“Women are not just little men.”
When asked, “What’s one key idea people should take away from your research?” that’s the first thing that Barbara Stranger said.
“Women have not been studied in biomedical research in large scale,” Stranger continued. “Women weren’t even mandated to be a part of clinical trials until 1993. So, we know very little about women’s health across the lifespan, and we have a lot of catching up to do. There are differences between sexes, those can vary across the lifespan, and we need to understand what these differences are.”
Barbara Stranger, PhD, is a professor of biomedical informatics, and holds the Lyda M. Ludeman Endowed Chair in Bioinformatics in Women’s Health Research at the University of Colorado Anschutz (CU Anschutz). Stranger and her lab, the Stranger Lab, conduct research in the field of statistical genetics, seeking to understand the basis of genetic traits in humans.
Specifically, the Stranger Lab is interested in uncovering how different groups differ—especially groups that have been historically underrepresented in research like women or people of certain ancestries. For example, the Stranger Lab might look at how different groups may exhibit different disease susceptibility or respond differently to drug treatments.
To accomplish this work, the Stranger Lab leverages large-scale genetics and genomics datasets, biobanks and electronic health records (EHRs) to uncover trends, patterns and differences across varying groups of people. This allows them to characterize how genetic variation within and between groups can result in meaningful biological differences that contribute to our knowledge of human health and disease.
“So the biggest mission driving our research is to really tailor medicine and health and treatment and diagnoses to individuals,” said Stranger. “Modern medicine, historically, has left out certain groups or not studied them in ways that considered differences between groups. And so really my mission is more toward equitable understanding of disease and health and response to treatments so that we can prioritize personalized care for people in the true sense of that word.”
The Stranger Lab spends a lot of time focused on women’s health, which has historically been underrepresented in biomedical research.
Traditionally, much of what research has discovered about human health has either:
Then, the findings have been extrapolated towards women, treating women as “little men.”
“What we know in medicine has been mostly learned from research focused on men—or men and women lumped together—and so we really need to take a good look at women’s health and consider where it might be different than men’s and how we can use that information to improve women’s health,” said Stranger.
There are countless examples of how these trends manifest in our understanding about health and human disease.
For one, men and women may present differently in the clinic. Stranger illuminated the idea with a salient example about heart attacks: “One place where men and women differ clinically is in heart attack symptoms. Clinicians who are trained—they learn that women have atypical symptoms. And it's kind of interesting, right? Because women make up more than 50% of the population, and yet we call their symptoms atypical—which, if you're more than 51%, you think it might actually be typical.”
“But it's because men are the baseline... in almost every context, men are the standard.
And so whatever women show is atypical,” said Stranger.
Men and women may also have different biological pathways underlying conditions that get grouped together in disease identification or common languages. “There could be a different pathway to get to the same point,” said Stranger. Pain, Stranger explained, is one example of how this manifests. “You might say: ‘people have pain.’ But the pathways can be quite different between men and women.”
In other words, two people may arrive at what appears to be the same clinical endpoint through different underlying biological mechanisms. Looking only at the endpoint could obscure those differences—and potentially obscure opportunities to better understand or treat a condition.
Another historical challenge in women’s health research was only focusing on one small component of women’s health: reproductive health.
However, reproductive health is clearly not the only way that men differ from women. For example, hormones, chromosomes, gene expression, immune function, metabolism and other biological systems can shape health throughout the body and across the lifespan. Additionally, men and women also may have different mechanisms underlying the same diseases, or they may exhibit the same diseases differently.
Sex is also more varied than two categories. Some people have sex chromosome complements other than XX or XY, such as XXY or a single X, and some have differences in sex development that don’t align with a single category. Studying this variation is scientifically valuable as well as inclusive: it helps researchers separate the effects of chromosomes from the effects of hormones.
“Sex is a fundamental feature for human biology,” emphasized Stranger. Although women’s health research has historically focused primarily on differences in reproductive health, there is much more to it.
“It’s not just reproductive health,” emphasized Stranger. “It’s mental health. It’s cardiovascular health. It’s immunology. It’s bone health...”
Stranger has helped build some of the field’s foundational evidence for this view. As a senior leader in the Genotype-Tissue Expression (GTEx) Consortium, a national effort to map how genetic variation shapes gene activity across the human body, she led a landmark 2020 study in Science that cataloged sex differences across 44 human tissue sources. The team found that 37% of all human genes are expressed at different levels in males and females in at least one tissue. These differences were not confined to reproductive tissues; they appeared throughout the body.
