Category: Gender

Sex-differentiation Genes Also Contribute to Disease Risks

Man and woman about to sprint
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Some physical traits that differ between sexes are known to be linked to certain single nucleotide polymorphisms (SNPs) outside the X and Y chromosomes. New research now suggests that many of these ‘sex-heterogenous’ SNPs also contribute to a person’s risk for a variety of diseases. Michela Traglia and colleagues at the University of California San Francisco presented their findings in PLOS Genetics.

Millions of SNPs are in each genome, with each SNP representing a difference in a certain DNA building block in a particular stretch of DNA. Many associations have been uncovered between certain SNPs and people’s distinct traits. Understanding SNPs has a number of applications, such as predicting individual treatment effectiveness or disease risks.

Traglia and colleagues previously found that SNPs associated with certain differences in physical traits between men and women, such as waist-hip ratio and basal metabolic rate, may also affect the biology of autism spectrum disorder and other complex diseases. Building on this work with two large genomic datasets, the identified an updated list of 2320 sex-heterogeneous SNPs.

Analysis of these SNPs revealed that they are also associated with a variety of health-related traits and diseases, some with strong sex bias and some without, including schizophrenia, type 2 diabetes, anorexia, heart failure, and ADHD.

These SNPs are located in stretches of DNA that are either within or near genes involved in skeletal and muscle development in a growing embryo. In addition, these SNPs appear to play a role in regulating gene expression and DNA methylation, which are fundamental processes by which a person’s DNA is translated into their distinct biology and traits.

Overall, the researchers conclude that the identified SNPs play a role in early-life biological processes shaping sex-distinct traits and which also affect health and disease risk later in life. More work is needed to understand the mechanisms behind these sex-heterogeneous SNPs.

“We found that genetic alleles with differing effects on measured physical traits in men and women also play an outsized role in health risks,” remarked study co-author Lauren Weiss. “We hope this work helps us to understand the genetic underpinnings of sexual dimorphism and its relationship with both early development and later disease risk.”

Source: EurekAlert!

Low Sex Hormone Levels Linked to Rotator Cuff Tears

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Patients with lower levels of sex hormones are more likely to need to undergo surgery for rotator cuff tears, suggests a study in The Journal of Bone & Joint Surgery

Sex hormone deficiencies “was associated with a significantly increased incidence of RCR within [two] independent databases,” according to the new research by Peter N. Chalmers, MD, and colleagues at University of Utah. These findings add to previous evidence that hormone levels may be a systemic factor contributing to the development of rotator cuff tears, a common condition that is a major cause of shoulder pain.

The study used health insurance data for nearly 230 000 adults under age 65 who underwent surgery to repair a torn rotator cuff from 2008 through 2017. Patients were matched for age, sex, and type of insurance to patients who did not undergo rotator cuff surgery.

Patients undergoing rotator cuff repair had an average age of 54 years, and 58% were men. Most patient characteristics were similar between those who underwent rotator cuff repair and those who did not, except tobacco use, which was more common in the surgical cohort.

Dr Chalmers and colleagues found that 27% of women and 7% of men undergoing rotator cuff surgery had diagnosed sex hormone deficiency, compared with 20% and 4% respectively in the control group. Controlling for other factors, rotator cuff repair likelihood was 48% higher in women with oestrogen deficiency and 89% higher in men with testosterone deficiency.

To confirm their findings, the researchers then accessed the Veterans Administration Genealogy database which has data on millions of individuals. Here, they found that rotator cuff repair was about 2.5 times more likely for women with oestrogen deficiency and three times more likely for men with testosterone deficiency.

This study builds on a prior study by the same research group, which demonstrated that women with mutations in an oestrogen receptor gene were more likely to develop rotator cuff disease, with higher rates of failed rotator cuff surgery.

Despite limitations such as not accounting for hormone replacement therapy, the observed association between sex hormone deficiency and rotator cuff repair strongly supports the theory that low oestrogen and testosterone levels may contribute to the development of rotator cuff tears. The researchers concluded that “Future prospective studies will be necessary to understand the relationship of sex hormones to the pathophysiology of rotator cuff disease.”

Source: EurekAlert!

