NDAR Federation Creates Largest Source of Autism Research Data to Date

NIH-funded Database Sets Standard for Collaboration and Data Sharing

Source: NDAR

A data partnership between the National Database for Autism Research (NDAR), and the Autism Genetic Resource Exchange (AGRE) positions NDAR as possibly the largest repository to date of genetic, phenotypic, clinical, and medical imaging data related to research on autism spectrum disorders (ASD)LPC Continuing Education

“The collaboration between AGRE and NDAR exemplifies the efforts of government and stakeholders to work together for a common cause,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health, part of NIH. “NDAR continues to be a leader in the effort to standardize and share ASD data with the research community, and serves as a model to all research communities.”

NDAR is supported by the National Institutes of Health; AGRE is an Autism Speaks program.

NDAR’s mission is to facilitate data sharing and scientific collaboration on a broad scale, providing a shared common platform for autism researchers to accelerate scientific discovery. Built around the concept of federated repositories, NDAR integrates and standardizes data, tools, and computational techniques across multiple public and private autism databases. Through NDAR, researchers can access results from these different sources at the same time, using the rich data set to conduct independent analyses, supplement their own research data, or evaluate the data supporting published journal articles, among many other uses.

Databases previously federated with NDAR include Autism Speaks’ Autism Tissue Program, the Kennedy Krieger Institute’s Interactive Autism Network (IAN), and the NIH Pediatric MRI Data Repository. AGRE currently houses a clinical dataset with detailed medical, developmental, morphological, demographic, and behavioral information from people with ASD and their families.

Approved NDAR users will have access to data from the 25,000 research participants represented in NDAR, as well as 2,500 AGRE families and more than 7,500 participants who reported their own information to IAN.

NDAR is supported by NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, the National Institute of Environmental Health Sciences, and the NIH Center for Information Technology.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Suspect Gene Variants Boost PTSD Risk after Mass Shooting

Profile of Risk Emerging for Trauma-triggered Molecular Scars

College students exposed to a mass shooting were 20-30 percent more likely to later develop post traumatic stress disorder (PTSD) symptoms if they harbored a risk version of a gene, NIMH-funded researchers have discovered. This boost in risk, traced to common variants of the gene that controls recycling of serotonin, was comparable to the risk conferred by close proximity to the shooting – for example, being in the room with the shooter versus just being on campus.

The discovery is the latest of several recently reported that collectively profile heightened biological vulnerability to developing PTSD following trauma – and the molecular scars it leaves in the brain.

For example, early this year, researchers linked high levels of a stress-triggered, estrogen-related hormone to PTSD symptoms in women, with certain versions of the hormone receptor’s gene conferring higher risk. A PET scan study in September traced increased PTSD symptoms to heightened levels of a serotonin receptor. Both studies suggest potential new drug targets for treating the disorder. Evidence is also mounting that trauma – particularly if experienced very early in life – can adversely alter the set-points of gene expression in brain stress circuits and compromise immune and inflammatory system function continuing education for counselors

Gene-by-environment – caught in the act

By chance, researchers at Northern Illinois University (NIU) had already collected data on students’ PTSD symptoms prior to the 2008 murder-suicide that killed six on the Dekalb, Illinois campus.*

“This provided a rare opportunity to pinpoint not just a correlation but a cause – to document that such a tragedy can conspire with a risk gene to produce the disorder,” explained Kerry Ressler, M.D., Ph.D., of Emory University.

NIMH grantees Ressler, NIU’s Holly Orcutt, Ph.D., and colleagues, report on discovery of this gene-by-environment interaction online September 5th 2011 in the Archives of General Psychiatry.

Previous efforts to confirm such an interaction in PTSD had been confounded by lack of data on individuals’ pre-trauma symptoms. Any pre-existing symptoms must be taken into account to establish a common baseline – so that new symptoms that develop can confidently be pegged to the traumatic event.

By chance, before the tragedy, Orcutt’s team had prospectively surveyed PTSD symptoms in more than a thousand NIU undergraduate women, as part of a longitudinal study on predictors of sexual victimization, which can trigger the disorder. Within a few weeks after the tragedy, they seized the opportunity and – with help from a NIMH RAPID grant – conducted follow-up surveys, using the same measures, in subsets of the original sample – and then again after several months – to track symptom changes. Ressler’s team ultimately analyzed saliva samples from 235 women for gene type.

