Archive | May, 2010

Storm in a teacup

15 May

A piece from the Philadelphia Inquirer demonstrates how various vaccine scares begin.

Using powerful new DNA technology, Delwart’s San Francisco team detected fragments of a pig virus in GlaxoSmithKline’s Rotarix, which protects babies from a diarrhea-causing infection. The pig virus is common in pork products and is not known to cause disease in animals or humans.

We expected to reassure; we ended up not reassuring,” Delwart, a virologist with the Blood Systems Research Institute, said this week. “We ended up creating quite a bit of a storm.

Yet of course the usual suspects used this total non-entity of a story to further their own anti-vaccine agenda:

This “is an important wake-up call for industry and government,” said Barbara Loe Fisher, president of the National Vaccine Information Center.

How exactly isn’t explained. This is after all a story where a vaccine carries a component that *is not known to cause disease* . Neither the FDA or the European Health Agency said the vaccines containing the component shouldn’t be used. As Paul Offit said:

“You could apply this new technology to things gummed by a 6-month-old – a Cheeto, a piece of apple – and find much worse” microbes than the pig virus, Offit said. “How does it help to find things that are not known to be harmful? It’s like taking thimerosal out of vaccines. Has that made vaccines safer? No.”

Or more dangerous.

We *have* to start getting over our collective heebie-jeebies every time something perfectly safe is found in a vaccine and start realising that the people who are advocating that we _do_ have an attack of the heebie-jeebies are those who have a single item agenda – promoting anti-vaccineism.

Mirror Neurons theory of autism refuted by fMRI study

14 May

Mirror neurons come up a lot in autism research. Perhaps the mirror neuron theory is, as one researcher put it, exaggerated with little evidence to support it.

This is discussed in the Simons Foundation sfari blog. Also, the authors have made a video to discuss the mirror neuron theory and their recent experiment (again, I found this on the sfari blog). I apologize that it is not closed captioned.

http://vimeo.com/moogaloop.swf?clip_id=11711513&server=vimeo.com&show_title=0&show_byline=0&show_portrait=0&color=6854a1&fullscreen=1

Normal Movement Selectivity in Autism from Simons Foundation on Vimeo.

I don’t want to just rephrase what has been said in these two presentations, so I will refer you to the sfari blog and the video from the researchers.

International Meeting for Autism Research abstracts are online

14 May

INSAR, the International Society for Autism Research, hosts a conference each year. IMFAR, the International Meeting for Autism Research is the largest autism conference held.

IMFAR is being held in Philadelphia, Pennsylvania (US) this year, May 20 to May 22nd. The conference abstracts give you an idea for the latest research trends.

You can search the program online. Alternatively, you can download the program or the abstracts as pdf’s.

Autistic researcher Michelle Dawson is listed as the anchor author on a study, Perception in Autism, 2006 – 2009: Updating the Enhanced Perceptual Functioning Model.

Dr. Lisa Croen from Kaiser Permanente has a paper on whether maternal infections are linked to autism. Maternal Infection During Pregnancy and Risk of Autism Spectrum Disorders. They find an increased risk due to bacterial infections in the second half , similar to results from a recent paper from Denmark.

Dr. Gail Windham’s group has a study, Autism and Distribution of Hazardous Air Pollutants at Birth in Southern California. This is a follow on to their study of Hazardous Air Pollutants in Northern California (Autism Spectrum Disorders in Relation to Distribution of Hazardous Air Pollutants in the San Francisco Bay Area) which is often cited in support for the mercury-causation hypothesis. The conclusion to the news study states: ” Examining HAPs in another region of California with higher concentrations and larger numbers did not replicate the original results. Metals as a group were not associated, but instead aromatic solvents yielded the highest risks”

Prof. David Mandell of the University of Pennsylvania has large number of papers. I follow his work since one of his areas involves under-represented groups such as minorities and adults. For example, one of his papers is Services Utilized by Adults with Autism Spectrum Disorders.

