Recently in Pediatrics Category
The onset of this year's rotavirus season was delayed by 2-4 months, and its magnitude was reduced by more than 50%, when compared with the previous 15 seasons of viral activity. These data coincide with the increasing use of the rotavirus vaccine (RotaTeq; Merck) in infants, according to an early release report from the MMWR. The live, oral vaccine was approved by the FDA in 2006, and its routine administration at 2, 4, and 6 months of age is recommended by the CDC's Advisory Committee on Immunization Practices.
Data from the National Respiratory and Enteric Virus Surveillance System (NREVSS) and the New Vaccine Surveillance Network* (NVSN) indicate that this year's rotavirus season began in late February, while the median onset of seasons during 1991-2006 occurred in mid-November (MMWR figure). Also the proportion of all positive rotavirus tests from mid-November 2007 to mid-April 2008 was substantially lower than the minimum number of positive tests during the previous 15 years.
Percentage of Positive Rotavirus Tests From NREVSS
(Data from 2008 are current through May 3)
*Data are from Monroe County, NY; Hamilton County, OH; and Davidson County, TN.
Mainstream media outlets and blogs are chattering about the news that Harvard psychiatrists Joseph Biederman, Timothy Wilens, and Thomas Spencer did not fully disclose their pharma consulting fees to the university, possibly in violation of academic and federal conflict-of-interest rules. According to the online Congressional record, Senator Chuck Grassley (Iowa-R) began an investigation last fall, which sought to determine the full extent of industry fees paid to the psychiatrists. The doctors also received NIH grants for clinical studies of commercial pharmaceuticals.
Persistent investigation by Grassley revealed that, from 2000 to 2007, Biederman and Wilens each earned more than $1.6 million from commercial sources, and that Spencer earned more than $1 million, according to the record. The majority of these fees (for services that are not specified) had not been reported to the university. The propriety, or even legality, of the physicians' reporting behavior is the subject of much online speculation. However, it remains unclear what led Grassley to investigate these physicians in the first place—among any number of possible targets.
Grassley may have been alerted to Biederman (and thereby, his Harvard colleagues) through the death of 4-year-old Rebecca Riley. As reported by "60 Minutes" in September of last year, Rebecca Riley died on December 13, 2006, at her home in Hull, Massachusetts, due to an overdose of psychiatric drugs. The drugs—Depakote (divalproex; Abbott), Seroquel (quetiapine; AstraZeneca), and clonazepam—were prescribed by Tufts psychiatrist Kayoko Kifuji for the child's bipolar disorder, which was diagnosed at the age of 2 years. Before her death, Rebecca had also been given an over-the-counter cold medication and at least one additional, unprescribed dose of clonazapam by her mother (and possibly more for a period of time before the child's death).
According to "60 Minutes," Dr. Kifuji's prescribing practices were heavily influenced by the research and views of Biederman, who was interviewed for the news show. Biederman has evidently been instrumental in the trend to apply the diagnosis of bipolar disorder, in broader terms, to very young children. And with the diagnosis goes pharmaceutical treatment in the form of some drugs that have not been systematically tested in children.
In a Boston Globe story, Kifuji's lawyer stated that the Harvard psychiatrists were "by far the leading lights in terms of providing leadership in the treatment of children who have disorders such as bipolar." The paper also wrote of the extensive financial ties between pharma and Biederman, who had "received research funding from 15 drug companies and serves as a paid speaker or adviser to seven of them," including Eli Lilly (Zyprexa [olanzapine]) and Janssen (Risperdal [risperidone]). The Congressional record also reports financial ties between Biederman and BMS (Abilify [aripiprazole]), Cephalon (Vivitrol [naltraxone]), GSK, JNJ, and Pfizer.