Previous studies had linked PTSD to a version of the gene that codes for the serotonin transporter (SERT), the protein on neurons that recycles the chemical messenger serotonin back into the cell after it is secreted into the synapse. So the researchers focused their genetic analysis on this variation, noting that it is “the most commonly described polymorphism in the psychiatric genetics literature.”

For example, this same site of genetic variation has also been linked to increased risk for anxiety - and, in some studies, increased risk for depression following stressful life events, although the latter findings remain controversial. Some hypothesize that these implicated variants may have less to do with conferring disease risk, per se, than with increased sensitivity to environmental influences more generally.**

Antidepressant medications, serotonin selective reuptake inhibitors (SSRIs), work by blocking SERT, thereby enhancing serotonin activity. SSRIs are the main medication treatment for PTSD.

Everyone inherits two copies of the SERT gene, one from each parent. So people can inherit one or two copies of risk-associated versions that are common in the population. Carrying any combination of these risk versions had been associated with increased risk for PTSD in 8 out of 9 previous studies.

The new study more definitively connects the dots between the environmental trigger and these risk gene types. Among 204 women without prior symptoms, 20 percent of those who showed acute symptoms within a few weeks after the shooting had developed PTSD symptoms when surveyed several months later. Proximity to the shooting and the risk gene types were about equally predictive of increased risk among this group.

These results come at a time of ferment in the field over confidence in gene-by-environment findings. A recent analysis by NIMH grantees of more than 100 such studies over the past decade uncovered what they call “publication bias.” They found that positive new findings were more likely to get published, while direct replications – which tend be less likely to confirm positive new findings – were under-reported. The net effect: an unintentional bias toward false positive reports. Notably, the researchers singled out as a prime example of this bias the scientific literature on serotonin transporter gene-by-environment interactions.

“How we measure environment may be at least as important as how we measure genetics, but to date, little effort has been focused on that,” noted Ressler. “We think that performing prospective studies in populations with shared trauma may be one way to 'hold constant' the environment variable, thus allowing for more clarity in the role of genetics.”

PTSD symptoms of NIU undergraduate women with a risk-associated serotonin transporter gene type (s/s, lG/lG, s/lG) increased 20-30 percent more than in classmates with a protective gene type after the 2008 campus shootings (Time 2). The increased risk was comparable to that conferred by close proximity to the shooting.
Source: Kerry Ressler, M.D., Ph.D., Emory University

Why Women are More Vulnerable

Earlier this year, Ressler and colleagues reported findings that may help to explain why women are twice as likely as men to develop PTSD. They linked PTSD symptoms in women to higher blood levels of what has been dubbed the “master regulator” of the stress response, a hormone called PACAP (pituitary adenyl cyclase-activating peptide).

PTSD symptoms were 5-fold higher in women with above average PACAP levels, compared to women with below average levels. Also in women only, a certain version of the gene that codes for PACAP’s receptor, PAC-1, conferred increased vulnerability. Experiments in rodents confirmed that this variable part of the PAC-1 gene is regulated, in part, by the female hormone estrogen.

This suggests that heightened vulnerability to PTSD in females may be traceable to this brain system critical to proper stress circuit function. Genetic variation in a different pathway may similarly be linked to increased risk for PTSD in men, say the researchers.

Females with higher-than-average levels of the stress-managing hormone PACAP had 5 times more PTSD symptoms than females with lower-than-average levels. By contrast, PACAP levels were unrelated to PTSD symptoms in males. Since the PACAP system is shaped, in part, by the female hormone estrogen, these differences could help to explain why women are twice as likely as men to develop the disorder.
Source: Kerry Ressler, M.D., Ph.D., Emory University

PACAP, “master regulator” of the stress response.
Source: Lee Eiden, Ph.D., NIMH Section on Molecular Neuroscience

Molecular scars

The Emory researchers also found increased methylation – epigenetic regulation of gene expression in response to the environment – in the part of Pac1 associated with PTSD in both women and men. Adverse experiences can induce molecules called methyl groups to attach to DNA and block genes from turning on. This results in enduring changes in the proteins the genes express. These molecular scars can weaken the brain’s defenses against PTSD.

