Misinformation about the findings of “Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity,” a study by D’Onofrio et al. (2014)

The Short Story:

D’Onofrio et al. (2014) is a study of associations between paternal age at conception and offsprings’ risks for developing mental illnesses and academic problems. It was widely covered in the world media in late February and March, 2014. Most media reports about the findings of the study—for example, this one—included risk statements that were direct quotes from the following sentence in Dr. D’Onofrio’s original press release:

When compared to a child born to a 24-year-old father, a child born to a 45-year-old father is 3.5 times more likely to have autism, 13 times more likely to have ADHD, two times more likely to have a psychotic disorder, 25 times more likely to have bipolar disorder and 2.5 times more likely to have suicidal behavior or a substance abuse problem.

These alarming numbers are completely WRONG. What D’Onofrio et al. actually showed was much less alarming:

When compared to a child born to a 24-year-old father, a child born to a 45-year-old father is 1.5 times more likely to have autism, .7 times less likely to have ADHD, 1.3 times more likely to have a psychotic disorder, 1.5 times more likely to have bipolar disorder, .9 times less likely to have suicidal behavior, .8 times less likely to have a substance abuse problem, .7 times less likely to have failing grades in school, .9 times less likely to have low educational attainment, .8 times less likely to have a low IQ; and 1.5 times more likely to have some higher education.

Note the shocking misrepresentations of the risks in Dr. D’Onofrio’s original press release. For example, the study actually found that children of older fathers were at 1.5 times the risk of developing bipolar disorder compared to children of younger fathers, not 25 times the risk. The study also showed that children of older fathers were LESS likely to develop ADHD, not 13 times more likely. In absolute terms, the risks seem even less alarming. For example, approximately 6 of 1000 children born to younger fathers (aged 20 -24) versus 9 of 1000 children born to older fathers (aged 45+) will develop bipolar disorder.

The correct risk estimates do not appear in numerical form anyplace in the original report or the appendices. They can be visually estimated from the “Baseline” curves in the Figure that appears in the report.  They can be precisely calculated from the data that appears in eAppendix 1 of the report’s Supplemental Content.  For example, eAppendix 1 shows that the rate of bipolar disorder among children of the fathers in their study who were aged 20 – 24 was .58% and was .85% for fathers aged 45 or more. This means that the risk of bipolar disorder for children of the older fathers was 1.47 (=.85/.58) times higher than the risk for children of younger fathers, not 25 times higher.

I am posting this corrective analysis because I am concerned that the errors in Dr. D’Onofrio’s press release have caused unwarranted, and potentially severe, psychological harm—worry and guilt—to thousands of older parents who saw the media reports that quoted the erroneous risk estimates in the press release. See, for example, this report on the study by an older father. Some older parents may even decide to take actions that could actually harm their children in a misguided effort to try to prevent a problem that their children are at very low risk of developing.

The Long Story:

I am Steve Herman, PhD, a Stanford-trained psychologist, and an associate professor of psychology at the University of Hawaii at Hilo. I also happen to be an older father. I was shocked and worried when I saw one of the hundreds of media reports about the results of D’Onofrio et al. (2014) claiming that children like mine are at high risk of developing bipolar disorder, ADHD, and other serious life problems. The risk estimates seemed unbelievably high. When I read the original report of the study in JAMA Psychiatry article, it became clear that the actual findings of D’Onofrio et al. were much different, and much less alarming, than what was reported in the media.

When I discovered that the erroneous statements about risks were direct quotes from a misleading press release put out by the lead author, Dr. D’Onofrio, I became angry, and determined to do something to try to correct these errors.

My initial attempts to try to correct these alarming errors have not been successful. First, I wrote a letter to the editor of JAMA Psychiatry. My letter was rejected on the (somewhat justified) grounds that media misinterpretations of studies published in JAMA Psychiatry should be addressed with the media outlets where the mistaken reports appeared. I tried contacting some of the journalists who wrote the erroneous reports, with little success so far. I asked Dr. D’Onofrio to correct his press release to clearly show the real risks, and to inform journalists who had relied on his press release that their reports were mistaken. He declined to do so, although he did make an unhelpful correction to his original press release (see below).