Right or wrong, Biederman and his colleagues Wilens and Spencer have evidently influenced the diagnosis and treatment of bipolar disorder, as well as those of ADHD, through the medical literature (for example: Frazier JA et al. J Child Adolesc Psychopharmacol. 2001;11:239-250; Wilens TA et al. J Child Adolesc Psychopharmacol. 2003;13:495-505) and through pharma-supported CME programs (for example: "The Evolving Face of ADHD" and "Focus on ADHD"). The question is whether commercial funding influenced Biederman et al to promote the relatively aggressive, unapproved use of pharmaceuticals in children with psychiatric problems. The chief of psychiatry at MGH, Jerrold Rosenbaum, wrote in an e-mail to the Boston Globe, "I think a pharma person would not dare to tell Joe [Biederman] what to say...For Joe, it is his ideas and mission that drive him, not the fees."
As far as the aftermath of Rebecca Riley's death is concerned, the child's parents, Carolyn and Michael, were charged with first-degree murder and await trial. Dr. Kifuji agreed to suspend her medical practice pending an investigation by the Massachusetts medical board.
Photo: iStockPhoto.
Mercury-containing dental fillings may harm pregnant women and young children.
That's the general, and not particularly useful, lede provided by most media outlets last week, while reporting on a settlement in the case of Moms Against Mercury et al v. Leavitt et al. As part of the settlement, the FDA will reopen a comment period, beginning July 28, 2008, to potentially reclassify dental amalgam and will issue a final ruling 1 year later. And that's really all that's news, if you call that news.
Essential background on the issue can be found from the American Dental Association, which states in a press release that the "FDA has different classifications for encapsulated amalgam and its component parts, dental mercury and amalgam alloy. The FDA's proposed reclassification, which the ADA has supported since 2002, would place encapsulated amalgam and its components under one classification." The organization also writes, "As far as the ADA is aware, the FDA has in no way changed its approach to, or position on, dental amalgam."
However, last week the media latched onto the following statements made at the FDA web site, in response to the settlement:
Dental amalgams contain mercury, which may have neurotoxic effects on the nervous systems of developing children and fetuses. When amalgam fillings are placed in teeth or removed from teeth, they release mercury vapor. Mercury vapor is also released during chewing. FDA’s rulemaking...will examine evidence concerning whether release of mercury vapor can cause health problems, including neurological disorders, in children and fetuses.
Pregnant women and persons who may have a health condition that makes them more sensitive to mercury exposure, including individuals with existing high levels of mercury bioburden, should not avoid seeking dental care, but should discuss options with their health practitioner.
This information is best couched in the FDA's statements indicating that there is not enough information to know whether dental amalgam—which is approximately 50% mercury and has been widely used for more than a century—is harmful to pregnant women or young children. Other countries (Canada, France, Sweden), follow a "precautionary principle" in these populations, given the lack of data. During the comment period, the FDA requests "empirical data and scientific evidence concerning this classification and special controls for dental amalgam."
The original cause of the brouhaha, the "Petition to Order Mercury Amalgam Withdrawn From Interstate Commerce," is, itself, a curious document. For one, the diverse group of petitioners (listed) shows how the ultra-right and ultra-left often come together in their own Bizarro World. They are the following:
- Moms Against Mercury, a nonprofit organization located in North Carolina and founded by Amy Carson, who believes that the ethylmercury-containing vaccine preservative Thimerosal causes autism—despite a wealth of medical data to the contrary.
- The Connecticut Coalition for Environmental Justice, an organization dedicated to eliminating environmental toxins in the state and their effects, particularly on low-income or minority populations. The coalition is led by president Mark A. Mitchell, MD.
- Oregonians for Life, a pro-life/anti-abortion organization.
- California Citizens for Health Freedom, one of the more "out-there" health-related nonprofits. The CCHF is dedicated to a "toxic-free environment" and the right to access alternative medical treatments for cancer. The organization also opposes the fluoridation of public drinking water.
-
Kevin J. Biggers, a candidate for the California state senate and a public member of the Dental Board of California.
-
Karen Johnson, an Arizona state senator whose "issues of concern" include the "precious right to life of the unborn," "eradicating pornography," and "standing resolutely against the homosexual agenda."
-
Linda Brocato, an Illinoisan who believes that mercury-containing dental fillings caused her multiple sclerosis, and that her symptoms improved substantially after the removal of these fillings.
