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“The first direct evidence of a genetic link to attention deficit hyperactivity disorder has been found,” reported BBC News.

The research behind this news compared the DNA of 366 children with attention deficit hyperactivity disorder (ADHD) and 1,047 control subjects not known to have the condition. It found that 14% of children with ADHD had large, rare variations in their DNA that were present in only 7% controls.

Although this has been called ‘the first direct evidence’ that ADHD is a genetic disorder, results from other genetic research and studies in twins have already highlighted the role that genetics play in ADHD. More research is now needed to confirm that the variations identified cause ADHD and to identify other variants involved. The exact causes of ADHD are not yet known, but it is currently thought that both genetic and environmental factors play a role.

The results of the current study add to what is known about possible genetic risk factors for ADHD, but do not have immediate implications for the care or treatment for ADHD. As the researchers state, “there is no single gene behind ADHD, and the work is at too early a stage to lead to any test for the disorder.”

 

Where did the story come from?

The study was carried out by researchers from Cardiff University School of Medicine and other research centres, including deCODE Genetics in Iceland. It was funded by Action Research, the Baily Thomas Charitable Trust, the Wellcome Trust, the UK Medical Research Council and the European
Union. The study was published in the peer-reviewed medical journal The Lancet.

BBC News, the Daily Mirror, The Guardian and The Daily Telegraph covered this story. In general, they covered the basics of the study accurately, although some coverage incorrectly implies that this is the first evidence of a genetic link with ADHD or that the study rules out a role for any non-genetic factors in ADHD. The BBC News blog offers a good summary of these issues.

 

What kind of research was this?

This case-control study looked at whether large deletions and duplications within DNA (called copy number variants or CNVs) might be more common in people with ADHD. If this were the case, it might indicate that the variants play a role in causing the condition. Genetic factors are known to contribute to ADHD, but the exact genes have not been conclusively identified.

Rare CNVs have been found to contribute to conditions such as autism, intellectual disability and schizophrenia, so the researchers wanted to determine whether they might also contribute to ADHD. They were particularly interested in whether ADHD, autism and schizophrenia might all be linked to specific CNVs.

The methods used by the researchers were appropriate for examining the potential role of CNVs in ADHD, and they used various standard quality checks in their DNA analyses.

 

What did the research involve?

The researchers first compared DNA from 366 UK children with ADHD and 1,156 unrelated, ethnically-matched participants drawn from the general population. They looked at whether large, rare CNVs were more common in children with ADHD than in the controls.

The participants were children aged 5 to 17 years, of white UK origin, who were diagnosed with ADHD based on accepted criteria. The researchers did not include any children with autistic spectrum disorders, Tourette’s syndrome, schizophrenia or conditions such as epilepsy. The children’s intellectual ability was assessed using standard intelligence tests.

The researchers looked at single letter-variations in the DNA across the children’s chromosomes to determine where there were CNVs. They also used an additional genetic technique to confirm the presence of the CNVs they identified in children with ADHD. They specifically looked for large CNVs that were rare in the general population (affecting less than 1% of people).

The control subjects were part of a long-running study called the 1958 British Birth Cohort and were born in 1958. They had not been assessed for psychiatric diagnoses, but these were likely to be uncommon.

The researchers first compared the average number of CNVs in cases (children with ADHD) and controls. Because CNVs have been linked to intellectual disability, they also separately looked at the CNVs found in children with ADHD with and without intellectual disability. There were 33 children with ADHD and intellectual disability in the UK sample.

The researchers also specifically looked at 20 areas of the DNA where CNVs associated with autism or schizophrenia have previously been found, to see whether the same areas were affected by CNVs in ADHD.

The researchers then checked some of their results in a separate sample of 825 people with ADHD and 35,243 controls from Iceland.

 

What were the basic results?

The researchers found that large CNVs were more common in children with ADHD than in controls. They identified 57 large, rare CNVs in children with ADHD and 78 in controls. The average number of CNVs in each individual was about twice as high in cases than in controls, with an average of 0.156 CNVs per child with ADHD and 0.075 CNVs per control. Large CNVs were present in 14% of the children with ADHD and in 7% of controls.

These large, rare CNVs were more common in children with ADHD (both those with and without intellectual disability) than in controls, although they were particularly common in those with intellectual disability. Among children with ADHD and intellectual disability, 36% carried a large CNV compared with 11% of children with ADHD but no intellectual disability. Some regions where CNVs were found in children with ADHD overlapped with some regions where CNVs linked to autism and schizophrenia have been found.