Indeed, methylation increases pervasively in PTSD, according to Ressler and colleagues. Notably, they pinpointed such increases in several genes implicated in inflammatory and immune system abnormalities that go along with PTSD. They also saw abnormalities in immune system chemical messengers, called cytokines. Increased blood levels of one such cytokine TNF-alpha, known to trigger stress response symptoms, correlated with a history of child abuse and cumulative life stresses.

Early trauma may deplete resilience molecule

In September, a NIMH-funded brain imaging study reported that levels of a type of serotonin receptor (1B) were markedly lower in stress circuits of PTSD patients than in others exposed to trauma. This protein on neurons, to which the neurotransmitter binds, plays a pivotal role in stress resilience and antidepressant effect. By contrast, PET scans revealed that people who had experienced trauma but didn’t develop PTSD had only slightly fewer receptors than healthy controls.

NIMH grantee Alexander Neumeister, M.D., of Mount Sinai School of Medicine, and colleagues, traced both the severity of symptoms and the depleted receptors largely to the age at which trauma was first experienced. The earlier the age and the more subsequent trauma exposures, the fewer receptors expressed and the more severe the PTSD symptoms and overlap with depression. The dearth of receptors likely reflects such features of patients’ trauma histories, with those who develop PTSD also having other genetic or environmental vulnerabilities, say the researchers.

Patients with PTSD (right) had significantly fewer serotonin 1B receptors (yellow & red areas) in their brain stress circuits than healthy controls (left). PET scan images show destinations of a radioactive tracer that binds to serotonin 1B receptors. Front of brain is at bottom.
Source: Alexander Neumeister, M.D., Mount Sinai School of Medicine

Possible Uses: Risk profile and treatment targets?

Such epigenetic and genetic signatures of PTSD proneness in blood and brain, together with behavioral measures, may collectively prove useful in profiling a patient’s risk for developing the disorder. Molecules such as PACAP and the serotonin 1B receptor may also hold promise as potential targets of new drugs aimed at correcting specific abnormalities in the affected brain pathways, suggest the researchers.


NIMH RAPID grant helps salvage science from tragedy
2/14/08 Mass shooting on NIU campus
2/19/08 NIU researcher Holly Orcutt, Ph.D., contacts NIMH to discuss how to make the most of her prospectively collected data on PTSD and other parameters to learn from the tragedy.
3/26/08 Orcutt submits a concept for a follow-up study under the NIMH Rapid Assessment Post Impact of Disaster (RAPID) research program announcement – a unique time sensitive mechanism for expediting funding of research grants in response to emergency situations.
5/17/08 Grant application submitted.
6/18/08 Application undergoes peer review.
9/18/08 Grant awarded to NIU and Orcutt.

References

Acute and Posttraumatic Stress Symptoms in a Prospective Gene x Environment Study of a University Campus Shooting. Mercer KB, Orcutt HK, Quinn JF, Fitzgerald CA, Conneely KN, Barfield RT, Gillespie CF, Ressler KJ. Arch Gen Psychiatry. 2011 Sep 5. [Epub ahead of print]
PMID:21893641

A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry. Duncan LE, Keller MC. Am J Psychiatry. 2011 Sep 2. [Epub ahead of print]
PMID: 21890791

Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.
Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V.Nature. 2011 Feb 24;470(7335):492-7. Erratum in: Nature. 2011 Sep 1;477(7362):120.
PMID:21350482

PACAP: a master regulator of neuroendocrine stress circuits and the cellular stress response.
Stroth N, Holighaus Y, Ait-Ali D, Eiden LE. Ann N Y Acad Sci. 2011 Mar;1220:49-59. doi: 10.1111/j.1749-6632.2011.05904.x. Review. PMID:21388403

The Effect of Early Trauma Exposure on Serotonin Type 1B Receptor Expression Revealed by Reduced Selective Radioligand Binding. Murrough JW, Czermak C, Henry S, Nabulsi N, Gallezot JD, Gueorguieva R, Planeta-Wilson B, Krystal JH, Neumaier JF, Huang Y, Ding YS, Carson RE, Neumeister A. Arch Gen Psychiatry. 2011 Sep;68(9):892-900. PMID:21893657

Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, Tang Y, Gillespie CF, Cubells JF, Ressler KJ. Am J Med Genet B Neuropsychiatr Genet. 2011 Sep;156(6):700-8. doi: 10.1002/ajmg.b.31212. Epub 2011 Jun 28. PMID:21714072