- R. Andrew Landerman, DDS, a California dentist whose advertised "services" include acupuncture, ayurveda, homeopathy, and the use of the Cavitat device.
- Anita Vasquez Tibau, the California organizer of the Consumers for Dental Choice. Tibau believes that mercury in dental fillings caused her asthma.
The hapless respondents demonstrate, once again, that a visible government job is a gift that keeps on giving: Mike Leavitt, DHHS Secretary; Andrew von Eschenbach, MD, FDA Commissioner; and Dan Schultz, MD, and Mary S. Runner, DDS, both of the FDA's CDRH.
Generally the petitioners allege that the FDA has been negligent in its duty to classify dental amalgam and specifically imply that the FDA has taken a deliberate, passive stance to maintain a profitable status quo for the subversive, pro-amalgam ADA and amalgam manufacturers.
Among the more intriguing allegations in the petition is the following:
It should come as no surprise that all government literature reviews on amalgam's toxicity have been managed by groups composed mainly of dentists. For example, a multimillion dollar grant to study amalgam was given to a dentist sitting on the ADA's Council of Scientific Affairs; that person chose a defenseless group—institutionalized Portuguese orphans—on which to experiment with mercury, without disclosures of health risks. The study is now under investigation by the Secretary's Office of Human Research Protections, the watchdog charged with stopping unethical medical experimentation.
The petitioners are presumably referring to a 2006 study in JAMA by DeRouen et al from the University of Washington and the University of Lisbon. The prospective study was funded by the Cooperative Agreement U01 DE11894 for the National Institute of Dental and Craniofacial Research (NIDCR) of the NIH. According to a 2005 Business Wire story, the University of Washington School of Dentistry did receive $22 million from the NIDCR; however, it is highly unlikely that this chunk of change was consumed by the JAMA study. The story indicated that DeRouen was the designated principal investigator and chair of a research network among his institution, the Washington Dental Service, and the School of Dentistry at Oregon Health Sciences University.
In the JAMA study, more than 500 Portuguese children (aged 8-10 years) received either randomly assigned posterior dental amalgam or resin-based composite as required dental work. The children enrolled were students within the Casa Pia system. According to Wikipedia, Casa Pia is Portugal's largest educational institution for children at risk of "social exclusion or without parental support." Casa Pia has been described as an orphanage in the mainstream press and, parenthetically, is at the center of an ongoing sex-abuse scandal and trial—which should be neither here nor there as far as the DeRouen study is concerned.
It is noted within the JAMA article that the study protocol was approved by the institutional review boards at the University of Washington and the University of Lisbon, and that written, informed consent was obtained from parents or guardians. DeRouen et al reported no significant differences in urinary mercury levels or neurologic function between the 2 treatment groups over the course of 7 years. However, after 5 years, "the need for additional restorative treatment was approximately 50% higher in the composite group."
Regarding implied ethical violations by the study investigators (and presumably the petitioners are referring to the DHHS Office for Human Research Protections), a 2006 AP news report indicated that the counsel for Consumers for Dental Choice, Charlie Brown (who, by george, is one of the petition drafters) found the Casa Pia study unethical because "guardians were never told of the potential risks of the mercury fillings."
DeRouen shot back in the AP story, "We weren't doing anything experimental. We were giving standard dental treatment." A University of Washington review board evidently found the allegations to be unfounded; however, a spokesperson for the OHRP said that the DeRouen study was "under investigation."
According to letters at the OHRP web site, the office did find that the University of Washington's informed consent document "failed to adequately describe the reasonably foreseeable risks of amalgams and composite materials used in dental procedures," as required by DHHS regulations. In response, UW developed a new policy and guidance for its institutional review board concerning the risks of standard-of-care procedures and revised its informed-consent templates to reference this policy. These changes, which appear to be general changes regarding the risks of standard of care and not mercury-related risks specifically, satisfied the OHRP as of April 2007.
Photo: iStockPhoto.
