Can Genetic Testing Help Shed Light on the Autism Epidemic?
Autism cases are still on the rise, and scientists don't know why. In April, the Centers for Disease Control (CDC) reported that rates of autism had increased once again, now at an estimated 1 in 59 children up from 1 in 68 just two years ago. Rates have been climbing steadily since 2007 when the CDC initially estimated that 1 in 150 children were on the autism spectrum.
Some clinicians are concerned that the creeping expansion of autism is causing the diagnosis to lose its meaning.
The standard explanation for this increase has been the expansion of the definition of autism to include milder forms like Asperger's, as well as a heightened awareness of the condition that has improved screening efforts. For example, the most recent jump is attributed to children in minority communities being diagnosed who might have previously gone under the radar. In addition, more federally funded resources are available to children with autism than other types of developmental disorders, which may prompt families or physicians to push harder for a diagnosis.
Some clinicians are concerned that the creeping expansion of autism is causing the diagnosis to lose its meaning. William Graf, a pediatric neurologist at Connecticut Children's Medical Center, says that when a nurse tells him that a new patient has a history of autism, the term is no longer a useful description. "Even though I know this topic extremely well, I cannot picture the child anymore," he says. "Use the words mild, moderate, or severe. Just give me a couple more clues, because when you say autism today, I have no idea what people are talking about anymore."
Genetic testing has emerged as one potential way to remedy the overly broad label by narrowing down a heterogeneous diagnosis to a specific genetic disorder. According to Suma Shankar, a medical geneticist at the University of California, Davis, up to 60 percent of autism cases could be attributed to underlying genetic causes. Common examples include Fragile X Syndrome or Rett Syndrome—neurodevelopmental disorders that are caused by mutations in individual genes and are behaviorally classified as autism.
With more than 500 different mutations associated with autism, very few additional diagnoses provide meaningful information.
Having a genetic diagnosis in addition to an autism diagnosis can help families in several ways, says Shankar. Knowing the genetic origin can alert families to other potential health problems that are linked to the mutation, such as heart defects or problems with the immune system. It may also help clinicians provide more targeted behavioral therapies and could one day lead to the development of drug treatments for underlying neurochemical abnormalities. "It will pave the way to begin to tease out treatments," Shankar says.
When a doctor diagnoses a child as having a specific genetic condition, the label of autism is still kept because it is more well-known and gives the child access to more state-funded resources. Children can thus be diagnosed with multiple conditions: autism spectrum disorder and their specific gene mutation. However, with more than 500 different mutations associated with autism, very few additional diagnoses provide meaningful information. What's more, the presence or absence of a mutation doesn't necessarily indicate whether the child is on the mild or severe end of the autism spectrum.
Because of this, Graf doubts that genetic classifications are really that useful. He tells the story of a boy with epilepsy and severe intellectual disabilities who was diagnosed with autism as a young child. Years later, Graf ordered genetic testing for the boy and discovered that he had a mutation in the gene SYNGAP1. However, this knowledge didn't change the boy's autism status. "That diagnosis [SYNGAP1] turns out to be very specific for him, but it will never be a household name. Biologically it's good to know, and now it's all over his chart. But on a societal level he still needs this catch-all label [of autism]," Graf says.
"It gives some information, but to what degree does that change treatment or prognosis?"
Jennifer Singh, a sociologist at Georgia Tech who wrote the book Multiple Autisms: Spectrums of Advocacy and Genomic Science, agrees. "I don't know that the knowledge gained from just having a gene that's linked to autism," is that beneficial, she says. "It gives some information, but to what degree does that change treatment or prognosis? Because at the end of the day you have to address the issues that are at hand, whatever they might be."
As more children are diagnosed with autism, knowledge of the underlying genetic mutation causing the condition could help families better understand the diagnosis and anticipate their child's developmental trajectory. However, for the vast majority, an additional label provides little clarity or consolation.
Instead of spending money on genetic screens, Singh thinks the resources would be better used on additional services for people who don't have access to behavioral, speech, or occupational therapy. "Things that are really going to matter for this child in their future," she says.
Sloppy Science Happens More Than You Think
The media loves to tout scientific breakthroughs, and few are as toutable – and in turn, have been as touted – as CRISPR. This method of targeted DNA excision was discovered in bacteria, which use it as an adaptive immune system to combat reinfection with a previously encountered virus.
Shouldn't the editors at a Nature journal know better than to have published an incorrect paper in the first place?
It is cool on so many levels: not only is the basic function fascinating, reminding us that we still have more to discover about even simple organisms that we thought we knew so well, but the ability it grants us to remove and replace any DNA of interest has almost limitless applications in both the lab and the clinic. As if that didn't make it sexy enough, add in a bicoastal, male-female, very public and relatively ugly patent battle, and the CRISPR story is irresistible.
And then last summer, a bombshell dropped. The prestigious journal Nature Methods published a paper in which the authors claimed that CRISPR could cause many unintended mutations, rendering it unfit for clinical use. Havoc duly ensued; stocks in CRISPR-based companies plummeted. Thankfully, the authors of the offending paper were responsible, good scientists; they reassessed, then recanted. Their attention- and headline- grabbing results were wrong, and they admitted as much, leading Nature Methods to formally retract the paper this spring.