There are a number of papers discussing regression. For example, about 33% of autistic children underwent some form of regression in this study. Dr. Swedo’s team at NIMH looked closer at regression in autistic children in Regression Histories in Young Children with Autism: Timing and Associations Out of 185 children whose parents were interviewed:

Among the 80 cases with significant regression, parents of 26 children indicated physical illness/medical issues may have been related to loss of skills, and 21 responses indicated an associated psychosocial stressor (in 7 of these cases, both illness and psychosocial stressors were reported). However, only 8 reports clearly indicated a sudden loss of skills. Five of the 8 cases with sudden loss included both loss of language loss and social engagement/responsiveness. Two of the sudden loss cases were reported to be associated with a physical illness/medical issue and 3 were reported to be associated with a psychosocial stressor (with 1 reported to have both).

Obviously, there is more. Much more. I’m still working my way through the program book. D’oC will be attending IMFAR and blogging here at LeftBrainRightBrain with support from the Autism Science Foundation.

US Court of Appeals denies vaccine court case

14 May

The first of the vaccine court autism cases has been denied by the United States Court of Appeals, Federal Circuit. The Vaccine court (or, more accurately, the U.S. Court of Federal Claims) grouped the autism claims into an “Omnibus”, something like a class action case, where evidence to prove vaccines cause autism was presented in a few “test cases”, rather than hearing all the cases individually. The Omnibus Autism Proceeding heard six test cases, three on the theory that the MMR vaccine causes autism and three on the theory that thimerosal (a mercury containing perservative) causes autism.

The appeals decision is for the test case of Yates Hazelhurst, one of the MMR test cases. The case was summarized by the Special Master who decided the case:

[P]etitioners assert that the measles component of the MMR vaccine causes an immune dysfunction that impairs the vaccinee’s ability to clear the measles virus. Unable to properly clear the measles virus from the body, the vaccinee experiences measles virus persistence which leads to chronic inflammation in the gastrointestinal system and, in turn, chronic inflammation in the brain. Petitioners argue that the inflammation in the brain causes neurological damage that manifests as autism.

The Special Master (essentially the Judge in the vaccine court) denied the claim. The family appealed to the Court of Federal Claims, who upheld the decision. The recent decision is from the United States Court of Appeals, Federal Circuit, making this the second appeal affirming the original decision.

The family appealed on the basis, as the appeals judge put it:

On appeal to this court, the Hazlehursts argue that the special master improperly relied on certain evidence that should have been excluded and disregarded other evidence that should have been considered.

The MMR theory for autism causation relies on the notion that the measles virus from the vaccine persists in the guts of children. This, in turn relies on research by Dr. Andrew Wakefield’s team and in particular, the Unigenetics laboratory. The government brought in a witness, Dr. Stephen Bustin, to refute the validity of the results from the Unigenetics lab. Dr. Bustin’s testimony and level of expertise were very clear in showing that the Unigenetics results were faulty.

The special master found that Dr. Wakefield’s work had been largely discredited within the scientific community and that none of the studies indicating the presence of measles virus in autistic children had been successfully replicated by an accredited laboratory independent of Dr. Wakefield or Unigenetics. In particular, the special master found that Dr. Wakefield’s early 1990s research on persistent measles infections was reviewed by the Medical Research Council of the United Kingdom and found to lack important controls and sufficiently specific reagents for detecting measles virus. She also found that Dr. Wakefield’s subsequent research was dismissed by the scientific community as methodologically unsound. In that regard, she noted that 10 of 12 co-authors on Dr. Wakefield’s controversial 1998 article in the medical journal The Lancet subsequently retracted their support for the article’s conclusion that there is a potential causal link between the MMR vaccine and autism.

The Special Masters allowed the petititioners (including the Hazelhursts) time to rebut Dr. Bustin’s testimony, through cross examination and through documentation from the UK MMR litigation. The petitioners did not avail themselves of this opportunity.

Over objection, the government sought to introduce Dr. Bustin’s reports and testimony regarding the Unigenetics laboratory, which, by that time, had gone out of business.[ 2 ] The special master in the Cedillo case provisionally admitted the evidence. The three special masters in the omnibus proceeding then deferred decision on whether to rely on that evidence and stated that they would “favorably consider joining in a request” by the petitioners “for the release of relevant reports” from the UK litigation. The record remained open for more than a year following the Cedillo hearing to afford the petitioners sufficient time to present rebuttal evidence, to conduct additional cross-examination of Dr. Bustin, and to obtain documents from the British court. However, none of the petitioners recalled Dr. Bustin for further questioning or applied for access to any of the materials from the UK litigation.