Sex Differences in Nonalcoholic Fatty Liver Disease Explained

Toilet sign male and female
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Investigators may have discovered the reason why fewer women than men develop nonalcoholic fatty liver disease (NAFLD). They published their findings in Nature Communications.

One of the most common disorders globally, NAFLD is a leading cause of death worldwide. Its progressive form, ‘nonalcoholic steatohepatitis’ (NASH), affects about 30% of all NAFLD patients, and can lead to cirrhosis and liver cancer. Despite intensive research, the underlying mechanisms of NAFLD/NASH are still poorly understood and effective treatment is lacking as a result.

However, it is known that NAFLD/NASH is more common among men than women, especially premenopausal women. The reasons for this are still unclear, but evidence so far suggests that oestrogen plays a protective role. On the other hand, the protein formyl peptide receptor 2 (FPR2) is known to play an important role in mediating inflammatory responses in multiple organs. However, no study so far has determined its role in the liver. Could FPR2 be involved in the sex-related differences regarding NAFLD prevalence and severity?

Addressing this question, a research team led by Professor Youngmi Jung of Pusan National University, Korea, recently conducted a study using mice model, shedding light on the role of FPR2 in NAFLD/NASH and its relationship to the observed sex-based differences. This work is among the very few studies on NAFLD that relies on sex-balanced animal experiments rather than the more common male-only designs.

The researchers first found that Fpr2 was highly expressed in healthy livers of female mice. Furthermore, it was expressed differently in the livers of male and female mice that were fed a special NAFLD-inducing diet. Silencing the Fpr2 gene made the male and female mice equally vulnerable to NAFLD, suggesting that FPR2 has a protective effect on the liver.

Interestingly, the researchers also found that FPR2 production in the liver is mediated by oestrogen. Males supplemented with external oestrogen produced more Fpr2 and were more resistant to NAFLD, whereas females that had their ovaries removed exhibited reduced liver Fpr2 levels. “Taken together, our findings suggest that FPR2 is a potential therapeutic target for developing pharmacological agents to treat NAFLD/NASH,” says Prof Jung. “In addition, our results could help in the development of gender-based therapies for NASH.”

This unprecedented discovery of the female-specific production of FPR2 in the liver and its role in providing resistance against NAFLD/NASH will hopefully pave the way not only for novel treatments but also a more comprehensive and sex-aware approach when doing science. Prof Jung remarked on this: “Our research highlights the pressing need for designing and developing better sex-balanced animal experiments, considering that the sex-specific expression of FPR2 in the liver had been completely overlooked in previous studies.”

Source: Pusan National University

The Pandemic’s Negative Impact on Women in Academic Medicine

Female scientist in laboratory
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Like women in every other sector of the economy, the COVID pandemic has negatively impacted those working in academic medicine according to a commentary which appears in Nature Medicine.

Co-author Anne B. Curtis, MD, professor at the University at Buffalo, laid out the problem: “During the first year of the pandemic, when schools shut down and went to 100% remote learning, we saw that it affected women disproportionately, having to stay home and teach their children while their research languished.”

Even before the COVID pandemic, women in academic medicine were paid less than men in comparable positions, received lower startup funds for laboratory research and were promoted later.

Additionally, they wrote that, compared to men, women have fewer “conventional markers of achievement” in academia, such as principal investigator positions on research grants. Women write fewer grant applications; they have fewer grant renewals; they get lower funding amounts for initial grants; and are first or last author on fewer papers.

The reasons for these are well known, the authors wrote.

“Society expects women to assume the major portion of the burden for child rearing, and women themselves feel an obligation to put family above their own needs, to the detriment of their own career development,” she said. “There still isn’t the sharing of responsibilities in two-career families to mitigate these problems.”

The paper includes a detailed ‘menu’ of proposed solutions. These include providing financial support to hire technicians for two to three years to carry on lab research while women researchers focus on child care at home, or otherwise supporting child care at home so women can continue their lab research.

The paper also proposes slowing down tenure clocks, delaying the tenure decision by two to three years to make up for lost time while women give birth and care for young children.

In addition to such programs, the list includes a category of solutions termed “cultural,” described as creating the cultural expectation that gender equity is a shared responsibility and incorporating those expectations into bonuses and merit raises of institutional leaders. Also included is the need to engage university and hospital boards of trustees to support gender equity.