Psychiatry: A molecular shield from trauma. Stein MB. Nature. 2011 Feb 24;470(7335):468-9. No abstract available. PMID:21350472

*http://en.wikipedia.org/wiki/Northern_Illinois_University_shooting

** http://www.theatlantic.com/magazine/archive/2009/12/the-science-of-success/7761/

HIV Variants in Spinal Fluid May Hold Clues in Development of HIV-related Dementia

NIMH-funded researchers found two variants of HIV in the cerebrospinal fluid (CSF) of infected study participants that were genetically distinct from the viral variants found in the participants’ blood. The study, published October 6, 2011, in the journal PLoS Pathogens, suggests these CSF variants may help to inform research on the development and treatment of cognitive problems related to HIV infection.

Background

The advent of antiretroviral medications has helped many with HIV to manage the illness effectively. But even with proper treatment, a significant percentage of HIV-infected people develop HIV-associated dementia (HAD) or more mild neurological disorders. Research suggests that some people with HAD harbor variants of HIV in their cerebrospinal fluid (CSF) that may be less responsive to current treatments and thus contribute to cognitive decline. Understanding the role of HIV in HAD may also inform efforts to treat or prevent mild neurocognitive disorders associated with HIV.

To explore this issue, Ronald Swanstrom, Ph.D., of the University of North Carolina at Chapel Hill, and colleagues collected samples of blood and CSF from 11 people with HIV. All samples were collected just before and shortly after the person started antiretroviral therapy. The researchers also had access to additional samples from two of the 11 participants, collected several years prior to their starting treatment ceus for counselors

Results of the Study

The researchers found two variants of HIV in participants’ CSF that were genetically distinct from HIV found in their blood. Among participants diagnosed with HAD, the HIV variants in CSF showed greater genetic differences from the type of HIV in their blood, compared with participants with no HAD symptoms.

HIV typically targets a type of immune cell called T-cells. However, researchers found that one CSF variant replicated in macrophages, a different type of immune cell that typically lives longer than T-cells. In one of the participants with longer-term data, the researchers found evidence of this variant before the participant was diagnosed with HAD. During that time, the participant’s neurological assessments reported only mild impairment. The proportion of macrophage-targeting variants in the CSF increased over time, particularly in the first month after the participant was diagnosed with HAD.

In the other participant with longer-term data, the researchers noted the presence of the second CSF variant, which targeted T-cells, after the participant was diagnosed with HAD. Before the participant was diagnosed with HAD, the T-cell-targeting variant was not present in CSF samples.

Significance

The findings indicate that the genetically distinct variants of HIV in the CSF may each play a role in the development of HAD and related neurological disorders.

According to the researchers, the variant that targets macrophages provides clues to how HIV may evolve in order to replicate in a new cell type. The presence of the T-cell-targeting variant suggests that HIV infection may cause T-cells to migrate into the CSF. If confirmed, this migration would provide an alternative mechanism for maintaining viral replication in the central nervous system, which is associated with neurocognitive impairment.

What’s Next

Examining samples of blood, CSF, and brain tissue from a larger number of HIV- infected people with more mild symptoms of neurocognitive impairment may reveal physiological features that distinguish the two CSF variants identified in the current study. According to the researchers, identifying such features may help predict either current or future neurocognitive impairment and would emphasize the benefits of starting treatment early.

Reference

Schnell G, Joseph S, Spudich S, Price RW, Swanstrom. HIV-1 Replication in the Central nervous System Occurs in Two Distinct Cell Types. PLoS Pathog. 2011 Oct;7(10):e1002286

Training Peers Improves Social Outcomes for Some Kids with ASD

NIH-funded Study Finds Engaging Peers in Social Skills Intervention May Be More Helpful than Training Children with ASD Directly

Children with autism spectrum disorder (ASD) who attend regular education classes may be more likely to improve their social skills if their typically developing peers are taught how to interact with them than if only the children with ASD are taught such skills. According to a study funded by the National Institutes of Health, a shift away from more commonly used interventions that focus on training children with ASD directly may provide greater social benefits for children with ASD. The study was published online ahead of print on November 28, 2011, in the Journal of Child Psychology and Psychiatry.

