Recently in Epidemiology Category

Two articles in this week's Neurology consider the significance of biomarkers for Alzheimer disease in the cognitively normal elderly.

Essentially confirming a recently published Mayo Clinic study, investigators from Texas reported the high prevalence of beta amyloid deposits (detected with Avid Pharmaceutical's PET tracer florbetapir) in the brains of a substantial portion (~20%) of healthy elderly subjects (aged 60 years or older). A high burden* of beta amyloid was associated with 1) the presence of the e4 allele of APOE, a genetic risk factor for AD and 2) poorer cognitive performance on more sophisticated** cognitive tests. The authors, two of whom receive financial support or have a financial interest in Avid Pharmaceuticals, suggest that "subtle cognitive changes accrue as amyloid progresses." The implication being that brain amyloid in the so-called healthy elderly may be more predictive than not about the risk of AD (an essential point or spin, if you will, which argues for the clinical utility of Avid's amyloid tracer). However, the authors also concede that "the relative contribution of amyloid vs other well-demonstrated predictors of cognitive aging (eg, regional atrophy, leukoaraiosis) is unclear." Among recommended follow-up studies is the assessment of the long-term consequences of amyloid deposition—ie, Are cognitively normal elderly with high amyloid burdens more like to development AD...that is, if they live long enough?. The question can only be answered with longitudinal follow-up study, which is planned.

Another multi-multi-authored international study assessed the effect of aging on the diagnostic value of CSF biomarkers for AD—specifically the triad of decreased amyloid and increased total and phosphorylated tau—in cognitively normal elderly. This study was distinctive in that, in addition to assessing individuals with AD and healthy elderly controls, a short (2-year) longitudinal assessment was made of subjects with mild cognitive impairment (MCI). The related conclusions (if I'm reading this article correctly and can recall anything useful about specificity, sensitivity, and positive and negative predictive values***) are 1) that there is substantial overlap in the biomarker distributions among these subgroups with advancing age and 2) that (therefore) the specificity of the biomarkers for ruling out AD decreases with age. Nevertheless, the sensitivity (85% cutoff) for the triad in MCI and AD, perhaps not too surprisingly, remained stable. In other words, the biomarker triad lost its strength to identify people with truly negative results as they aged (a decreased negative predictive value), but its ability to recognize truly AD-consistent findings (positive predictive value) remained stable—at least according to the authors and/or how I'm reading the study.

The overall conclusion, therefore, is that positive biomarkers for AD become less and less meaningful (as an indicator of AD) in the general elderly population—which is, ironically, the group in which these tests are most likely to be needed and used.

Addendum: Some would view these study results to mean that amyloid deposits and the triad of CSF changes are suggestive (or even indicative) of age-dependent cognitive dysfunction, albeit very subtle cognitive dysfunction. But the capacity of these tests to support or even confirm a diagnosis of clinical AD—depending on how we're defining the condition (there's the rub, isn't it?)—appears to be eroded in the older, general population (because they're more likely to demonstrate these findings, regardless of whether they demonstrate clinical meaningful cognitive dysfunction).

APOE = apolipoprotein E; SUVR = standardized uptake value ratio.

* At a mean SUVR cutoff of 1.22 or greater.
** Meaning more sophisticated than the Mini-Mental State Examination (MMSE).
*** Damn you, rudimentary biostatistics, when will you leave me alone!

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

And probably rightly so, given a number of issues.

• The Harvard press release is terribly (and irresponsibly) overdramatic, emphasizing the "endocrine-disrupting" effect of bisphenol A (which is only documented in laboratory animals, to my knowledge) and the >1200% increase in urinary BPA after consuming canned soup (Progresso) for 5 days. There is no mention of absolute numbers in the attention-grabbing press release, just the astonishing percentage jump.
  
• The JAMA report, available here (courtesy of JunkScience.com), is actually published as a letter and not a more stringently peer-reviewed article.
  
• JunkScience.com takes the letter authors to task for not distinguishing between the urinary measurement of BPA (which is evidently not possible or very difficult) and that of a quickly produced metabolite. BPA is evidently rapidly processed in the body, and its "biologically inactive" metabolite (not BPA per se) was actually measured in urine, says JunkScience.com (the blog further claims that at least some of the authors should have known or do know this fact).
  