How did this happen? Shouldn't the editors at a Nature journal know better than to have published this in the first place?
Alas, high-profile scientific journals publish misleading and downright false results fairly regularly. Some errors are unavoidable – that's how the scientific method works. Hypotheses and conclusions will invariably be overturned as new data becomes available and new technologies are developed that allow for deeper and deeper studies. That's supposed to happen. But that's not what we're talking about here. Nor are we talking about obvious offenses like outright plagiarism. We're talking about mistakes that are avoidable, and that still have serious ramifications.
The cultures of both industry and academia promote research that is poorly designed and even more poorly analyzed.
Two parties are responsible for a scientific publication, and thus two parties bear the blame when things go awry: the scientists who perform and submit the work, and the journals who publish it. Unfortunately, both are incentivized for speedy and flashy publications, and not necessarily for correct publications. It is hardly a surprise, then, that we end up with papers that are speedy and flashy – and not necessarily correct.
"Scientists don't lie and submit falsified data," said Andy Koff, a professor of Molecular Biology at Sloan Kettering Institute, the basic research arm of Memorial Sloan Kettering Cancer Center. Richard Harris, who wrote the book on scientific misconduct running the gamut from unconscious bias and ignorance to more malicious fraudulence, largely concurs (full disclosure: I reviewed the book here). "Scientists want to do good science and want to be recognized as such," he said. But even so, the cultures of both industry and academia promote research that is poorly designed and even more poorly analyzed. In Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Millions, Harris describes how scientists must constantly publish in order to maintain their reputations and positions, to get grants and tenure and students. "They are disincentivized from doing that last extra experiment to prove their results," he said; it could prove too risky if it could cost them a publication.
Ivan Oransky and Adam Marcus founded Retraction Watch, a blog that tracks the retraction of scientific papers, in 2010. Oransky pointed out that blinded peer review – the pride and joy of the scientific publishing enterprise – is a large part of the problem. "Pre-publication peer review is still important, but we can't treat it like the only check on the system. Papers are being reviewed by non-experts, and reviewers are asked to review papers only tangentially related to their field. Moreover, most peer reviewers don't look at the underlying or raw data, even when it is available. How then can they tell if the analysis is flawed or the data is accurate?" he wondered.
Mistaken publications also erode the public's opinion of legitimate science, which is problematic since that opinion isn't especially high to begin with.
Koff agreed that anonymous peer review is valuable, but severely flawed. "Blinded review forces a collective view of importance," he said. "If an article disagrees with the reviewer's worldview, the article gets rejected or forced to adhere to that worldview – even if that means pushing the data someplace it shouldn't necessarily go." We have lost the scientific principle behind review, he thinks, which was to critically analyze a paper. But instead of challenging fundamental assumptions within a paper, reviewers now tend to just ask for more and more supplementary data. And don't get him started on editors. "Editors are supposed to arbitrate between reviewers and writers and they have completely abdicated this responsibility, at every journal. They do not judge, and that's a real failing."
Harris laments the wasted time, effort, and resources that result when erroneous ideas take hold in a field, not to mention lives lost when drug discovery is predicated on basic science findings that end up being wrong. "When no one takes the time, care, and money to reproduce things, science isn't stopping – but it is slowing down," he noted. Mistaken publications also erode the public's opinion of legitimate science, which is problematic since that opinion isn't especially high to begin with.
Scientists and publishers don't only cause the problem, though – they may also provide the solution. Both camps are increasingly recognizing and dealing with the crisis. The self-proclaimed "data thugs" Nick Brown and James Heathers use pretty basic arithmetic to reveal statistical errors in papers. The microbiologist Elisabeth Bik scans the scientific literature for problematic images "in her free time." The psychologist Brian Nosek founded the Center for Open Science, a non-profit organization dedicated to promoting openness, integrity, and reproducibility in scientific research. The Nature family of journals – yes, the one responsible for the latest CRISPR fiasco – has its authors complete a checklist to combat irreproducibility, à la Atul Gawande. And Nature Communications, among other journals, uses transparent peer review, in which authors can opt to have the reviews of their manuscript published anonymously alongside the completed paper. This practice "shows people how the paper evolved," said Koff "and keeps the reviewer and editor accountable. Did the reviewer identify the major problems with the paper? Because there are always major problems with a paper."
Your Digital Avatar May One Day Get Sick Before You Do
Artificial intelligence is everywhere, just not in the way you think it is.
These networks, loosely designed after the human brain, are interconnected computers that have the ability to "learn."
"There's the perception of AI in the glossy magazines," says Anders Kofod-Petersen, a professor of Artificial Intelligence at the Norwegian University of Science and Technology. "That's the sci-fi version. It resembles the small guy in the movie AI. It might be benevolent or it might be evil, but it's generally intelligent and conscious."
"And this is, of course, as far from the truth as you can possibly get."
What Exactly Is Artificial Intelligence, Anyway?