Compared with controls, an area on chromosome 16 had an excess of large CNVs in children with ADHD who did not have intellectual disability. This area also had an excess of CNVs in the people with ADHD from the Icelandic sample compared to Icelandic controls. Two children from the UK sample with ADHD had CNVs in this region. In one case, these were inherited from the child’s mother, and in the other case were the result of a new mutation not inherited from either parent.

 

How did the researchers interpret the results?

The researchers say their findings provide evidence of an increased number of large copy number variants in people with ADHD. They say that this “refute[s] the hypothesis that ADHD is purely a social construct, which has important clinical and social implications for affected children and their families”.

 

Conclusion

This study suggests that large, rare deletions and duplications of DNA could play a role in ADHD. Further study is likely to focus on confirming these results in other samples and assessing whether the inheritance of these genetic variations in families is consistent with them being causes of ADHD. Researchers will also want to take a closer look at the functions of the genes affected by these variations, and how changes in these areas might be involved in the condition.

The causes of ADHD are not known, but both genetic and environmental factors are considered to play a role. It is important to note that this study does not rule out a role for other genetic factors in ADHD, nor for environmental factors.

Links To The Headlines

New study claims ADHD ‘has a genetic link’. BBC News, September 30 2010

Kids inherit ADHD from mum & dad. Daily Mirror, September 30 2010

ADHD ’caused by genetic faults’. The Daily Telegraph, September 30 2010

Hyperactive children may suffer from genetic disorder, says study. The Guardian, September 30 2010

Links To Science

Williams NM, Zaharieva I, Martin A et al. Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis. The Lancet, Early Online Publication, 30 September 2010

“Bottle-fed babies are primed for a life of obesity,” reported the Daily Express. Babies who put on weight too fast in their first months are more likely to become fat, the newspaper added.

The story comes from two studies which looked at the effect of giving nutrient–enriched formula to babies who were born too small for their age. The studies found that, at 5–8 years old, children who were given the enriched formula had more body fat than those who were given normal formula. This suggests that faster weight gain as a baby causes children to gain a higher proportion of fat tissue (fat mass) when they’re older.

The results of these two studies seem to support previous research that suggests “overfeeding” in infancy – in this case by using nutrient-enriched formula – increases the risk of obesity later in life. These findings were independent of factors such as gender, height in childhood or socioeconomic status. However, the studies had some limitations. Both studies had a high drop-out rate, which could undermine the reliability of the results. Also, the studies did not look at children who had normal birth weight. Finally, it is not clear if the early feeding influenced the appetite and diet of the children as they grew or if it independently influenced fat mass.

The study did not measure obesity, as defined by Body Mass Index (BMI). Instead, it looked at the children’s fat mass. As the children were not followed up into adolescence and adulthood, it is incorrect to say that these children were “primed for a life of obesity”.

 

Where did the story come from?

The study was carried out by researchers from University College London, University Hospital Nottingham, Leicester General Hospital, Royal Hospital for Sick Children in Glasgow, the Wishaw General Hospital, the Southern General Hospital in Glasgow and the Danone Research centre for Specialized Nutrition in the Netherlands. It was funded by the Medical Research Council (UK) and other organisations, with contributions from Farley’s Health Products and Nutricia Ltd.

The study was published in the peer-reviewed American Journal of Clinical Nutrition.

The Daily Express’s claim that bottle milk makes children obese and that “breast is still best if you want your child to be slim” is incorrect. The study compared children who were fed enriched or normal formula, and the former group was found to have more fat tissue later. Likewise, the Daily Mail’s headline that “Baby formula milk could make your child obese” and The Guardian’s “Bottle-feeding babies can lead to adult obesity, says study” were also misleading.

 

What kind of research was this?

This research comprised two randomised controlled trials. They looked at the body composition of children who were given extra nutrition to encourage growth because they were born small for their gestational age. The authors point out that previous observational studies have suggested that “overnutrition” and rapid growth in infancy may increase the risk of obesity later, but that the results of these studies could have been affected by both genetic and lifestyle factors. Randomised controlled trials are the best type of studies to look at the effects of certain interventions. By selecting subjects at random and having a control group, they eliminate bias.

 

What did the research involve?

The researchers recruited newborn babies as soon as possible after birth from 10 UK hospitals to take part in the two studies. Study 1 recruited babies between 1993 and 1995, and study 2 between 2003 and 2005. All the babies were born at full term (after 37 weeks) but were small for gestational age (SGA). The babies in study 1 were below the 10th percentile for their gestational age and those in study 2 were below the 20th percentile, according to UK growth charts.

Babies of the mothers who had already decided to bottle feed were randomly assigned to receive either standard formula (the control group) or a nutrient-enriched formula (the intervention), with a higher protein and energy content designed to promote rapid growth. The formulas were given until the babies were nine months old in study 1 and until they were six months old in study 2. A total of 545 babies were originally enrolled in the two studies, and in study 1 a reference group of 175 breastfed babies was also recruited.