If you're at a loss to understand the slogan of yesterday's anti-vaccination march on Washington, DC—led by Jenny McCarthy and Jim Carrey—you're not alone. The costar of Witless Protection* and the star of Horton Hears a Who! evidently want to promote "cleaner" vaccines (whatever that means—more bacteriocidal Thimerosal?). But what they really want to do is alter the current CDC-recommended schedule for vaccinating children...to God only knows what.
Orac dives into the mess and provides commentary.
*You know, the vehicle for Larry the Cable Guy.
Photo: Jenny McCarthy playing with garden hose in kiddie pool.
This post represents the third installment of my review of the study by Young et al, which links exposure to Thimerosal-containing vaccines with autism. Previous posts on the subject can be found here, here, here, and here.
Results
Table 3 presents the rate ratios and 95% confidence intervals for each diagnosis assuming a µg increase in mercury exposure from Thimerosal-containing vaccines administered from birth to 7 months and birth to 13 months. It was observed that there were significantly increased rate ratios for the neurodevelopmental disorders of autism, autism spectrum disorder (ASD), hyperkinetic syndrome of childhood (attention deficity disorder/attention deficity hyperactivity disorder), developmental disorder/learning disorder—not otherwise specificied, disturbance of emotions specific to childhood and adolescence, and tics following additional Hg exposure from Thimerosal-containing childhood vaccines...By contrast, no significantly increased rate ratios for the control disorders of pneumonia, congenital anomalies, and failure to thrive were observed with increasing Hg exposure from Thimerosal containing vaccines.
The rate ratios, given a 100-µg increase in vaccine-related ethylmercury exposure, are reproduced below from Young et al's Table 3:
|
Condition |
Rate Ratio (95% CI), |
Rate Ratio (95% CI), Birth-13 Months |
|
Neurodevelopmental |
|
|
|
Autism |
2.87 (1.19, 6.94) |
2.62 (1.15, 6.01) |
|
Autism spectrum |
2.44 (1.16, 5.10) |
2.20 (1.10, 4.40) |
|
Hyperkinetic syndrome |
3.15 (2.38, 4.17) |
4.51 (3.48, 5.84) |
|
Developmental disorder/ learning disorder—not otherwise specified |
1.73 (1.08, 2.75) |
1.81 (1.17, 2.80) |
|
Disturbance of emotions |
2.27 (1.36, 3.80) |
2.91 (1.81, 4.68) |
|
Tics |
3.39 (1.64, 6.79) |
4.11 (2.12, 7.94) |
|
Control |
|
|
|
Pneumonia |
0.98 (0.86, 1.11) |
0.92 (0.82, 1.04) |
|
Congenital anomalies |
0.62 (0.34, 1.14) |
0.57 (0.33, 1.00) |
|
Failure to thrive (FTT) |
1.05 (0.74, 1.47) |
0.92 (0.67, 1.27) |
There's little to say about these numbers, other than they have to be taken on faith, which is a dubious proposition in my opinion. The rate (or risk) ratios for the neurodevelopmental disorders are very high, suggesting (in some cases) a several-hundred-fold increased risk for a neurodevelopmental disorder with what is really a very small (ie, 100-µg) increase in ethylmercury exposure. The 95% confidence intervals for the neurodevelopmental disorders are also exceptionally wide, especially when compared with those for the control conditions. The following graphs of the rate ratios and 95% CIs illustrate this point.
Birth-13 Months
Also, given these data, couldn't it be concluded (although a P value is not provided) that a 100-ug increase in vaccine-related ethylmercury exposure reduces the risk of congenital anomalies by approximately 40%?
Next: Discussion.
The following is the second installment of a review of "Thimerosal exposure in infants and neurodevelopmental disorders," by Young et al, which links thimerosal exposure to autism. Statements from the materials and methods section are discussed, with otherwise heavy deferrals to EpiWonk.
The study protocol employed was approved by the US [CDC], the Institutional Review Board (IRB) of Kaiser North-West, and the IRB of Kaiser Northern California. The data were analyzed at the secure Research Data Center of the National Center for Health Statistics in Hyattsville, MD.