"Real life doesn't happen in a lab, but few research studies reflect that," said Thomas R. Insel, director of the National Institute of Mental Health (NIMH), a part of NIH. "As this study shows, taking into account a person’s typical environment may improve treatment outcomes." CEUs for Counselors

The most common type of social skills intervention for children with ASD is direct training of a group of children with social challenges, who may have different disorders and may be from different classes or schools. The intervention is usually delivered at a clinic, but may also be school-based and offered in a one-on-one format. Other types of intervention focus on training peers how to interact with classmates who have difficulty with social skills. Both types of intervention have shown positive results in studies, but neither has been shown to be as effective in community settings.

Connie Kasari, Ph.D., of the University of California, Los Angeles, and colleagues compared different interventions among 60 children, ages 6-11, with ASD. All of the children were mainstreamed in regular education classrooms for at least 80 percent of the school day.

These children were randomly assigned to either receive one-on-one training with an intervention provider or to receive no one-on-one intervention. The children were also randomized to receive a peer-mediated intervention or no peer-mediated intervention. The two-step randomization resulted in four intervention categories, each with 15 children who had ASD:
Child-focused: direct, one-on-one training between the child with ASD and intervention provider to practice specific social skills, such as how to enter a playground game or conversation
Peer-mediated: group training with the intervention provider for three typically developing children from the same classroom as the student with ASD; the affected student did not receive any social skills training. The participating children were selected by study staff and teachers and were taught strategies for engaging students with social difficulties.
Both child-focused and peer-mediated interventions
Neither intervention.

All interventions were given for 20 minutes two times a week for six weeks. A follow-up was conducted 12 weeks after the end of the study. After the follow up phase, all children with ASD who had received neither intervention were re-randomized to one of the other treatment categories.

Children with ASD whose peers received training—including those who may also have received the child-focused intervention—spent less time alone on playgrounds and had more classmates naming them as a friend, compared to participants who received the child-focused interventions. Teachers also reported that students with ASD in the peer-mediated groups showed significantly better social skills following the intervention. However, among all intervention groups, children with ASD showed no changes in the number of peers they indicated as their friends.

At follow-up, children with ASD from the peer-mediated groups continued to show increased social connections despite some of the children having changed classrooms due to a new school year and having new, different peers.

According to the researchers, the findings suggest that peer-mediated interventions can provide better and more persistent outcomes than child-focused strategies, and that child-focused interventions may only be effective when paired with peer-mediated intervention.

In addition to the benefits of peer-mediated interventions, the researchers noted several areas for improvement. For example, peer engagement especially helped children with ASD to be less isolated on the playground, but it did not result in improvement across all areas of playground behavior, such as taking turns in games or engaging in conversations and other joint activities. Also, despite greater inclusion in social circles and more frequent engagement by their peers, children with ASD continued to cite few friendships. Further studies are needed to explore these factors as well as other possible mediators of treatment effects.

The study was supported by NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Institute on Deafness and Other Communication Disorders through the Studies to Advance Autism Research and Treatment (STAART) network program and received additional funding from the Health Resources and Services Administration (HRSA).

Reference

Kasari C, Rotheram-Fuller E, Locke J, Gulsrud A. Making the Connection Randomized Controlled Trial of Social Skills at School for Children with Autism Spectrum Disorders. J Ch Psychol Psychiatry. 2011 Nov 28. [epub ahead of print]

Clinical Trials Number: NCT00095420

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Psychologists chase down sleep demons

What do Moby Dick, the Salem witch trials and alien abductions all have in common? They all circle back to sleep paralysis.

Less than 8 percent of the general population experiences sleep paralysis, but it is more frequent in two groups -- students and psychiatric patients -- according to a new study by psychologists at Penn State and the University of Pennsylvania.

Sleep paralysis is defined as "a discrete period of time during which voluntary muscle movement is inhibited, yet ocular and respiratory movements are intact," the researchers state in the current issue of Sleep Medicine Reviews. Hallucinations may also be present in these transitions to or from sleep.

Alien abductions and incubi and succubi, as well as other demons that attack while people are asleep, are implicated as different cultural interpretations of sleep paralysis. The Salem witch trials are now thought possibly to involve the townspeople experiencing sleep paralysis. And in the 19th-century novel Moby Dick, the main character Ishmael experiences an episode of sleep paralysis in the form of a malevolent presence in the room.

