger GU.
Department of Neurology, Philipps University, Marburg, Germany.

Mitochondrial complex I appears to be dysfunctional in progressive supranuclear palsy (PSP). Coenzyme Q(10) (CoQ(10)) is a physiological cofactor of complex I. Therefore, we evaluated the short-term effects of CoQ(10) in PSP. We performed a double-blind, randomized, placebo-controlled, phase II trial, including 21 clinically probable PSP patients (stage </= III) to receive a liquid nanodispersion of CoQ(10) (5 mg/kg/day) or matching placebo. Over a 6-week period, we determined the change in CoQ(10) serum concentration, cerebral energy metabolites (by (31)P- and (1)H-magnetic resonance spectroscopy), motor and neuropsychological dysfunction (PSP rating scale, UPDRS III, Hoehn and Yahr stage, Frontal Assessment Battery, Mini Mental Status Examination, Montgomery Asberg Depression Scale). CoQ(10) was safe and well tolerated. In patients receiving CoQ(10) compared to placebo, the concentration of low-energy phosphates (adenosine-diphosphate, unphosphorylated creatine) decreased. Consequently, the ratio of high-energy phosphates to low-energy phosphates (adenosine-triphosphate to adenosine-diphosphate, phospho-creatine to unphosphorylated creatine) increased. These changes were significant in the occipital lobe and showed a consistent trend in the basal ganglia. Clinically, the PSP rating scale and the Frontal Assessment Battery improved slightly, but significantly, upon CoQ(10) treatment compared to placebo. Since CoQ(10) appears to improve cerebral energy metabolism in PSP, long-term treatment might have a disease-modifying, neuroprotective effect.

PubMed ID#: 18464278 (see pubmed.gov)

Depression preceding the onset of progressive supranuclear palsy (PSP)

My online friend Joe Blanc posted this abstract today to the Society for PSP’s Forum.  It’s a case report that describes depression preceding the onset of progressive supranuclear palsy.  Joe said that the “description of the phenomenon matches very well what I observed with my late wife Nutey.”

The abstract is below.



J Neuropsychiatry Clin Neurosci 20:247-a-248, May 2008
© 2008 American Neuropsychiatric Association

Depression Preceding the Onset of Progressive Supranuclear Paralysis: A Case Report

Arnim Quante, M.D., Franziska Jakob, M.D. and Juergen Wolf, M.D., Department of Psychiatry and Psychotherapy, University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany

To the Editor: Progressive supranuclear palsy is a movement disorder which often causes parkinsonian symptoms. Typical clinical findings in progressive supranuclear palsy are supranuclear vertical gaze palsy, postural instability, gait abnormality, bradykinesia, dysarthria, an increased axial tone, and a frightened facial expression. There are hints that patients diagnosed with progressive supranuclear palsy have an increased risk for developing depressive-like syndromes within the next years.1 However, to our knowledge, there is no data recording major depression as an antecedent symptom of later diagnosed progressive supranuclear palsy.

Case Report
A 57-year-old man was admitted to our hospital for a major depressive syndrome without psychotic features. His main symptoms were depressed mood, anhedonia, apathy, loss of activity, difficulties in concentration, and self-reproach feelings. Attention and short-term memory were slightly impaired.

He indicated that this first depressive episode began 4 years earlier. No neurological, general medical, or psychiatric diseases had been described or diagnosed before. Within the first 3 months of the episode, depressive symptoms improved spontaneously; however, slightly depressed mood and concentration difficulties persisted until the time of admission. During the last year, decreased motor activity with slowed movements was observed. Moreover, he sometimes stumbled, had a tendency to fall backward, and had difficulties in walking down stairs. During the last month before admission these symptoms worsened. His wife described a change in his manner: he had become more and more apathetic, had increasing cognitive declines, and neared almost complete motor inactivity. He was admitted to our hospital for further diagnosis.