Alleged violations of this study's protocol by the Geiers (father-and-son duo) are discussed here and here. According to an 05/21/08 e-mail from the Kaiser IRB office, the objections stated in 2004 by the CDC and Kaiser were resolved, and the study was ultimately approved by the IRB. However, Kaiser did not specify how the objections were resolved. At the time of this post, a statement from the CDC regarding the alleged protocol violations is pending.
The study was conducted based upon a retrospective ecological [emphasis added] assessment of neurodevelopment disorders that were identified a priori as possibly related to Hg exposure.
There are several uses of the term "ecological" in the article to describe this study and others. Perhaps EpiWonk can provide some insight into the word's meaning in this context; the distinction's lost on me. The authors acknowledge the preselection of a list of neurodevelopmental disorders (eg, autism) that are presumptively (ie, "a priori") related to mercury exposure.
Only those individuals who had a non-missing date of birth and were born before January 1, 1997 were examined. This date was chosen to allow for at least 4 years of follow-up for each member of the cohort which was believed to be an adequate amount of time to observe the outcomes of interest.
Here the authors acknowledge that a minimum 4-year time frame should be sufficient to assess the occurrence of preselected neurodevelopmental disorders in the VSD, which was created in 1991 and updated through the year 2000. However, the authors later contend that the time frame is not sufficient, to justify their addition of presumptive cases. (An aside: Data from Kaiser North-West, Kaiser Northern California, and Kaiser Colorado were examined by Young et al; however, an IRB nod from Kaiser Colorado was not mentioned in the previous, relevant paragraph.)
All children who received an oral polio vaccine within 3 months of their birth date and who were born before January 1, 1997 were used as the denominator or population at risk for this study.
The time period for the study is from 1990 (0.6% of the study population) to 1996, inclusive. A total of 278,624 children were identified. (Another aside: Because of the very rare incidence of vaccine-induced polio associated with the administration of the oral vaccine [1 case in 2.4 million doses], it was recommended in 2000 that all US children should receive only inactivated polio vaccine).
The outcome files (inpatient and outpatient diagnoses) from this population were then reviewed to find the first instance of diagnosis of the disorders of interest. If there were multiple instances of the same diagnosis in a child, only the first instance of diagnosis was counted. Then the total numbers of each diagnosis for each disorder of interest were determined by birth cohort. The counts of each diagnosis of interest represented the numerator or outcomes for this study.
Okay, I'm still following along at this point. The authors tallied the first instance of each preselected ICD-9 code and divvied the total counts by birth cohort (ie, year). Referral to Table 2 reveals, for instance, that there were 583 identified cases of autistic disorder, current or residual (ICD-9 codes 299.00, 299.01), among the 278,624 children (ages 4-10 years) who received oral polio vaccine within 3 months of birth, to produce an overall 0.21% frequency of autistic disorder. However, note in Table 2 that the authors' adjusted overall prevalence rate for autism is 25.4/10,000, or 0.254%. More on this later.
The prevalence of each diagnosis was then calculated by birth cohort by dividing the count of a diagnosis in that birth year by the total number of children from the study population that were born in that same year.
The number of children per birth cohort (year) can be calculated by using percentage data in Table 1; however, the raw numbers of autism (and other) cases by birth year are not provided. (Figure 1 does provide graphically the number of autism cases per 10,000 per year [with imputed data for 1995 and 1996 presumably included—as indicated, more on added cases later]). EpiWonk talks extensively about birth year as a confounder in this study.
Because of concern that the cohorts from 1995-1996 had only 4-6 years of follow-up, frequency distributions of age at diagnosis were examined for all years. This revealed that for some of the disorders a sizable proportion of children were diagnosed after 4.5 years. Adjustments were made for counts of cases as needed for birth cohorts depending upon the disorders examined to correct for under ascertainment that occurred due to shorter follow-up times. These adjustments were made for all disorders including the control disorders as appropriate based on the age distribution.