Brian A. Sharpless, clinical assistant professor of psychology and assistant director of the psychological clinic at Penn State, noted that some people who experience these episodes may regularly try to avoid going to sleep because of the unpleasant sensations they experience. But other people enjoy the sensations they feel during sleep paralysis.

"I realized that there were no real sleep paralysis prevalence rates available that were based on large and diverse samples," Sharpless said. "So I combined data from my previous study with 34 other studies in order to determine how common it was in different groups." MHC CEUs

He looked at a total of 35 published studies from the past 50 years to find lifetime sleep paralysis rates. These studies surveyed a total of 36,533 people. Overall he found that about one-fifth of these people experienced an episode at least once. Frequency of sleep paralysis ranged from once in a lifetime to every night.

When looking at specific groups, 28 percent of students reported experiencing sleep paralysis, while nearly 32 percent of psychiatric patients reported experiencing at least one episode. People with panic disorder were even more likely to experience sleep paralysis, and almost 35 percent of those surveyed reported experiencing these episodes. Sleep paralysis also appears to be more common in non-Caucasians.

"Sleep paralysis should be assessed more regularly and uniformly in order to determine its impact on individual functioning and better articulate its relation to other psychiatric and medical conditions," said Sharpless.

He looked at a broad range of samples, and papers were included from many different countries.

People experience three basic types of hallucinations during sleep paralysis -- the presence of an intruder, pressure on the chest sometimes accompanied by physical and/or sexual assault experiences and levitation or out-of-body experiences.

Up to this point there has been little research conducted on how to alleviate sleep paralysis or whether or not people experience episodes throughout their lives.

"I want to better understand how sleep paralysis affects people, as opposed to simply knowing that they experience it," said Sharpless. "I want to see how it impacts their lives." Sharpless hopes to look at relationships between sleep paralysis and post-traumatic stress disorder in the future.

This research was supported in part by the National Institute of Mental Health.

Also working on this research was Jacques P. Barber, professor of psychiatry, University of Pennsylvania.

Diagnoses of autism spectrum disorders vary widely across clinics

Archives of General Psychiatry study suggests common diagnostic subcategories like asperger syndrome are flawed and provides questionable value

NEW YORK (Nov. 9, 2011) -- To diagnose autism spectrum disorders, clinicians typically administer a variety of tests or scales and use information from observations and parent interviews to classify individuals into subcategories listed in standard psychiatric diagnostic manuals. This process of forming "best-estimate clinical diagnoses" has long been considered the gold standard, but a new study demonstrates that these diagnoses are widely variable across centers, suggesting that this may not be the best method for making diagnoses MHC Continuing Education

"Clinicians at one center may use a label like Asperger syndrome to describe a set of symptoms, while those at another center may use an entirely different label for the same symptoms. This is not a good way to make a diagnosis," says the study's lead investigator, Dr. Catherine Lord, director of the Institute for Brain Development, a partnership of Weill Cornell Medical College, NewYork-Presbyterian Hospital and Columbia University Medical Center. "Autism spectrum disorders are just that -- a spectrum of disorders. Instead of using subcategories, it would be better to simply report the results from agreed-upon tests and scales. This approach would provide more consistent and accurate information about individual patients."

The new study, published on Nov. 7 in the journal Archives of General Psychiatry, adds to previous evidence that standardized diagnostic instruments accurately predict who has autism and will continue to have it over time. It is also in line with recent skepticism about the value of categorical groupings of autism spectrum disorders in standard diagnostic manuals, such as the Diagnostic and Statistical Manual of Mental Disorders – IV – text revision (DSM-IV-TR) and the International Statistical Classification of Diseases. "There has been a lot of controversy about whether there should be separate diagnoses for autism spectrum disorder, especially Asperger syndrome," Dr. Lord says. "Most of the research has suggested that Asperger syndrome really isn't different from other autism spectrum disorders."