The incorrect, alarming risk estimates in Dr. D’Onofrio’s press release are wildly inconsistent with findings from most other studies. However, the actual population risks found by D’Onofrio et al. are consistent with findings from other studies. For example, Frans et al. (2008) found a 1.37 times greater risk of bipolar disorder for children of men aged 55+ compared to men aged 20 – 24 using a dataset that overlapped with, or included, the dataset used by D’Onofrio et al. Another large study, McGrath et al. “A Comprehensive Assessment of Parental Age and Psychiatric Disorders” (2014) found the following increased risks for paternal age, comparing men aged 45+ to men aged 25-29: 1.8 for autism, 1.24 for bipolar disorder, and 1.47 for schizophrenia. In another large study, Parner et al. (2012) found that children of men aged 40+ were 1.35 times more likely to have autism as children of men who were less than 35. Hultman et al. (2011) found a 2.2 times increased risk of autism for offspring of men aged 50+ compared to offspring of men aged 29 or less.

The numbers that Dr. D’Onofrio cites in his misleading press release come from what are described as “within-sibling,” “sibling comparison,” or “fixed effects” analyses. These are covariate analyses, and the numbers produced by such analyses do not represent the real risks to real people in the study population, but are “adjusted” for variables called covariates. In essence, the numbers from the within-siblings analyses represent hypothetical risks in a counterfactual world in which many relevant variables could be held constant, but paternal age would be allowed to vary. For example, in this counterfactual world, only fathers, but not mothers, grow old; all fathers have the same level of higher education; all fathers have the same likelihood of having been arrested for a crime; all families have the same income; and family income does not change over time. To present these adjusted statistics as if they represented real risks to real people is misleading.

Although it was not clearly stated in the original press release, a few media reports correctly noted that the numbers cited in the press release referred to the within-sibling analyses, but incorrectly interpreted what that meant. Some reports interpreted the press release as implying that the risk estimates referred only to the risks for offspring who had siblings. That this is an incorrect interpretation can be seen from the “baseline” graphs in Author’s Appendix B (available here).

After I complained to Dr. D’Onofrio about the misleading press release, he revised one version of the press release to read as follows:

Among the numerous findings are the following, based on sibling comparisons: When compared to a child born to a 24-year-old father, a sibling born to the same father at the age of 45 is 3.5 times more likely to have autism, 13 times more likely to have ADHD, two times more likely to have a psychotic disorder, 25 times more likely to have bipolar disorder and 2.5 times more likely to have suicidal behavior or a substance abuse problem. For most of these problems, the likelihood of the disorder increased steadily with advancing paternal age, suggesting there is no particular paternal age at childbearing that suddenly becomes problematic. 

The New York Times report about the study was also revised to reflect this new press release wording. Note that this revised risk statement is very different from the original, which referred to all fathers. This revision refers to a very small, unusual subset of offspring—offspring who have a sibling from the same father who is at least 20 years older, probably fewer than 1% of the population. Although the risks for the offspring in this small subset may be somewhat higher than those of most children of 45+ year old fathers, I do not believe that even this revised risk statement is accurate, because the numbers are adjusted for some of the most important advantages associated with advancing paternal age. The true population risks for this tiny subset of offspring cannot be calculated from the data available in the original article or the appendices.

In summary, the risk numbers cited in Dr. D’Onofrio’s press release do not describe the real risks to offspring in the entire study population or to offspring with older siblings. They do not even seem to correctly describe the risks to offspring who have siblings from the same father who are 20 or more years older.