• While the percentage increase of mean urinary BPA values among canned-soup eaters is very impressive, we're talking about differences in MICROGRAMS PER LITER: 1.1 mcg/L after 5 days of fresh-soup consumption vs 20.8 mcg/L after 5 days of canned-soup consumption, for a difference of 19.7 mcg/L.*
  
• The urinary spike in BPA (or its metabolite) was probably transient, and the authors themselves acknowledge, "The effect of such intermittent elevations in urinary BPA concentration is unknown." 

So it's a non-peer-reviewed study highlighting the transient rise of urinary BPA (or really, a biologically inactive BPA metabolite) after eating canned soup, the significance of which is unknown.

* In the updated National Health and Nutrition Examination Survey, levels of BPA were detected in all subjects older than 6 years of age. Geometric means were approximately 2 mcg/L, but levels rose to 20 mcg/L (or thereabouts) in the 95th-percentile groups.

Image of can of Progresso vegetable minestrone soup from progresso.com.

A rare and poorly understood form of pediatric epilepsy, head-nodding syndrome is spreading in the new nation of South Sudan,* reports Meredith Wadman of Nature. CDC experts on site remain stumped about the cause of the apparent seizure disorder, which is associated with malnutrition, subclinical seizures, and focal brain atrophy or gliosis (aka scarring of brain tissue) in some cases. A link to endemic river blindness, or infection with Onchocerca volvulus, is tenuous, and genetic susceptibility provides only a partial explanation as to the origin of HNS.

The disease, locally called kifafa,** was first recognized in the early 1960s in Tanzania (in the East African territory of Tanganyika) by Dr. Louise Jilek-Aall (right), who founded the Mahenge Epilepsy Clinic (link to a youtube video).

For more background on HNS, click here for a 2008 article.

HT: American Academy of Neurology.

* Capital, Juba, "Jeopardy!" fans.
** Swahili for epilepsy.

On Friday, the CDC reported the growing resistance of Neisseria gonorrhoeae, the bacterium that causes (not surprisingly) gonorrhea, to the class of antibiotics called cephalosporins. This is concerning because, as the CDC stressed, "No other well-studied and effective antibiotic treatment options or combinations currently are available." Most recently the CDC had recommended dual antibiotic therapy for the treatment of gonorrhea in the United States, consisting of ceftriaxone (the most-effective cephalosporin for the venereal disease) and azithromycin or doxycyline. This recommendation has changed slightly on the basis of data from the CDC-sponsored Gonococcal Isolate Surveillance Project (GISP).

According to GISP, ceftriaxone-resistant N. gonorrhoeae in the United States increased threefold, from 0.1% in 2000 to 0.3% last year. And while the CDC continues to recommend ceftriaxone as part of effective therapy for gonorrhea, the agency appears to be bracing for growing antibiotic resistance—like that seen with N. gonorrhoeae and fluoroquinolones at the turn of the century. The CDC recommends that the other half of currently recommended therapy for uncomplicated gonorrhea should now consist of azithromycin (not doxycycline) because of the sensitivity/resistance patterns of the latest cephalosporin-resistant N. gonorrhoeae isolates.

The history of antibiotic-resistant N. gonorrhoeae is nearly as old as the history of antibiotics. Before the advent of antimicrobial drugs, gonorrhea was treated in a haphazard way with various concoctions, delivered either systemically or locally. One such treatment, prescribed to a victim of Elixir of Sulfanilamide, called for a mixture of zinc sulphate, lead acetate, colorless hydrastis (the herb goldenseal), and bismouth subnitrate, which was to be injected by way of a penis syringe.

Sulfanilamide was the first widely available antibiotic shown to be effective against the venereal disease (see Dees JE, Colston JAC. The use of sulfanilamide in gonococcic infections. J Am Med Assoc. 1937;108:1854-1858). But sulfonamide resistance was reported as early as the mid-1940s, and preferred therapy for gonorrhea became penicillin, until N. gonorrhoeae resistance to this mainstay emerged in the 1960s (see here, here, and here for example) and grew throughout the 1970s. Tetracycline-resistant N. gonorrhoeae emerged in the 1980s (see here for example), and fluoroquinolone-resistant bugs (eg, to ciprofloxacin, ofloxacin) showed up in Hawaii in the mid-90s.

Gram stain showing N. gonorrhoeae diplococci from the CDC/M. Rein (1978).

Where: Mostly Germany (concentration in northwest Germany), with about 30 cases in Sweden, 12 in Denmark, and a handful in various other European countries. The CDC has reported 4 suspected or confirmed cases of infection in the United States (3 with HUS), and Canada has reported 1 suspected case (without HUS).

They seemed like good, though not particularly original, ideas at the time: Initiate a med-pharma blog and inaugurate the coming new year with the top 10 stories from the waning year.