Although the authors originally proposed that 4 years of follow-up would be sufficient, they now conclude that more follow-up time is needed. This conclusion is presumably based on their discovery in earlier birth cohorts that, for some of the ICD-9 codes (essentially all of the neurodevelopmental conditions, except 315.9), the median (not mean) age at diagnosis was 4.5 years or older (Table 2). Therefore, the authors made "adjustments" to "correct for under ascertainment" by adding cases "as appropriate." EpiWonk talks about this "extremely dubious" imputation of data here. Also, although the authors say that "adjustments were made for all disorders including the control disorders," Table 2 reveals that the median ages for these conditions (pneumonia, congenital anomalies, failure to thrive) were below the 4-year time frame, suggesting that "adjustments" may not have been necessary for these particular control conditions.
For example, 37% of autism cases in the study were diagnosed after 5 years old with about 50% diagnosed after 4.5 years old. This is a conservative estimate since it includes the 2 years (1995-1996) that had shorter follow-up times. Examination of the distribution of age of diagnosis by birth year for autism revealed that only about 15% of cases were diagnosed after 5 years of age in the 1995 birth cohort while the 1996 cohort had no cases diagnosed after 5 years of age and only 3.5% of cases diagnosed between 4.5 and 5 years of age.
So among the 583 total number of autism cases identified in the VSD (which presumably do not include the imputed cases), a little more than 200 (~37%) were diagnosed after 5 years of age. The authors argue that this is an underestimate because of the relatively shorter follow-up times for the 1995 and 1996 cohorts. For the 1995 cohorts (with presumably 6 years of follow-up, 1995-2000 inclusive), 15% of cases (not 37%) were diagnosed after 5 years of age. Because the follow-up for the 1996 cohort was 1 year less, no cases of autism were detected after 5 years of age.
Based on the average age at diagnosis for all cohorts, the 1995 count of autism cases was increased by 45 cases with the assumption that all of these would have been added in the 5 year+ age group (bringing this percentage close to the overall average of 37% diagnosed after 5 years of age). The same was done for 1996, but the number of cases was augmented by 80 because it was assumed that these would be diagnosed in the 4.5 to 5 and 5+ groups essentially bringing the percentage diagnosed after age 4.5 close to the overall average of 50% diagnosed after 4.5 years of age. The new augmented frequency counts of cases in 1995 and 1996 birth cohorts were then used as the new case counts in the analysis.
Here's where my head starts to rotate on its axis. The number of autism cases for the 1995 cohort were increased by 45 to increase the rate of autism cases diagnosed after the age of 5 years from 15% to 37%. Therefore, we can conclude that 22% (37% – 15%) of the imputed autism cases for 1995 equals 45 cases. Working backwards, we can actually estimate raw data from the later birth cohorts. There were approximately 160 autism cases orginally identified in the 1995 cohort (45/22 x 100 = 205; 205 – 45 = 160). Therefore, the original rate of autism for the 1995 cohort (using data from Table 1) was 0.31%; the imputed rate is 0.39%. Similar calculations can be performed for the 1996 cohort. Eighty cases of autism were originally identified in the 1996 cohort, for a rate of 0.17%; the imputed rate is double that, or 0.33%. (Also note that the authors now refer to the "average age at diagnosis," not the median age. It's unclear if the lack of the distinction between median and average age is an oversight or an intentional slide.)
For the entire "autism" cohort (all birth years), 125 cases were added. By using data from Table 2, we can calculate how many cases were added overall for each diagnosis, with the presumption that most (if not all) cases were added to the birth cohort data for 1995 and 1996.