Neurological examination showed moderate hypomimia with a frightened facial expression, pathological eye movements with voluntary saccades, ocular pursuit movements, and vertical gaze palsy (impairment of voluntary vertical eye movements with preservation of reflex vertical eye movements). His motor activity was decreased; he had a slight rigor of the left arm and an increased axial tone with neck extension. Furthermore, we found a slight bradykinesia of the left arm and an unstable gait. He also described writing difficulties, but the type face was not changed in terms of a micrography.

No pathological findings were obtained by physical examination or standard laboratory tests including the liquor cerebrospinalis, EEG, ECG, and MRI of the head. To differentiate progressive supranuclear palsy from Parkinson’s disease and other related disorders, we tested the response to L-dopa. The intake of dopamine (Madopa® 500 mg/day) did not lead to any improvements. This lack of appreciable response to L-dopa and dopaminergic drugs characterizes progressive supranuclear palsy.
Taking all findings together, we diagnosed a progressive supranuclear palsy which started with a major depressive episode according to the DSM-IV criteria.

As far as we know, this case report is the first published report of a patient with a depressive episode as a first (“soft”) sign of a progressive supranuclear palsy. There are reports and even studies of progressive supranuclear palsy-associated depressive-like symptoms, especially apathy, disinhibition, dysphoria, and anxiety.2 Awareness of possibly preceding psychiatric aspects like a depressive state as the first symptom of developing progressive supranuclear palsy may be helpful for an early diagnosis of this and other neurodegenerative diseases.

1. Menza MA, Cocchiola J, Golbe LI: Psychiatric symptoms in progressive supranuclear palsy. Psychosomatics 1995; 36:550–554
2. Litvan I, Mega MS, Cummings JL, et al: Neuropsychiatric aspects of progressive supranuclear palsy. Neurology 1996; 47:1184–1189


Do people near the end “starve to death” or “die of thirst”?

This is an excerpt of a post recently published on the Society for PSP’s Forum, an online discussion group.  The author is my online friend Ed Plowman.  Though he writes about his wife Rose with progressive supranuclear palsy, his comments apply to those nearing the end with any disorder.  Ed addresses whether those nearing the end suffer from starvation or thirst.



Excerpt of a post by Ed Plowman
Society for PSP Forum
Mon May 05, 2008 11:05 pm

Two hospice doctors and a hospice nurse explained to me what the final days for Rose will be like if she no longer can swallow or take fluid, and remains adamant about no feeding tube or IV hydration. Morphine likely will be administered. (I was with a dying friend recently who was on morphine; he seemed completely normal, not in a “drugged stupor” — a common misconception about the effects of morphine, as I understand it — and we conversed normally for hours with each other and members of his family. He knew the end was near, he seemed relaxed and calm.)

My youngest daughter said she could not stand by while her mother starves to death or dies of thirst. The hospice docs explained that with morphine, that doesn’t happen. The patient has no desire to eat, and often has no sensation of thirst. Moistening the lips and mouth will alleviate discomfort from “dryness.” After the patient stops eating, the body normally will begin the shutdown process; it will produce and release from the pituitary gland endorphins, or endomorphines — a natural form of morphine. These biochemicals give the patient a calming sense of wellbeing. Eventually, in many cases, when the respiratory system begins to shut down, the patient falls asleep, breathing becomes shallow, and the end is peaceful. (That’s how it was with the dying friend I mentioned above.)

The end script is not exactly the same for everyone, of course. But the hospice staff said they’ve not seen any of their patients, many of whom could not eat or drink at the end, die of hunger or thirst as many people commonly envision.

I think it’s important that the family gather together in harmony, compassion, and loving appreciation as the end nears. It wouldn’t hurt to recount a few unforgettable positive memories involving the loved one. Some families sing favorite hymns; someone may feel led to say a prayer of thankfulness for what the loved one has meant in the lives of family members. The loved one with PSP may not be able to speak or even move. But he or she will hear and understand all that is said and done. This can be a precious, joyful time for him or her.

I believe we are fast approaching this time of transition at our house.

ed p.