Seemingly good ideas can become millstones with time; nevertheless, these 2 particular self-inflicted burdens have been carried for at least another 365 days—to make a grand total of 3 years. Happy freekin' birthday, Pathophilia. Here's what really plagued, worried, or otherwise elevated our royal-we blog spirits in 2010.

No. 10: A Record-Busting Pertussis Outbreak in California.

Way to go, California parents who eschew routine childhood vaccinations.* Nice erosion of herd immunity. You've contributed to the worst statewide outbreak of pertussis (aka whooping cough) in the last 63 years. The last 63 years. Meaning since Truman was President. Meaning since Jackie Robinson broke the MLB color line.

Here's the latest from the California Department of Public Health while I/we simply stew in my/our juices of frustration: 

• There have been 7824 confirmed, probable, or suspect cases of pertussis reported between January 1st and December 15th. (There were 9394 reported cases in 1947.)
• This year's pertussis incidence rate in California is 20.0 per 100,000, which is the highest rate in 52 years. (The rate was 26.0 cases per 100,000 in 1958.)
• There have been 10 deaths, 9 of which were Hispanic infants (who were too young to be immunized)
• Children younger than 6 months of age have been particularly vulnerable to disease.
• The California outbreak peaked in late July-early August, but "relatively high numbers of cases continue to be reported each week."
• Because a high level of herd (aka community) immunity is needed to reduce the incidence and spread of pertussis and the fact that vaccine-induced immunity wanes with time, a campaign to urge booster shots among adolescents and adults is ongoing. 
• According to the CDPH, mothers or other close contacts are the most likely sources of pertussis for at-risk infants. The agency advises,

Thus vaccinating household contacts, health care personnel, and child care workers against pertussis is recommended at least 2 weeks before their contact with young infants. Increasing community immunity through widespread immunization will also decrease the chances that vulnerable infants will be exposed to pertussis. Immunization will also prevent debilitating cases of pertussis in older children, adolescents, and adults.

Unlike the historic California outbreak, which appears to be subsiding, a pertussis epidemic in upstate New York is gaining steam. It's now at the point at which the Public Health Agency of Canada is advising its citizens "to be on guard against" the disease in the United States. Yes, Canadian officials are now warning about infectious travel risks...south of the 49th parallel.

* Because of, largely, the disproven fears of vaccine-related autism.

Photo of symptomatic child with pertussis from pertussis.com.

As someone who's recently cut the landline cord, I wondered how many other Americans are tossing the same—like a vintage Broderick Crawford rotary phone. The answer: a lot. And who's keeping tabs on this information? The CDC.

According to the Centers' most recent information, published last spring, the percentage of American households relying solely on wireless coverage has increased from about 10% in the first half of 2006 to about 24% in the last half of 2009 (see the CDC's impressive growth table below). Yes, about 1 in 4 homes (as of 1 year ago) use cell phones exclusively.

An expected outcome of the CDC's ongoing survey: sole reliance on cell phone use is age dependent, with only about 15% of cell-phone users aged 45-64 years without a landline. Among individuals aged 65 years or older, that percentage drops to about 5%.

Other factors that increased the likelihood of going completely wireless (which, in some cases, are probably age dependent):

• living with unrelated adult roommates
• renting (vs owning)
• being male
• living in or near poverty
• not living in the Northeast
• being Hispanic

Why does the CDC care about the wireless trend? Because the CDC, like many other organizations, collects much of its health survey data by phone. The Centers' admonition:

The potential for bias due to undercoverage is not the only threat to surveys conducted on landline telephones. Researchers are also concerned that some people living in households with landlines cannot be reached on those landlines because they rely on wireless telephones for all or almost all of their calls.  

There are mixed messages from a newly published Swedish study, which examined the potential association between suicidal behavior and Accutane, but the authors correctly hedge their overall finding with some important caveats. 

The blunt-force trauma of the study is that there is a significantly increased risk of suicide attempts during the first 6 months of Accutane treatment.* According to data from Sweden's socialized-medicine database, the standardized incidence ratio** for all suicide attempts (n = 128 among 5756 treated patients) was 1.78 (95% CI: 1.04, 2.85) and that for first-time attempts was 1.93 (95% CI: 1.08, 3.18). Moreover, these incidence ratios declined after the completion of Accutane therapy (see Table). The knee-jerk conclusion: Accutane increases the risk of attempted suicide.