The Hazelhurst’s argued that evidence should have been allowed that was not. In particular, they argued that some unpublished results demonstrate the persistent measles theory.

The special master further concluded that the unpublished and preliminary findings of the Walker group should not be accorded significant weight. She observed that Dr. Hepner had declined to “draw any conclusions about the biological significance” of the investigators’ findings and had testified that negative controls were not included with each experimental run. The special master also noted that the petitioners’ experts based their opinions on the characteristics of the “wild-type” measles virus, as opposed to the vaccine-strain measles virus, which is far less virulent and replicates poorly in the human body.

In the end, the appeals judge ruled that there was no reason to overturn the original decision:

Because we find no error in the special master’s consideration of the evidence, we also find no error in her decision to discount Dr. Corbier’s opinion that the MMR vaccine caused Yates’s autism. By Dr. Corbier’s own admission, his opinion depended heavily on the reliability of the scientific studies purporting to show measles virus persistence in autistic children.

Compensation under the Vaccine Act is limited to those individuals whose injuries or deaths can be linked causally, either by a Table Injury presumption or by a preponderance of “causation-in-fact” evidence, to a listed vaccine. The special master concluded that the Hazlehursts’ evidence failed to demonstrate the necessary causal link, and the petitioners have not identified any reversible error in the special master’s decision reaching that conclusion.

The petitioners now have the choice of appealing to the U.S. Supreme Court. As noted above, the Supreme Court hears cases which help define laws and this does not appear to be such a case. It would seem unlikely, then, that the Court would agree to hear this case. If so, this is the end of the appeals for the Hazelhurst’s in their case against the U.S. government. The next step would, then, be to take their case to civil court against the vaccine manufacturers. Such cases have not been successful so far. Civil cases require a higher level of evidence and expertise than the vaccine court. Having failed in the Federal Court, where the rules are more favorable to the petitioners, it would seem a difficult battle to win the case in civil court.

Byrd and Melanie Billings

13 May

Byrd and Melanie Billings were adoptive parents. They took care of disabled children, including autistic children. New stories vary on how many kids the Billings’ had, but one states that they had 16 kids, 12 of whom were adopted. Many of their children were disabled, including autism and Down syndrome.

I’m am in awe of these people.

Unfortunately the way I’ve heard about this family is through tragedy. Apparently a small group (seven men and a woman) entered their home and murdered them. Their children were present. This happened last year, but some of the people involved in this murder have decided to cooperate in return for lower sentences.

Byrd and Melanie Billings Murder: Teen Pleads in Fla. Slaying of Wealthy, Adoptive Parents

More here: Billings suspect enters plea of no contest

Here is video from last year, talking about the case. But it talks about the family as well.

http://abcnews.go.com/assets/player/walt2.6/flash/SFP_Walt.swf

An older sibling plans to care for the 13 children.

Mike Stanton Speaks

13 May

The following is taken from a piece from Secondary Education.

A leading expert on autism has said that mainstream schools should re-evaluate how they respond to children with Autistic Spectrum Disorder (ASD).

According to Mike Stanton, a teacher at the George Hastwell School in Cumbria, which caters for children with severe learning difficulties, many schools often treat autism as a behavioural problem rather than a communication problem.

Instead of viewing difficult students’ actions as “challenging behaviour”, he encourages teachers to take a different attitude and consider what lies behind the situation.

By trying to understand why the pupil is reacting in a certain way, Mr Stanton thinks that the problem of strained relationships between teachers and autistic children – sometimes caused when the child is asked to do something they do not want to – could be avoided.

“There’s a thin line between fight and flight in autistic children,” he said.

Mr Stanton told us this “fine balance” can be more sensitively addressed in the classroom by looking at two principal ASD issues: time and space.

Unstructured time and social interaction are difficult for autistic children, he says, but strategies can be implemented to make these easier. For example, providing respite from the hustle and bustle of the school in the form of a quiet room, or structured, quiet activities such as playing chess.

Beth Reid, policy manager for the National Autistic Society, agrees that there are basic things that can be done, such as changing the ways in which autistic children are spoken to.

For example, as people with ASD can often take things literally, teachers can avoid using complicated, metaphorical language. She told us: “We can be more aware of the environment that they are sensitive to.”

However, Mr Stanton feels that beyond the school gates, services and provisions should be put in place to more effectively tackle barriers such as a lack of teacher training, and the examination system.