In the new study, Dr. Lord and co-author Dr. Eva Petkova, a biostatistician at NYU, studied about 2,100 people between the ages of 4 and 18 who were given a diagnosis of autism spectrum disorder by clinicians at 12 university-based centers. The participants were recruited from the Simons Simplex Collection, a multi-site project aimed at studying de novo genetic variations in families affected by autism spectrum disorders. The clinicians, who are experts in autism spectrum disorders, received training on how to administer and score the same set of cognitive tests and standardized instruments assessing social and communication skills and repetitive behavior, including the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview -- Revised (ADI-R). However, they received no specific training in making best-estimate clinical diagnoses. They used the DSM-IV-TR to classify individuals into three categories of varying severity: autistic disorder, pervasive developmental disorder -- not otherwise specified (PDD-NOS), and Asperger syndrome.

The researchers found that diagnoses of specific categories of autism spectrum disorder varied dramatically from site to site across the country. For instance, clinicians at one site gave only a diagnosis of autistic disorder, while clinicians at other sites gave that diagnosis to fewer than half of the participants. The proportion of individuals receiving a diagnosis of Asperger syndrome ranged from zero to nearly 21 percent across sites. These site differences were the second most important factor accounting for variation in the diagnoses (after social and communication deficits). However, the individuals with autism spectrum disorders did not vary significantly across sites in terms of their demographic information or developmental and behavioral characteristics, as measured by standardized instruments.

"The labels are pretty meaningless, because people are using the same general terms as if they mean the same thing, when they really don't," Dr. Lord says. "Because clinicians may not be using labels appropriately or diagnosing accurately, they may not be getting a sense of children's strengths and weaknesses and what therapy is best for them."

Clinicians across centers varied in how they weighed different factors and in the thresholds they set to make diagnoses. Although verbal IQ strongly influenced diagnoses at most centers, there were striking differences in the cutoff points used at each site to classify individuals into specific categories. The effect of age on diagnoses, and the specific age cutoff points, also varied dramatically across sites. "This doesn't make sense. You don't want to be told that you have a cold if you're 7 and a bacterial infection if you're 12, when you present with identical symptoms," Dr. Lord says.

The variability in clinical diagnoses could reflect regional differences, Dr. Lord says. For instance, services in some regions may be available only to children with a diagnosis of autistic disorder, but this same diagnosis may be stigmatizing or limit school options in other regions. Clinicians may also vary in how they take into account an individual's level of irritability and hyperactivity when judging the severity of autism spectrum disorder, Dr. Lord adds.

Because of the inconsistencies in best-estimate clinical diagnoses, the use of standard diagnostic manuals to classify individuals into subcategories of autism spectrum disorder should be reconsidered, Dr. Lord says. "It's very important for clinicians to use information from dimensions that directly relate to autism spectrum disorders, in addition to verbal IQ and the level of irritability and hyperactivity," she says. "The take-home message is that there really should be just a general category of autism spectrum disorder, and then clinicians should be able to describe a child's severity on these separate dimensions."

"This is an extremely important paper regarding our understanding of the various components of autism spectrum disorder from a group that has been crucial in defining the features of autism over many years," says Dr. Gerald D. Fischbach, scientific director of the Simons Foundation Autism Research Initiative. "They call attention to quantifiable traits rather than existing diagnostic categories. We are proud to have funded this project and to have gathered the Simons Simplex Collection on which this study is based under Dr. Lord's leadership."

In future research, Dr. Lord will work on improving diagnostic instruments --making them shorter, easier to use, and more appropriate for a wider variety of patients -- and assessing whether certain dimensions are really distinct from one another. This work will build on her previous pioneering efforts in developing these commonly used scales.


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Additional collaborating institutions include Columbia University Medical Center in New York City; the Simons Foundation in New York City; the University of Michigan in Ann Arbor; Emory University School of Medicine in Atlanta, Ga.; Emory University School of Medicine and Marcus Autism Center, Children's Healthcare of Atlanta, Ga.; Children's Hospital of Philadelphia in Pennsylvania; the University of Washington in Seattle; Vanderbilt University Medical Center in Nashville, Tenn.; Harvard Medical School in Boston, Mass.; the University of California, Los Angeles; Montreal Children's Hospital in Quebec, Canada; the University of Missouri in Columbia; Baylor College of Medicine in Houston, Texas; the University of Illinois at Chicago; Cincinnati Children's Hospital Medical Center in Ohio; the University of Minnesota in Minneapolis; and Indiana University in Bloomington.

This research was funded by the Simons Foundation and the National Institute of Mental Health.