Let's start with how you got to this piece. You likely came to it through social media. Your Facebook account, Twitter feed, or perhaps a Google search. AI influences all of those things, machine learning helping to run the algorithms that decide what you see, when, and where. AI isn't the little humanoid figure; it's the system that controls the figure.
"AI is being confused with robotics," Eleonore Pauwels, Director of the Anticipatory Intelligence Lab with the Science and Technology Innovation Program at the Wilson Center, says. "What AI is right now is a data optimization system, a very powerful data optimization system."
The revolution in recent years hasn't come from the method scientists and other researchers use. The general ideas and philosophies have been around since the late 1960s. Instead, the big change has been the dramatic increase in computing power, primarily due to the development of neural networks. These networks, loosely designed after the human brain, are interconnected computers that have the ability to "learn." An AI, for example, can be taught to spot a picture of a cat by looking at hundreds of thousands of pictures that have been labeled "cat" and "learning" what a cat looks like. Or an AI can beat a human at Go, an achievement that just five years ago Kofod-Petersen thought wouldn't be accomplished for decades.
"It's very difficult to argue that something is intelligent if it can't learn, and these algorithms are getting pretty good at learning stuff. What they are not good at is learning how to learn."
Medicine is the field where this expertise in perception tasks might have the most influence. It's already having an impact as iPhones use AI to detect cancer, Apple watches alert the wearer to a heart problem, AI spots tuberculosis and the spread of breast cancer with a higher accuracy than human doctors, and more. Every few months, another study demonstrates more possibility. (The New Yorker published an article about medicine and AI last year, so you know it's a serious topic.)
But this is only the beginning. "I personally think genomics and precision medicine is where AI is going to be the biggest game-changer," Pauwels says. "It's going to completely change how we think about health, our genomes, and how we think about our relationship between our genotype and phenotype."
The Fundamental Breakthrough That Must Be Solved
To get there, however, researchers will need to make another breakthrough, and there's debate about how long that will take. Kofod-Petersen explains: "If we want to move from this narrow intelligence to this broader intelligence, that's a very difficult problem. It basically boils down to that we haven't got a clue about what intelligence actually is. We don't know what intelligence means in a biological sense. We think we might recognize it but we're not completely sure. There isn't a working definition. We kind of agree with the biologists that learning is an aspect of it. It's very difficult to argue that something is intelligent if it can't learn, and these algorithms are getting pretty good at learning stuff. What they are not good at is learning how to learn. They can learn specific tasks but we haven't approached how to teach them to learn to learn."
In other words, current AI is very, very good at identifying that a picture of a cat is, in fact, a cat – and getting better at doing so at an incredibly rapid pace – but the system only knows what a "cat" is because that's what a programmer told it a furry thing with whiskers and two pointy ears is called. If the programmer instead decided to label the training images as "dogs," the AI wouldn't say "no, that's a cat." Instead, it would simply call a furry thing with whiskers and two pointy ears a dog. AI systems lack the explicit inference that humans do effortlessly, almost without thinking.
Pauwels believes that the next step is for AI to transition from supervised to unsupervised learning. The latter means that the AI isn't answering questions that a programmer asks it ("Is this a cat?"). Instead, it's almost like it's looking at the data it has, coming up with its own questions and hypothesis, and answering them or putting them to the test. Combining this ability with the frankly insane processing power of the computer system could result in game-changing discoveries.
In the not-too-distant future, a doctor could run diagnostics on a digital avatar, watching which medical conditions present themselves before the person gets sick in real life.
One company in China plans to develop a way to create a digital avatar of an individual person, then simulate that person's health and medical information into the future. In the not-too-distant future, a doctor could run diagnostics on a digital avatar, watching which medical conditions presented themselves – cancer or a heart condition or anything, really – and help the real-life version prevent those conditions from beginning or treating them before they became a life-threatening issue.
That, obviously, would be an incredibly powerful technology, and it's just one of the many possibilities that unsupervised AI presents. It's also terrifying in the potential for misuse. Even the term "unsupervised AI" brings to mind a dystopian landscape where AI takes over and enslaves humanity. (Pick your favorite movie. There are dozens.) This is a concern, something for developers, programmers, and scientists to consider as they build the systems of the future.
The Ethical Problem That Deserves More Attention
But the more immediate concern about AI is much more mundane. We think of AI as an unbiased system. That's incorrect. Algorithms, after all, are designed by someone or a team, and those people have explicit or implicit biases. Intentionally, or more likely not, they introduce these biases into the very code that forms the basis for the AI. Current systems have a bias against people of color. Facebook tried to rectify the situation and failed. These are two small examples of a larger, potentially systemic problem.
It's vital and necessary for the people developing AI today to be aware of these issues. And, yes, avoid sending us to the brink of a James Cameron movie. But AI is too powerful a tool to ignore. Today, it's identifying cats and on the verge of detecting cancer. In not too many tomorrows, it will be on the forefront of medical innovation. If we are careful, aware, and smart, it will help simulate results, create designer drugs, and revolutionize individualize medicine. "AI is the only way to get there," Pauwels says.