Prof Curtis said that the paper aims to highlight the persistence of these gender differences persist and that global phenomena like the pandemic only worsen them.

“As much as we would like to think that gender differences in career development no longer exist, they do, and they adversely affect women more than men,” she said. “Understanding these issues and implementing solutions are the best ways to minimise potentially adverse effects on women’s careers.”

As the pandemic and its associated restrictions ease, Prof Curtis warned, “The situation is improving now that schools are open, but the next pandemic may only be a mutation away.”

Source: Buffalo University

Hypertension Risk for Women After Sexual Assault or Harassment

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A new study has found that women who have experienced sexual assault or harassment are at higher long-term risk of developing hypertension than women who have not.

The study appears in the Journal of the American Heart Association.

In the US, nearly 43% of women aged 20 and older have hypertension. Defined as a blood pressure of 130/80mmHg or higher, hypertension is a major risk factor for cardiovascular disease – the number one killer of women, causing one in three deaths each year.

“We know that experiences of sexual violence in the form of sexual assault and workplace sexual harassment are common, and that women are disproportionately victims of such violence, with 13–44% of women reporting sexual assault and up to 80% of women reporting workplace sexual harassment,” said study author Rebecca B. Lawn, PhD. “However, exposure to sexual violence is not widely recognized as a contributor to women’s cardiovascular health. We felt it was important to investigate the relationship among common forms of sexual violence with the risk of developing hypertension. These links could help in the early identification of factors that influence women’s long-term cardiovascular health.”

In this study, researchers analysed data over the course of seven years beginning with a 2008 follow-up of the Nurses’ Health Study II, an ongoing cohort study of US women. The 2008 follow-up measured the incidence of sexual violence and other trauma exposure, as well as post-traumatic stress disorder (PTSD) and symptoms of depression, among a subset of 54 703 of the study’s original participants.

From that subset, Lawn and colleagues analysed data for 33 127 women (95% non-Hispanic white women; average age of 53 years at the beginning of the 2008 follow-up) who had no history of hypertension or had not taken medication for high blood pressure as of the start of the 2008 follow-up.

The analyses found:

  • At the seven-year follow-up in 2015, about 1 in 5 (nearly 7100) of the women self-reported they had developed hypertension, validated with medical records.
  • Sexual assault and workplace sexual harassment were common, with lifetime prevalence of 23% for sexual assault and 12% for workplace sexual harassment; 6% of women reported experiencing both.

Compared to women with no history of sexual assault or harassment, women who reported having experienced both had the greatest increased hypertension risk (21%), followed women who reported experiencing workplace sexual harassment (15%) and an women who reported experiencing sexual assault (11%).

“We did not find any association of increased risk for hypertension among women who had a history of other types of trauma and who did not experience sexual violence, suggesting that increased hypertension risk does not appear to be associated with all trauma exposure,” Dr Lawn said. “Our finding that experiencing both sexual assault and workplace sexual harassment had the highest risk of hypertension underscores the potential compounding effects of multiple sexual violence exposures on women’s long-term cardiovascular health.”

Dr Lawn observed screening for partner violence by primary care clinicians is becoming more common, sexual violence overall is not recognised as a risk factor among women for developing cardiovascular disease.

“These results suggest that screening for a broader range of experiences of sexual violence in routine health care, including sexual harassment in the workplace, as well as verbal harassment or assault, and being aware of and treating potential cardiovascular health consequences may be beneficial for women’s long-term health,” she said. “Reducing sexual violence against women, which is important in its own right, may also provide a strategy for improving women’s lifetime cardiovascular health.”

There are several limitations to the study, including memory biases in recall of sexual violence. The sexual assault and harassment had no measures of severity or timing. Most of the women in the study were white women in the nursing field, limiting generalisability.

“We hope future studies will examine these questions with more detailed information on sexual and other forms of violence. These questions need to be investigated in more diverse groups of people of various ages, races and ethnic backgrounds and gender,” Dr Lawn said. “Although women are disproportionately victims of sexual violence, men are also victims and the physical health implications of experiences of sexual violence against men warrants further investigation.”

Source: American Heart Association

Urinary Incontinence Worsens as Women Age

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A new study published in Menopause suggests postmenopausal women aged 45 to 54 years are more likely to have overactive bladder (OAB) syndrome. Additionally, obesity and multiple births put a woman at greater risk for stress urinary incontinence (SUI). 