|
Condition |
n |
Prevalence Rate, % |
Adjusted Prevalence Rate, % |
Calculated No. Added Cases |
|
Neurodevelopmental |
|
|
|
|
|
Autism |
583 |
0.209 |
0.254 |
125 |
|
Autism spectrum |
817 |
0.293 |
0.367 |
206 |
|
Hyperkinetic syndrome |
5712 |
2.05 |
2.51 |
1281 |
|
Developmental disorder/ learning disorder—not otherwise specified |
2248 |
0.807 |
0.948 |
393 |
|
Disturbance of emotions |
1694 |
0.608 |
0.762 |
429 |
|
Tics |
804 |
0.289 |
0.389 |
280 |
|
Control |
|
|
|
|
|
Pneumonia |
33,648 |
12.1 |
13.2 |
3130 |
|
Congenital anomalies |
1643 |
0.59 |
6.32 |
15,966 |
|
Failure to thrive |
4754 |
1.71 |
1.85 |
401 |
For the neurodevelopmental disorders, the number of cases overall were typically increased by approximately 20%-25%, with the exception of tic cases, which were increased by approximately 35%. The control cases (excepting congenital anomalies) were increased by much less, approximately 10%. (It is assumed that the adjusted prevalence rate for congenital anomalies [63.2/1000] is almost certainly a typo and should be 63.2/10,000. It is also assumed that ~1597 cases were added to the database, not 15,966 as calculated by the numbers given.)
In analyzing the adjustments made for follow-up corrections, varying levels of imputing additional cases were modeled to assess the sensitivity of the results to the assumptions made when imputing additional cases in specific birth cohorts. Sensitivity analyses revealed that point estimates were similar even when imputing 50% fewer cases than would be expected using the average age distributions as noted above. In addition, confidence intervals showed little variation and maintained statistical significance when imputing as low as 25% fewer cases than would be expected using the average age distributions.
Head now spinning like Michael Keaton's in Beetlejuice. How I read the above: the authors extensively monkeyed with the outcome data to determine how much "imputation" the data (or we) could possibly stand.
Because the study protocol did not permit us to match data across vaccine files, exposure was determined in aggregate by birth cohort for each vaccine and then summed across birth cohorts. The routine childhood vaccines of interest were Haemophilus influenza type b (Hib), hepatitis B vaccine, [DTaP], and [DTP] vaccines.
Young et al assumed that the mercury content from Thimerosal provided by each vaccine dose would be 25 µg, with the exception of hepatitis B vaccine (12.5 µg per dose). The authors cite the FDA study by Ball et al from 1999, which indicates that Thimerosal-free vaccines were available for Hib (FDA approved September and November 1996), DTaP (January 1997), and a combination Hib-hepatitis B vaccine (October 1996). So it is possible that children in the VSD, specifically those in the later birth cohorts, may have received some Thimerosal-free vaccines (Hib at 2, 4-6, and ≥12 months; DTaP at 2, 4, 6, and 15-18 months; and the combination Hib-hepatitis B at times of Hib administration). Nevertheless, Young et al assumed the mercury content per vaccine dose as described.
Within each vaccine file, the cumulative Hg dose for each individual was calculated based on the number of each type of vaccine received...This calculation resulted in an average Hg dose per person for each birth cohort which served as the exposure variable. Because of interest in particular windows of exposure, Hg doses from vaccine exposure were calculated for the following periods: 1) birth to 7 months; and 2) birth to 13 months.
In other words, the authors tallied up the number of Hib, hepatitis B, DTaP, and DTP vaccines received from birth to 7 months or birth to 13 months for each birth-year cohort. So for every dose of Hib, DTaP, or DTP vaccine dose, 25 µg of mercury was added; for every hepatitis B vaccine dose, 12.5 µg was added. Young et al then divided that cumulative mercury dose for each birth-year cohort by the number of children in the cohort—for instance, approximately 51,267 for 1995. This number, the average mercury dose per person per birth cohort, was designated the "exposure variable."
Logic would dictate that the cited cases in the VSD could have received no vaccines (other than oral polio) between birth and 7 months or a maximum of 3 Hib, 3 DTaP, and 4 hepatitis B vaccines (including one at birth) during that time frame, for an ethylmercury dose ranging from 0 to 200 µg. Figure 1 bears out this thinking, with the exposure variable ranging from ~110 µg (for 1990) to ~145 µg (for 1992).
Graphs plotting the Hg dose by birth cohort as well as prevalence of a particular disorder by birth cohort were constructed. Poisson regression analysis was used to model the association between prevalence of event of interest and Hg dose...Parameter estimates from Poisson regression models were used to obtain rate ratios. Hg dose was modeled as a continuous variable and rate ratio estimates and 95% confidence intervals were calculated to determine the change in prevalence rate of each diagnosis per unit increase in Hg dose from Thimerosal-containing vaccines.