D’Onofrio et al. focused on estimating increases in risk due to disadvantages to offspring that are associated with advancing paternal age. But offspring of older fathers also have advantages compared with offspring of younger fathers. D’Onofrio et al. attempted to estimate the risks due solely to the disadvantages by statistically removing the effects of some of the advantages. In his press release, Dr. D’Onofrio cited risk estimates based on these disadvantage-only analyses. Some of the advantages that may accrue to offspring of older are probably the result of the higher incomes and greater stability of older fathers. Older fathers are more likely to have some higher education than younger fathers, and less likely to have been arrested for crimes. They may spend more time with their children than younger fathers. Children of older fathers may be healthier and live longer than children of younger fathers (Eisenberg et al., 2012). Disadvantages of older fathers with respect to risks for problems in offspring include consequences resulting from an increased risk of genetic mutations in the sperm cells of older fathers, as pointed out by D’Onofrio et al., but may also include other psychosocial factors such as the increased likelihood that a father will die during an offspring’s childhood.

The population risk estimates that can be calculated from eAppendix 1 make it clear that the advantages of having an older father compensate for most of the disadvantages with respect to the risks for autism, bipolar, and psychosis, so that offspring of 45+ year old men compared to 20 – 24 year old men are at only moderately higher risks (1.3 to 1.5 times more) for those three problems. The advantages of having an older father outweigh the disadvantages with respect to the risks of ADHD, suicide attempts, substance abuse problems, failing a grade, and low educational attainment, so that the risks for these five problems in the 45+ vs 20 - 24 comparison are actually lower (.7 to .9 times less) among offspring of the older fathers. None of this is made clear in either the original or revised versions of Dr. D’Onofrio’s alarming and misleading press release.

I have confirmed that my analysis of the real population risks is correct with a number of colleagues, psychologists and biostatisticians. If you find it difficult to believe all of this, as I did at first, I suggest that you take a close look at eAppendix 1. You could also ask Dr. D’Onofrio (bmdonofr@indiana.edu) to confirm that what I am telling you about the real population risks to real offspring in their study population is accurate.

I do not know why Dr. D’Onofrio chose to put out such an alarmingly misleading press release, you can ask him that yourself. I do know that exaggerations and misrepresentations of research findings in order to attract media attention are quite common. This problem is so common that it is explicitly addressed in guidelines for the ethical dissemination of research findings published on the website of Sweden’s prestigious Karolinska Institute, the institutional home of Dr. D’Onofrio’s coauthors:

Communication with the media
When communicating with the media researchers at the Karolinska Institute should provide balanced information on the significance and applicability of the study.…  When risks are described it is similarly prudent to state how many individuals may be at risk and how much the risk increases in absolute terms upon exposure to a certain situation or treatment.… Scientists should not create unfounded expectations or fear among laymen via the media.

Please email me if you have any questions.

Steve Herman, PhD

Associate Professor of Psychology
University of Hawaii at Hilo
hermans@hawaii.edu

Copy of the Original Press Release for D'Onofrio et al. (2014)

This press release was published here on February 26, 2014
_________________________________________________________________________________

 

PUBLIC RELEASE DATE:

26-Feb-2014

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Contact: Brian D'Onofrio
bmdonofr@indiana.edu
812-856-0843
Indiana University

IU study ties father's age to higher rates of psychiatric, academic problems in kids

		IMAGE: This is Brian D'Onofrio. Click here for more information.

BLOOMINGTON, Ind. -- An Indiana University study in collaboration with medical researchers from Karolinska Institute in Stockholm has found that advancing paternal age at childbearing can lead to higher rates of psychiatric and academic problems in offspring than previously estimated.

Examining an immense data set -- everyone born in Sweden from 1973 until 2001 -- the researchers documented a compelling association between advancing paternal age at childbearing and numerous psychiatric disorders and educational problems in their children, including autism, ADHD, bipolar disorder, schizophrenia, suicide attempts and substance abuse problems. Academic problems included failing grades, low educational attainment and low IQ scores.

Among the findings: When compared to a child born to a 24-year-old father, a child born to a 45-year-old father is 3.5 times more likely to have autism, 13 times more likely to have ADHD, two times more likely to have a psychotic disorder, 25 times more likely to have bipolar disorder and 2.5 times more likely to have suicidal behavior or a substance abuse problem. For most of these problems, the likelihood of the disorder increased steadily with advancing paternal age, suggesting there is no particular paternal age at childbearing that suddenly becomes problematic.