Urinary incontinence symptoms are common in women and typically worsen as women age. In the United States, the prevalence of urinary incontinence is 17.1% in women aged 20 years or older and 38% in women aged 60 years and older.

There are two main types of urinary incontinence: urinary urge incontinence (UUI) and SUI. Urinary urge incontinence is defined as the involuntary loss of urine associated with the urge to urinate. Stress urinary incontinence, which women are more likely to be diagnosed with, is the involuntary loss of urine because of effort or physical exertion, including sporting activities, sneezing, and coughing. Overactive bladder syndrome is characterised by urinary urgency and is usually accompanied by increased daytime frequency and/or nocturia, with urinary incontinence.

This is the largest known study, with data from more than 12 000 women. Its goal was to investigate the prevalence and factors associated with urinary symptoms.

While the study showed a significant association of OAB in women aged 45 to 54 years and postmenopausal status, it also demonstrated that SUI symptoms may likely become less frequent after menopause. However, high body mass index and the number of times a woman has given birth were shown to increase SUI symptoms.
Other factors studied included smoking status, history of diabetes, hysterectomy, and the use of hormone therapy. The researchers suggest that additional studies should be conducted to consider the association between time since menopause and OAB symptoms in the perimenopause period.

“This study underscores how common urinary incontinence is in women, with nearly one in five Japanese women reporting urinary incontinence related to OAB or SUI in the last month. Midlife women were particularly affected by SUI (18.2% in women aged 50 to 54 years). Given the significant negative effect on quality of life and the presence of effective strategies for management of these burdensome symptoms, clinicians should routinely ask women about urinary incontinence,” said Dr Stephanie Faubion, The North American Menopause Society medical director.

Source: EurekAlert!

Older Women Struggle More with Daily Activities

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Older women are more likely to struggle with both regular daily tasks and mobility activities, according to new analysis of longitudinal cohort studies.

However, the researchers say disparities in ability to perform daily tasks have been steadily decreasing as the socioeconomic gap between the sexes has decreased.  

The international study, published in The Lancet Healthy Longevity, uses data from more than 27 000 men and 34 000 women aged 50 to 100, born between 1895 and 1960, to examine sex differences in daily activity and mobility limitations. Researchers at UCL and the National Institute of Health and Medical Research (INSERM) in France drew on four large longitudinal studies, covering 14 countries*.

Women were more found to be more likely than men to be limited in their ‘functional capacity’ (both tasks and mobility) as they get older. From age 75, women were also more likely to have three or more mobility issues (such as going up a flight of stairs) or limitations with more complex daily tasks (eg managing money) compared to men who were more likely to have just one or two. At age 85 years, the prevalence of three or more mobility limitations was 10% higher in women than in men.

Lead author, Mikaela Bloomberg, UCL PhD candidate, explained: “Our study of over 60,000 participants born between 1895 and 1960 provides new insights on functional limitations and sex differences.

“We found that women are more likely to be limited than men in carrying out daily tasks from age 70, while we observed women were more likely to be limited in mobility activities from age 50 onward.

“This is an important observation because mobility limitations can precede other more severe limitations and targeting these gaps at middle age could be one way to reduce sex differences in limitations at older ages.”

Historical socioeconomic differences between men and women in areas such as education and entrance to the labour force may partly explain these differences, as women are disproportionately exposed to associated health risks that can lead to disability.

“It appears that gender inequalities in the ability to carry out daily tasks at older age are decreasing over time and this could be explained by the fact that women have better access to education and are more likely to enter the paid labour force in recent generations,” said Bloomberg.

“And although reductions in socioeconomic inequalities may be associated with smaller disparities in simple daily tasks, we did not see the same reductions in sex disparities for mobility after accounting for socioeconomic factors. This might be partly due to sex differences in body composition such as body mass and skeletal muscle index but more research is needed to identify other factors.”

Co-author Dr Séverine Sabia added: “Developing targeted prevention policies to preserve independent living and quality of life for older adults requires an understanding of drivers of sex differences in functional limitations.