He said: “Mainstream schools operate under the burden of Ofsted inspections and exams. To change this, schools should be able test competencies, instead of having to implement stressful exams.”

Mr Stanton believes that the government should do more to reward schools that take on less-able children. He continues: “It is wrong that a school which takes children no one wants can be classed as a ‘failing school’.”

Furthermore, Mr Stanton claims that much of the research done into teaching autistic children is not getting through to educational establishments because the researchers themselves are using the wrong tactics.

“Teachers are bombarded by new initiatives and people telling them to change their approach,” he told us. “If the people doing the research could go into schools and find out what they need help with and what they can change, then that might work.”

Despite this, Mr Stanton says that things are gradually changing for the better, referring specifically to the Restorative Practices programme. Although not autism-specific, the programme’s approach has been found to be highly effective. Instead of attributing blame, it focuses on repairing relationships. By asking children questions like “what happened?” and “how did you feel?” a more co-operative response is elicited than if they feel accused.

Training for the programme is currently taking place in special needs schools across the country, and in some mainstream schools. However, a significant lack of awareness still exists about ASD.

Ms Reid continued: “I know of schools that are doing excellent work but I still hear of establishments that don’t think autism exists and perceive it as naughtiness.”

Mr Stanton added: “There is still a huge amount of ignorance surrounding ASD and people often don’t take it seriously.

“There is not enough respite provided for autistic children, and not enough trained staff. Also, those who are trained are overworked.”

Nature Fubar

13 May

Nature, the usually reputable Science magazine have launched a Scitable Autism section and with it screwed up their usual impeccable attention to detail.

Who for example thought it necessary to put:

Determining the cause of — and the cure for — autism is crucial for our society

I wonder. And who thought it necessary to link to no less than three anti-vaccine links on the home page of this….blog? Wiki? Two links to Autism Speaks whose controllers recently attended a DAN! conference and one link to ARI itself.

Its a ridiculous and desperately sad state of affairs when even Nature, that bastion of good science resorts to scaremongering about autism and promoting an anti-vaccine viewpoint.

Dr. Tom Insel on Demystifying Autism

12 May

Dr. Tom Insel wears many hats, as they say. He is the director of the National Institute of Mental Health (NIMH), one of the National Institutes of Health run by the US Government. As part of his function there, he chairs the Interagency Autism Coordinating Committee (IACC). The IACC prepares the “Strategic Plan” for the government’s activities in autism research.

Dr. Insel has obviously taken autism research very seriously. He doesn’t just chair the IACC, he obviously spends a lot of time reviewing autism research. I doubt many people at the Director level at NIH would spend the amount of time Dr. Insel obviously spends on autism.

He has recently given a few talks on autism, the current state of knowledge and the directions for research. One such talk was at NIH and was titled Demystifying Autism . Another talk was given at MIT and was hosted by the Simons Foundation. (sorry, I can’t find embed code for those talks)

Dr. Insel talks about how there is a large diversity in the autism population. The “spectrum” is broad, as likely most readers to this blog will already know. In both talks, Dr. Insel uses video from Dov Shestak (son of Portia Iverson and Jon Shestak, founders of Cure Autism Now, which is now part of Autism Speaks). This is used to give an example of regression in autistics.

Of course one large section is devoted to the increasing autism prevalence. Dr. Insel mentions the epidemiological work of Peter Bearman, which shows that much of the increase in the California Department of Developmental Services autism caseload can be accounted for by diagnostic changes and social factors. But, not all of the increase has been accounted for. Dr. Insel uses the term that the burden of proof is on those who would say that the increase is not “real”. I would put it differently–that given the lack of definitive information on the causes of the rise, we should continue to look for possible environmental causes. Many use the term “environmental cause” to mean “vaccines”. That’s not what I, or it appears, Dr. Insel mean though.

Dr. Insel discusses one yet-unpublished study: the California Twin Study.