Columbia University Medical Center


Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The Medical Center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States. For more information, please visit www.cumc.columbia.edu.

NewYork-Presbyterian Hospital


NewYork-Presbyterian Hospital, based in New York City, is the nation's largest not-for-profit, non-sectarian hospital, with 2,409 beds. The Hospital has nearly 2 million inpatient and outpatient visits in a year, including 12,797 deliveries and 195,294 visits to its emergency departments. NewYork-Presbyterian's 6,144 affiliated physicians and 19,376 staff provide state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, NewYork-Presbyterian/Morgan Stanley Children's Hospital, NewYork-Presbyterian/The Allen Hospital and NewYork-Presbyterian Hospital/Westchester Division. One of the most comprehensive health care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. NewYork-Presbyterian is the #1 hospital in the New York metropolitan area and is consistently ranked among the best academic medical institutions in the nation, according to U.S.News & World Report. The Hospital has academic affiliations with two of the nation's leading medical colleges: Weill Cornell Medical College and Columbia University College of Physicians and Surgeons. For more information, visit www.nyp.org.

Weill Cornell Medical College


Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.

Older adults in home health care at elevated risk for unsafe meds

New study shows 40 percent of seniors cared for by a home health agency are taking a prescription that is potentially unsafe or ineffective to them

NEW YORK (Nov. 21, 2011) -- Older adults receiving home health care may be taking a drug that is unsafe or ineffective for someone their age. In fact, nearly 40 percent of seniors receiving medical care from a home health agency are taking at least one prescription medication that is considered potentially inappropriate to seniors, a new study in the Journal of General Internal Medicine has revealed LPC Ceus

The study's researchers, led by Dr. Yuhua Bao, assistant professor of public health at Weill Cornell Medical College, found that home health care patients aged 65 and over are prescribed Potentially Inappropriate Medications, or PIMs, at rates three times higher than patients who visit a medical office. The researchers' data shows that home health care patients are taking 11 medications on average, and that the concurrent use of multiple medications is a strong indicator of the presence of PIMs.

"Elderly patients receiving home health care are usually prescribed medications by a variety of physicians, and it's a great challenge for home health care nurses to deal with prescriptions from many sources," says Dr. Bao.

Still, she sees the home health care model offering potential for improving this situation. "Having a medical professional enter an elderly patient's home is an opportunity to do a proper medication review and reconciliation," Dr. Bao explains.

The study used data from the National Home and Hospice Care Survey, conducted in 2007 by the Centers for Disease Control and Prevention (CDC), which is the most recent nationally representative epidemiological survey of home health patients. The 2002 Beers Criteria, an expert-panel-generated list that itemizes 77 medications or groups of medications considered inappropriate for elderly people, was the basis for the PIMs chosen.

In a review of data of 3,124 home health patients 65 years of age or older, the researchers found 38 percent were taking at least one PIM. Senior patients taking 15 or more medications were five to six times as likely to be prescribed PIMs as patients taking seven or fewer medications. Of those seniors taking at least one PIM, 21 percent were taking 15 or more medications.

According to Dr. Bao, the study, if anything, underestimates the prevalence of PIMs taken by home health patients: The researchers were not able to look at potentially problematic drug-to-drug interactions or drug-and-disease interactions because data were not available.

There is no one reason why PIMs are prevalent in home health care settings. "Anecdotal evidence shows that many physicians are not aware of what is on the PIM list," says Dr. Bao. "In our fragmented health care system, we generally don't have an electronic reference for a patient that lists all medications from different physicians, and there isn't a readily available means for professionals to share essential information. Enhanced physician communication with home health care nurses may help to address the problem, as well as better communication among physicians."

Dr. Bao sees incentives for improvement in communication and care coordination in the implementation of the Patient Protection and Affordable Care Act passed by the U.S. Congress in 2010. "The current payment system doesn't provide incentives to optimize coordination of care," says Dr. Bao. "But when providers in different settings as a group are held responsible for outcomes and costs of care through, for example, an accountable care organization -- a concept promoted in the Affordable Care Act -- this could create an impetus to break the communication barriers that currently exist."


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Co-authors include Huibo Shao, Tara F. Bishop, Bruce R. Schackman and Martha L. Bruce -- all from Weill Cornell Medical College.

The study was funded by the National Institute of Mental Health. The authors do not have conflicts of interest.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.