“Our study indicates improvements in socioeconomic conditions for women could play an important role in reducing these sex differences. Findings also highlight the importance of early prevention to tackle sex differences in mobility that may trigger sex differences in disability at older age.”

Source: University College London

Is That A Girl’s Voice or A Boy’s?

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Researchers have found that it is possible to distinguish a girl’s voice from a boy’s from as young as five years old, but identification requires the listener to perceive the size of the speaker, providing a clue to their likely age. 

Perceiving gender in children’s voices is of special interest to researchers, because in children, a girl’s voice and a boy’s are very similar before the age of puberty. Adult male and female voices are fairly easy to distinguish due to acoustic differences.

With children, gender perception is much more complicated because gender differences in speech may emerge before sex-related anatomical differences between speakers. This suggests listeners may need to consider speaker age when guessing speaker gender and the perception of gender may depend on acoustic information besides anatomical differences between boys and girls.

In the Journal of the Acoustical Society of America, researchers reported developing a database of speech samples from children ages five to 18 to answer two questions: What types of changes occur in children’s voices as they become adults, and how do listeners adjust to the enormous variability in acoustic patterns across speakers?

Listeners assess a speaker’s gender, age, height, and other physical characteristics based primarily on the speaker’s voice pitch and on the resonance (formant frequencies) of their voice.

“Resonance is related to speaker height — think violin versus cello — and is a reliable indicator of overall body size,” said co-author Santiago Barreda, from the University of California, Davis. “Apart from these basic cues, there are other more subtle cues related to behaviour and the way a person ‘chooses’ to speak, rather than strictly depending on the speaker’s anatomy.”
When co-authors Barreda and Peter Assmann presented listeners with both syllables and sentences from different speakers, gender identification improved for sentences. They said this supports the stylistic elements of speech that highlight gender differences and are better conveyed in sentences.

They made two other important findings. First, listeners can reliably identify the gender of individual children as young as five.

“This is well before there are any anatomical differences between speakers and before there are any reliable differences in pitch or resonance,” said Barreda. “Based on this, we conclude that when the gender of individual children can be readily identified, it is because of differences in their behavior, in their manner of speaking, rather than because of their anatomy.”

Second, they found identification of gender of speakers must take place along with the identification of age and likely physical size.

“Essentially, there is too much uncertainty in the speech signal to treat age, gender, and size as independent decisions,” he said. “One way to resolve this is to consider, for example, what do 11-year-old boys sound like, rather than what do males sound like and what do 11-year-olds sound like, as if these were independent questions.”

Their findings suggest that “perception of gender can depend on subtle cues based on behaviour and not anatomy,” said Barreda. “In other words, gender information in speech can be largely based on performance rather than on physical differences between male and female speakers. If gendered speech followed necessarily from speaker anatomy, there would be no basis to reliably identify the gender of little girls and boys.”

This study supports the notion that gender (as opposed to sex) is largely performative in nature, which has long been argued on theoretical grounds.

Source: American Institute of Physics

Gaps and Gender Differences in Diabetes Management

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A new study from the University of Eastern Finland revealed there are gaps and gender differences in diabetes management. Type 2 diabetes is often accompanied by elevated cholesterol levels, but many patients do not receive appropriate cholesterol-lowering treatment, according to the study, which appears in Scientific Reports.

Type 2 diabetes is a major risk factor of cardiovascular diseases, such as coronary artery disease and heart failure, as well as premature death. To prevent or at least delay complications, regular health care visits and good control of blood glucose, low-density lipoprotein cholesterol (LDL-C) and other risk factors are needed.

The present study shows that LDL-C control and statin prescriptions remain suboptimal in clinical practice – despite guidelines that consistently recommend treating elevated LDL-C with statins at moderate- to high-intensity. The study drew on electronic health records of 8592 type 2 diabetes patients between 2012 and 2017.

Analysing LDL-C values over time, researchers identified four groups with different trajectories. Most patients (86%) had relatively stable LDL-C values at moderate levels and only a few patients showed a significant increase (3%) or decrease (4%) during the follow-up. However, the second-largest group (8%) consisted of patients with alarmingly “high-stable” LDL-C levels at around 3.9 mmol/L.  

The “high-stable” LDL-C group had the lowest proportions of patients on moderate- and high-intensity treatment as well as any statin treatment. The proportion of patients receiving any statin treatment even decreased from 42% to 27% among men, and from 34% to 23% among women between 2012 and 2017.