So after all the aforementioned maneuvers, Young et al estimated a rate (or risk) ratio for each diagnosis per each 100-µg change in mercury exposure by using Poisson regression models, which is about as useful to me as saying, "Presto Change-o." It's now a deep-field punt to EpiWonk to discuss (further) the use and validity of a Poisson regression to estimate these ratios; but before I do, I ask 2 questions in particular: 1) Is it appropriate to assume a linear regression between ethylmercury and the ICD-9 codes, especially when considering such miniscule doses of ethylmercury? 2) Given that the average ethylmercury exposure per birth cohort is somewhere between 100 and 150 µg, does it make sense to stratify disease risk on the basis of 100-µg changes in ethylmercury exposure?
Conclusions: The most concerning methodologic issue in the study by Young et al is the liberal imputation of cases, which the authors justify on the basis of shorter follow-up times for later birth-year cohorts. The practice challenges credulity, in part because the percentage increases for neurodevelopmental diagnoses are so much higher than those for control cases (discounting congenital anomaly data). But also, the authors do not provide enough raw data (eg, prevalence rates per birth cohort) to enable the confirmation of data. The authors also make assumptions about the amount of ethylmercury delivered from vaccines, particularly in later years, which may not be accurate. Some Thimerosal-free vaccines were available in late 1996 and may have been administered to children in the 1995 or 1996 birth cohorts.
Last, the estimated rate ratios per change in mercury exposure demand a considerable amount of trust from the (nonstatistician) reader, which is sharply limited in this writer after the authors' imputation of cases.
Next: Results.
The idea that thimerosal-containing vaccines are associated with the development of autism has been broadly and compellingly refuted (see, for instance, authoritative conclusions rendered by the Institute of Medicine and the CDC). Moreover, autism rates have continued to climb, despite the removal of the ethylmercury preservative from routine childhood vaccines since 2001.* Nevertheless, the editorial board of the Journal of the Neurological Sciences, a self-described peer-review journal, finds it necessary to revive the debate in arguably unnecessary fashion by publishing a study that was funded by the Autism Petitioners' Steering Committee and written by plaintiffs' consultants in vaccine litigation.
Talk about your potential conflicts of interest. Given the well-known positions of the study's coauthors—in particular, those of Mark R. Geier, MD, PhD, and his son David Geier (see, for instance, a 2005 profile of the duo by the NYT and a considerable amount of research conducted by Kathleen Seidel at the neurodiversity blog)—it is not surprising that the authors concluded an "association between increased Hg exposure from Thimerosal-containing vaccine and neurodevelopmental disorders."
But the article and additional investigation raise several questions that go beyond the merits of the study itself (which will be discussed in another post). For instance:
- Was the study protocol, which drew on Kaiser HMO data from the CDC's Vaccine Safety Datalink (VSD), in fact, approved by Kaiser's institutional review board (IRB) as described?
- What was the decision process among the editorial members of the Journal of the Neurological Sciences that led to the publication of such a questionable study?
- What exactly is the nature of the body of work conducted by Geier and Geier?
For now, I will address (in as much as I can) the first and second questions.
In the article's Materials and Methods section, the authors claim, "The study protocol employed was approved by the US Centers for Disease Control and Prevention (CDC), the Institutional Review Board (IRB) of Kaiser North-West, and the IRB of Kaiser Northern California." However, an online source suggests that this may not be so, or that there was at least a hitch in the approval of the study given the conduct of its researchers.
In a February 2004 letter to the IRB administrator of Kaiser of Northern California, the then Acting Associate Director for Science of the National Immunization Program at the CDC, Jeanne Santoli, MD, warned Kaiser of "potential breaches in confidentiality and execution of analyses that were not approved in advance," when Mark and David Geier visited the CDC Research Center in Hyattsville, MD, in October 2003 and in January 2004