Here is his power point slide (which you can click to enlarge if you wish):

Slide showing results of yet unpublished twin study

Dr. Insel's slide on Twin Study

or–

Narrow criteria:
monozygotic (“identical”)–80% concordance
dizygotic (“fraternal”)– 26% concordance
.
broad criteria
monozygotic–87% concordance
dizygotic– 39% concordance

This is consistent with a recent study from the Kennedy Kreiger Institute at Johns Hopkins. While this wasn’t discussed by Dr. Insel, I include the abstract for that study below:

OBJECTIVES: To examine patterns of autism spectrum disorder (ASD) inheritance and other features in twin pairs by zygosity, sex, and specific ASD diagnosis. DESIGN: Cross-sectional study. SETTING: Internet-based autism registry for US residents. PARTICIPANTS: Survey results from 277 twin pairs (210 dizygotic [DZ] and 67 monozygotic [MZ]) aged 18 years or younger with at least 1 affected twin. MAIN EXPOSURES: Zygosity and sex. OUTCOME MEASURES: Concordance within twin pairs of diagnosis, natural history, and results from standardized autism screening. RESULTS: Pairwise ASD concordance was 31% for DZ and 88% for MZ twins. Female and male MZ twins were 100% and 86% concordant, respectively, and DZ twin pairs with at least 1 female were less likely to be concordant (20%) than were male-male DZ twin pairs (40%). The hazard ratio for ASD diagnosis of the second twin after a first-twin diagnosis was 7.48 for MZ vs DZ twins (95% confidence interval, 3.8-14.7). Affected DZ individual twins had an earlier age at first parental concern and more frequent diagnoses of intellectual disability than did MZ twins; MZ twins had a higher prevalence of bipolar disorder and Asperger syndrome and higher concordance of the latter. Results of autism screening correlated with parent-reported ASD status in more than 90% of cases. CONCLUSIONS: Our data support greater ASD concordance in MZ vs DZ twins. Overall higher functioning, psychiatric comorbidity, and Asperger syndrome concordance among affected MZ vs DZ twins may also suggest differential heritability for different ASDs. For families in which one MZ twin is diagnosed with ASD, the second twin is unlikely to receive an ASD diagnosis after 12 months. In addition, Internet parent report of ASD status is valid.

Concordance is when one child has an ASD, does the other one? 100% concordance would mean that if one twin has an ASD, the other twin does as well. That would indicate that autism is purely genetic.

Most people will concentrate on the monozygotic concordance. Even with the broad criteria, there is 87% concordance. That would indicate that at least some fraction of the cause of autism is not genetic. This is a very complicated question, as Joseph at the Autism Natural Variation blog has discussed.

What is astounding to me is the dyzogotic concordance. Take the 39% for the broad criteria. My recollection is that the concordance for siblings is about 4% if one sibling is male, and about 10% if one sibling is female. I’m trying to find the study on this. But, is there a higher concordance for dizygotic twins than for siblings in general?

Dr. Insel spends a fair amount of time on the genetic studies involved in autism. He attributes about 15% of the current autistic population as being linked to known genetic conditions. This is a pretty common estimate in the community.

One interesting fact: the known genes associated with autism are neurodevelopmental and involved with synapses. He even titles the slide as “Autism as a synaptic disease” and proposes that synaptic function might be the unifying feature of autism.

Dr. Insel notes that there are many chemicals whose neurotoxicity have not been determined. He also notes that there are some known chemicals which increase the risk of autism–valproic acid, Thalidomide and misoprostal. For all of these there is a critical window of time–in the first or early second trimester of pregnancy–where the autism risk is increased. Thalidomide, for example, is considered to be causal in a short period of time–from 20 to 24 days gestation.

If you want to see the direction Dr. Insel may take autism research in the future, these talks are worth listening to. I think it safe to say that autism research will continue to look for causes, genetic and environmental. Environmental cause research will likely focus on prenatal exposures. Study will continue on the physical structure of the brain, the “circuitry” to help define what autism is and what the phenotypes may be. Study will continue on interventions, with a look towards earlier interventions (before age 1, possibly before symptoms are visible). Intervention research will look to be tailored to the individual, which will require some way to phenotype autism.

As I noted above, I think Dr. Insel is taking a close interest in autism. He doesn’t dictate the goals for autism research, but I think listening to what he has to say gives in interesting insight into the directions it may be going.

Trends in US autism research funding: more money going to clinical and translational research

11 May

Where money is being spent on autism research is changing. Basic science, which still gets most of the money, is decreasing and clinical and translational research is increasing.

If you are like me, you have to look up “translational research”. From the link above, “To improve human health, scientific discoveries must be translated into practical applications.” I.e. this is research to “translate” basic findings into practical applications.