“We observed significant gender differences in care processes and outcomes,” said Laura Inglin, Early Stage Researcher, University of Eastern Finland. “In all the trajectory groups, women had significantly higher average LDL-C levels and received any statin treatment and high-intensity treatment less frequently than men.”

Significant differences were seen in terms of longitudinal care processes, outcomes, and treatments, pointing out gaps in current diabetes management. Efforts to control LDL-C should be increased – especially in patients with continuously elevated levels – by initiating and intensifying statin treatment earlier and re-initiating the treatment after discontinuation if possible.

Source: University of Eastern Finland

Biological Research Often Incorrectly Reports Sex Differences

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An analysis of published studies from a range of biological specialties shows that when data are reported by sex, critical statistical analyses are often missing and the findings are likely to be reported in misleading ways.

The analysis was published in the journal eLife.

“We found that when researchers report that males and females respond differently to a manipulation such as a drug treatment, 70% of the time the researchers have not actually compared those responses statistically at all,” said senior author Donna Maney, a professor of neuroscience in Emory’s Department of Psychology. “In other words, an alarming percentage of claims of sex differences are not backed by sufficient evidence.”

In the articles lacking the proper evidence, she added, sex-specific effects were claimed almost 90% of the time. In contrast, authors that tested statistically for sex-specific effects only reported them 63% of the time.

”Our results suggest that researchers are predisposed to finding sex differences and that sex-specific effects are likely over-reported in the literature,” Prof Maney said.

The problem is so pervasive not even her own work was safe. “Once I realised how prevalent it is, I went back and checked my own published articles and there it was,” she said. “I myself have claimed a sex difference without comparing males and females statistically.”

Prof Maney stressed that the problem should not be discounted; it is becoming increasingly serious, she said, because of mounting pressure from funding agencies and journals to study both sexes, and interest from the medical community to develop sex-specific treatments.

Better training and oversight are needed to ensure scientific rigor in research on sex differences, the authors wrote: “We call upon funding agencies, journal editors and our colleagues to raise the bar when it comes to testing for and reporting sex differences.”

Historically, biomedical research has often included just one sex, usually biased toward males. In recent decades, laws have been passed requiring US medical research to include females in clinical trials and report the sex of human participants or animal subjects.

“If you’re trying to model anything relevant to a general population, you should include both sexes,” Prof Maney explained. “There are a lot of ways that animals can vary, and sex is one of them. Leaving out half of the population makes a study less rigorous.”

As more studies consider sex-based differences, Maney adds, it is important to ensure that the methods underlying their analyses are sound.

For the analysis, Prof Maney and co-author Yesenia Garcia-Sifuentes, PhD candidate, looked at 147 studies published in 2019 to see what is used for evidence of sex differences. The studies ranged across nine different biological disciplines, including field studies on giraffes and immune responses in humans.

The studies that were analysed all included both males and females and separated the data by sex. Garcia-Sifuentes and Prof Maney found that the sexes were compared, either statistically or by assertion, in 80% of the articles. Of those articles, sex differences were reported in 70% of them and of those treated as a major finding in about half.

Statistical errors were seen in some studies, with a significant difference for one sex but not the other counted as a difference between them.  The problem with that approach is that the statistical tests conducted on each sex can’t give “yes” or “no” answers about whether the treatment had an effect.

“Comparing the outcome of two independent tests is like comparing a ‘maybe so’ with an ‘I don’t know’ or ‘too soon to tell,'” Maney explains. “You’re just guessing. To show actual evidence that the response to treatment differed between females and males, you need to show statistically that the effect of treatment depended on sex. That is, to claim a ‘sex-specific’ effect, you must demonstrate that the effect in one sex was statistically different from the effect in the other.”

Conversely, their analysis also encountered strategies that could mask sex differences, such as pooling data from males and females without testing for a difference.

“At this moment in history, the stakes are high,” Maney says. “Misreported findings may affect health care decisions in dangerous ways. Particularly in cases where sex-based differences may be used to determine what treatment someone gets for a particular condition, we need to proceed cautiously. We need to hold ourselves to a very high standard when it comes to scientific rigor.”

Source: EurekAlert!