"We were shocked by the findings," said Brian D'Onofrio, lead author and associate professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences at IU Bloomington. "The specific associations with paternal age were much, much larger than in previous studies. In fact, we found that advancing paternal age was associated with greater risk for several problems, such as ADHD, suicide attempts and substance use problems, whereas traditional research designs suggested advancing paternal age may have diminished the rate at which these problems occur."

The study, "Parental Age at Childbearing and Offspring Psychiatric and Academic Morbidity," was published today (Feb. 26) in JAMA Psychiatry.

Notably, the researchers found converging evidence for the associations with advancing paternal age at childbearing from multiple research designs for a broad range of problems in offspring. By comparing siblings, which accounts for all factors that make children living in the same house similar, researchers discovered that the associations with advancing paternal age were much greater than estimates in the general population. By comparing cousins, including first-born cousins, the researchers could examine whether birth order or the influences of one sibling on another could account for the findings.

The authors also statistically controlled for parents' highest level of education and income, factors often thought to counteract the negative effects of advancing paternal age because older parents are more likely to be more mature and financially stable. The findings were remarkably consistent, however, as the specific associations with advancing paternal age remained.

"The findings in this study are more informative than many previous studies," D'Onofrio said. "First, we had the largest sample size for a study on paternal age. Second, we predicted numerous psychiatric and academic problems that are associated with significant impairment. Finally, we were able to estimate the association between paternal age at childbearing and these problems while comparing differentially exposed siblings, as well as cousins. These approaches allowed us to control for many factors that other studies could not."

In the past 40 years, the average age for childbearing has been increasing steadily for both men and women. Since 1970 for instance, the average age of first-time mothers in the U.S. has gone up four years from 21.5 to 25.4. For men the average is three years older. In the northeast, the ages are higher. Yet the implications of this fact -- both socially and in terms of the long-term effects on the health and well-being of the population as a whole -- are not yet fully understood.

Moreover, while maternal age has been under scrutiny for a number of years, a more recent body of research has begun to explore the possible effects of advancing paternal age on a variety of physical and mental health issues in offspring. Existing studies have pointed to increasing risks for some psychological disorders with advancing paternal age. Yet the results are often inconsistent with one another, statistically inconclusive or unable to take certain confounding factors into account.

The working hypothesis for D'Onofrio and his colleagues who study this phenomenon is that unlike women, who are born with all their eggs, men continue to produce new sperm throughout their lives. Each time sperm replicate, there is a chance for a mutation in the DNA to occur. As men age, they are also exposed to numerous environmental toxins, which have been shown to cause mutations in the DNA found in sperm. Molecular genetic studies have, in fact, shown that sperm of older men have more genetic mutations.

This study and others like it, however, perhaps signal some of the unforeseen, negative consequences of a relatively new trend in human history. As such, D'Onofrio said, it may have important social and public policy implications. Given the increased risk associated with advancing paternal age at childbearing, policy-makers may want to make it possible for men and women to accommodate children earlier in their lives without having to set aside other goals.

"While the findings do not indicate that every child born to an older father will have these problems," D'Onofrio said, "they add to a growing body of research indicating that advancing paternal age is associated with increased risk for serious problems. As such, the entire body of research can help to inform individuals in their personal and medical decision-making."

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Co-authors include research scientist Martin Rickert from the Department of Psychological and Brain Sciences, and Emma Frans, Ralf Kuja-Halkola, Catarina Almqvist, Arvid Sjolander, Henrik Larsson and Paul Lichtenstein from the Department of Medical Epidemiology and Biostatistics at the Karolinska Institutet in Stockholm.

The research was funded with grants from the National Institute of Child Health and Human Development, the Swedish Research Council, and the Swedish Council for Working Life and Social Research.

D'Onofrio can be reached at 812-856-0843 and bmdonofr@indiana.edu. He is director of the Developmental Psychopathology Laboratory. For additional assistance, or a copy of the paper, contact Liz Rosdeitcher at 812-855-4507 or rosdeitc@indiana.edu, or Tracy James at 812-855-0084 or traljame@iu.edu.

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