This was analyzed in a paper published last year by a team at Stanford University in California:

Trends in US autism research funding.

Singh J, Illes J, Lazzeroni L, Hallmayer J.

Stanford Center for Biomedical Ethics, Center for Integration of Research on Genetics and Ethics, Stanford University, Palo Alto, CA, USA.
Abstract

This study shows that the number of autism research grants funded in the US from 1997 to 2006 significantly increased 15% per year. Although the majority of projects were concentrated in basic science (65%) compared to clinical (15%) and translational research (20%), there is a significant decrease in the proportion of basic research grants per year and a significant increase in the proportion of translational projects per year. The number of translational projects funded by the National Alliance for Autism Research and Cure Autism Now increased significantly, whereas the number of clinical projects significantly increased for the National Institutes of Health. In conclusion, this study demonstrates the shifting landscape of autism research from basic science to clinical and translational research.

The study analyzed grants up to 2006. This is before the increase in funding through the Combating Autism Act. The current budget for IACC proposes projects is about $220,000,000 per year, with a total for all years of over one billion dollars. Over $230 million are dedicated to “Which treatments and interventions will help?

As noted here on LeftBrainRightBrain, funding levels for areas such as environmental causation have increased, overtaking genetic only causation research in funding levels.

No Link Between Childhood Infections, Autism

10 May

One of the theories posited about autism causation is that childhood infections can result in autism. A recent study from the Arhus, Denmark, explores this by checking how often children are admitted to the hospital for infectious diseases. Given that maternal infections do appear to be associated with a greater risk of autism, the idea of childhood infections is worth considering. I would add that the attention to mitochondrial disorders and autism that was high in the past couple of years would also suggest this is a valuable area to consider.

Here is the abstract:

OBJECTIVE: To investigate the association between hospitalization for infection in the perinatal/neonatal period or childhood and the diagnosis of autism spectrum disorders (ASDs). DESIGN: A population-based cohort study. SETTING: Denmark. PARTICIPANTS: All children born in Denmark from January 1, 1980, through December 31, 2002, comprising a total of 1 418 152 children. EXPOSURE: Infection requiring hospitalization. MAIN OUTCOME MEASURE: The adjusted hazard ratio (HR) for ASDs among children hospitalized for infection compared with other children. RESULTS: A total of 7379 children were diagnosed as having ASDs. Children admitted to the hospital for any infectious disease displayed an increased rate of ASD diagnoses (HR, 1.38 [95% confidence interval, 1.31-1.45]). This association was found to be similar for infectious diseases of bacterial and viral origin. Furthermore, children admitted to the hospital for noninfectious disease also displayed an increased rate of ASD diagnoses (HR, 1.76 [95% confidence interval, 1.68-1.86]), and admissions for infection increased the rate of mental retardation (2.18 [2.06-2.31]). CONCLUSIONS: The association between hospitalization for infection and ASDs observed in this study does not suggest causality because a general association is observed across different infection groups. Also, the association is not specific for infection or for ASDs. We discuss a number of noncausal explanatory models.

Autistic children *are* admitted to the hospital for infectious diseases more often than the rest of the population. But, in general autistic children are admitted to the hospital more often than the rest of the population.

Bloomberg Businessweek discussed this paper in No Link Between Childhood Infections, Autism. They interviewed Dr. Andrew Zimmerman of the Kennedy Krieger Institute. Dr. Zimmerman concurred with the conclusions of the paper:

“Yes, there is an increased rate of hospitalization preceding the diagnosis of autism, but it doesn’t support a causal relationship between autism and infections,” Zimmerman said.

This is significant, in my view. Dr. Zimmerman is one of the doctors who treated Hannah Poling (the young girl whose case was conceded by the Department of Health and Human Resources in the vaccine court, sparking the public interest in the subject).

It is also worth noting that the study considered specific infections. From the Bloomberg/Newsweek story:

And the researchers could point to no particular infection that upped the risk.

They therefore conclude that childhood infections cannot be considered a cause of autism.

“We find the same relationship between hospitalization due to many different infections and autism,” noted lead study author Dr. Hjordis Osk Atladottir, of the departments of epidemiology and biostatistics at the Institute of Public Health, University of Aarhus in Denmark. “If there were a causal relationship, it should be present for specific infections and not provide such an overall pattern of association.”