The study also showed that the effects of genetic variants themselves can differ by sex. By combining these results with data from large studies of disease genetics, the team identified 58 links between genes and human traits driven by genetic regulation in only one sex. These are findings that would be diluted or missed entirely in an analysis that combined everyone.
Stranger also co-leads the Women’s Health Electronic Medical Records and Genomics Network that brings together researchers using big data analytics to conduct research in women’s health and sex differences leveraging large scale electronic health records.
So, how do we bridge the gap? How do we improve the representation of women and other groups in research?
For Stranger, it starts with acknowledging and searching for the differences between groups. “Without looking for differences between groups we can't know what's different,” said Stranger. “We also can't know what's ubiquitous for everyone.”
One shift in thinking that Stranger recommends is building subgroups into the study design.
“I would always recommend to people who are undertaking biomedical research that they consider subgroups at the beginning—that they work with statistical methods that can look for differences between subgroups,” said Stranger. “Not as an added on, post hoc kind of analysis—but built in from the beginning that we are going to try to assess whether there are differences between groups.”
Even if differences don’t exist, it’s worth searching for. “It's okay if we look and there aren't differences—that's fine, too. Then we’d know that a finding is applicable to everyone, which would be great,” said Stranger. The goal is not to assume we will find differences, but to objectively and systematically evaluate whether they exist.
The Stranger Lab leverages large-scale datasets to better understand differences among groups using the data we do have. They also search for gaps, highlighting the data we don’t have.
Some gaps are built into the genome analyses themselves. The sex chromosomes, X and Y, have routinely been left out of genome-wide association studies because they require different analytical methods. As a result, the parts of the genome that differ most directly between the sexes are among the least studied. “We’ve been leaving out the very chromosomes that differ between the sexes,” said Stranger.
Other gaps also exist in the health record. In a recent study published in Menopause, Stranger worked with other researchers at CU Anschutz to explore menopause data in the All of Us Research program. The study included nearly 396,000 women, and found that menopause was documented nearly seven times more often in participant surveys than in EHRs, suggesting a large gap in data collection for menopause. This illuminates how gaps in data collection can limit researchers’ ability to understand important components of women’s health.
Beyond specific research approaches, Stranger also emphasizes that it’s important to discuss this concept more often—what she called “bringing it up at the table.” The more awareness and conversation we can spark about these topics, the better.
In addition to her research in the Department of Biomedical Informatics (DBMI), Stranger works closely with the CU Anschutz Ludeman Family Center for Women’s Health Research—also known as the Ludeman Center. Her role here includes research strategy, mentoring junior scientists, reviewing seed grants, working with trainees and communicating science with the broader community.
But one of her priorities is connecting the expertise of the Ludeman Center with the data science and computational expertise housed within DBMI.
“One of the most important things for me right now is trying to integrate the Department of Biomedical Informatics with the Ludeman Center,” explained Stranger. “Here in our department we have probably the largest concentration of data scientists in the country working on women's health and sex differences research. And next door we have an incredibly successful Women's Health Research Center.”
The two groups approach many of the same problems from complementary directions, and Stranger hopes she can help facilitate more collaboration between these entities.
“Bringing those two sets of incredibly talented people together with such synergistic expertise really will allow us to make big strides together,” said Stranger.
For Stranger, the opportunity to bring those communities together was part of the appeal of joining CU Anschutz; “that's what brought me here, was the chance to be able to do that,” she said.
Those collaborations are already taking shape. Stranger is leading a new cross-campus initiative in women’s cardiovascular health that draws on CU Anschutz’s health record resources and the expertise of faculty across the campus. Cardiovascular disease is the leading cause of death for women; it is also an area where differences between women and men in symptoms, risk and treatment response are well documented but poorly understood.
That work is possible because of the campus-wide support of women’s health and sex differences research, as well as the scale and depth of data available at CU Anschutz. Health records from the campus’s affiliated health system capture the clinical histories of a large and diverse patient population over time. In addition, the Colorado Center for Personalized Medicine biobank links genetic data to the health records of more than 140,000 of those patients. Together, these resources give researchers the scale needed to test whether findings differ between women and men.
Ultimately, Stranger’s work focuses on one keystone principle: understanding human health means acknowledging both the similarities and the differences that exist between individuals. “By averaging everyone together, we can miss discoveries that are lost by lumping everyone together, or miss the fact that a specific finding is only valid for a subset of people,” said Stranger.
“And so, I really am interested in trying to make sure we consider everyone as an individual,” said Stranger. “And I hope our research can help push things forward toward more precise and equitable healthcare.”