Time period	Incidence Ratio (95% CI)
	First Suicide Attempts	All Suicide Attempts
3 years before treatment	0.89 (0.54, 1.37)	0.99 (0.65, 1.44)
1 year before treatment	1.36 (0.65, 2.50)	1.57 (0.86, 2.63)
6 months after treatment start	1.93 (1.08, 3.18)	1.78 (1.04, 2.85)
3 years after treatment	0.97 (0.64, 1.4)	1.04 (0.74, 1.43)

However, however:

The authors stressed that the incidence ratios for attempted suicide were already increasing before Accutane therapy—for unclear reasons, but possibly as a result of despondence over progressive acne. The authors speculated,  

Considering the increasing risk of attempted suicide during the years before treatment, we cannot state whether the continued rise during and immediately after treatment was due to the natural course of severe acne or to negative effects of the treatment.

Alternative explanations for the relative increase in suicide attempts during Accutane treatment were also provided:

• Despair over a lack of acne improvement
• Despair over a lack of improvement in social life after clearing of acne

The possibility that suicidal behavior may be related to acne rather than Accutane treatment could also explain the declining ratios after the completion of therapy, when acne had cleared because of Accutane treatment. The authors concluded,

We must stress that we cannot exclude the possibility that the raised risk of suicide attempts during treatment and six months after treatment is due to the exposure to isotretinoin. However, a more probable interpretation is that the underlying severe acne may best explain the raised risk.

Supporting this conclusion is the observation that patients (n = 32) who made their first suicide attempt before treatment did not seem to have their suicidal behavior reinforced during or after Accutane treatment: Only 38% of these patients made new suicide attempts or committed suicide during follow-up. On the other hand, among the 14 patients who made a first suicide attempt during treatment or within 6 months after the end of treatment, 71% made a new attempt or committed suicide during follow-up.

* The mean length of Accutane treatment was approximately 6 months.

** The denominator was the age-, sex-, and season-adjusted background rate of suicide attempts for the population.

N.B. A previous review of the literature at this blog suggests that the risk of suicide with Accutane treatment is idiosyncratic.

As of October 12 (last Tuesday), the number of confirmed, probable, or suspect cases of pertussis in California is 5658. The pertussis caseload has grown by 40% in 1 month (from 4017 on September 14) and has now surpassed the number of pertussis cases that were recorded in the state during the mid-1950s. The latest pertussis incidence rate is 14.5 per 100,000. The death tally remains at 9 (all infants).

According to the California Department of Public Health (CDPH), pertussis cases peaked in 1950, at 6613, and the highest incidence of pertussis in the state was 16.1 cases per 100,000 in 1959.

In an attempt to stymie the spread of pertussis, the CDPH recommends, in addition to the routine schedule for DTaP during childhood, Tdap for 1) women of childbearing age, 2) persons who are in close contact with infants, 3) healthcare personnel, and 4) individuals with wounds. Tdap is similar to the standard tetanus-diphtheria booster (Td) received by adolescents and adults every 10 years, with an important exception. The Tdap vaccine also boosts immunity against pertussis. According to the CDC, a "single dose of Tdap is recommended for adolescents 11 or 12 years of age, or in place of one Td booster in older adolescents [or] adults age 19 through 64."

DTaP = diptheria, tetanus, and acellular pertussis.

Photo of symptomatic child with pertussis from pertussis.com.

Another study showing that thimerosal—the ethylmercury-containing vaccine preservative—does not increase the risk of autism hardly seems necessary. For the rational majority, who are inclined to believe the results of credibly authored reports, there are at least 5 studies that fail to show a link between pre- or postnatal exposure to thimerosal and poor neuropsychologic outcomes or autism. (Moreover autism rates continue to rise despite the removal of thimerosal from childhood vaccines in 1999.) For the small group of irrational and very vocal citizens who maintain a causal connection between thimerosal and autism, no amount of negative data appears sufficient.

Nevertheless the results of a new case-control study, published in Pediatrics, are now available. And not only do they deny an increased risk of autism with thimerosal exposure (either in utero or later); they actually indicate that postnatal exposure to thimerosal significantly reduces the risk of autism—by about 40%. The authors (perhaps wisely) avoided speculating as to the reason for the reduced risk, however.

The case-control data were collected from children* enrolled continuously in 3 managed care organizations that participate in the CDC's Vaccine Safety Datalink. The study methods are distinctive in that the authors, in addition to mining electronic databases and medical charts, validated autism diagnoses in person and conducted parent interviews.

* 256 with autism spectrum disorder and 752 controls matched for birth year, sex, and MCO.