Researchers followed up babies between 1999 and 2002 in study 1 and between 2008 and 2009 in study 2. In study 1, the children’s body composition was measured by a nurse at home, using “bioelectric impedance analysis”, a standard technique to measure the proportion of fat and lean body mass. In study 2, a method called “deuterium dilution”, which measures total body water, was used to calculate fat-free mass. In both studies, researchers estimated fat mass using callipers to measure skin fold thickness.

They used standard statistical techniques to analyse the effects of early feeding on body fat later.

 

What were the basic results?

The researchers followed up 243 of the original 545 infants enrolled in the study. In both studies, fat mass in those who had been given normal formula was lower than in those given the enriched formula (after adjustment for sex) at 5–8 years of age.

• In study 1, children who had been on normal formula had 38% less fat mass than those in the enriched formula group (95% confidence interval [CI] -67% to -10%).
• In study 2, children who had been on normal formula had 18% less fat mass than those in the enriched formula group (95% [CI] -18% to -0.3%).

In a separate non-randomised analysis, the researchers also found that babies who had grown faster were more likely to have a higher proportion of fat mass in childhood. This suggests that the rate of growth is the important factor in determining later fat mass.

A further analysis suggested that in the group of breastfed babies, faster weight gain in infancy was also associated with greater fat mass later.

 

How did the researchers interpret the results?

The researchers say their results suggest that there is a causal link between overfeeding and faster infant growth and a higher risk of obesity later. This link is independent of genetic or lifestyle factors. These results have implications, they suggest, for the prevention of obesity, which should begin in infancy.

 

Conclusion

These two well-conducted studies show that small for gestational age (SGA) babies who were fed enriched formula to promote rapid growth had higher proportions of body fat in later childhood. However, as the authors note, a causal link has not been established. It is possible that genetic factors influenced the babies’ appetites and, therefore, “overfeeding” and later obesity. It is interesting to note that among breastfed babies, those who grew more rapidly also had higher fat mass later.

As the authors note, the study had several limitations:

• Most importantly, the study had a poor follow-up rate. In study 1, 51.2% of the children were followed up, and in study 2 only 36.6% were followed up. Although these studies had large sample sizes initially, in any randomised controlled trial a completion rate of above 80% would be expected in order to increase the reliability of the results.
• The study involved SGA babies. It is not clear if the findings would apply to babies of normal birth weight.
• It is possible that there were inaccuracies in the techniques used to measure body fat, which  is not a measure of obesity.
• It is also possible that the children’s diets after bottle feeding influenced the later fat measurement.

Links To The Headlines

How baby formula milk could make your child obese by the age of five. Daily Mail, September 30 2010

Bottle-feeding babies can lead to adult obesity, says study. The Guardian, September 30 2010

Bottle milk makes babies obese. Daily Express, September 30 2010

Links To Science

Singhal A, Kennedy K, Lanigan J et al. Nutrition in infancy and long-term risk of obesity: evidence from 2 randomized controlled trials. American Journal of Clinical Nutrition, September 29, 2010.

“Caffeine helps cut brain cancer risk,” said the Daily Express, reporting that a daily cup of tea or coffee can stop tumours growing by restricting blood flow to the brain.

The large study behind this story followed 410,000 men and women across 10 European countries for 8.5 years and looked at the development of two forms of brain tumour. Brain tumours are rare, and during follow-up there were only 588 new cases in total. The researchers found no meaningful associations when they looked at each country separately, although combining all the national results showed a trend between greater caffeine consumption and lower cancer risk.

The results echo those of a previous study and are likely to lead to further research into how caffeine may affect the working processes in the brain. However, the research has numerous important limitations, including the fact that variable methods were used for measuring caffeine intake across countries. Overall, while this research is of scientific interest it has limited implications for current medical treatment.

 

Where did the story come from?

The study was carried out by researchers from Imperial College London, and numerous other academic institutions in Europe and the US. Sources of funding were not reported. The study was published in the peer-reviewed American Journal of Clinical Nutrition.

This study has several important methodological limitations, which the papers have generally not reported on.

 

What kind of research was this?

This was a cohort study designed to examine the association between coffee and tea intake and the risk of developing glioma and meningioma, types of brain tumour. Gliomas are tumours of glial cells, which protect nerve cells, while a meningioma is a tumour in the meninges, the protective cells surrounding the brain and spinal cord. A similar US study recently noted an inverse association between caffeine intake and glioma, i.e. glioma became less common as caffeine intake increased.

This was a cohort study, which is a design used to assess the effects of an exposure on an outcome and to provide evidence to answer the question of whether one thing causes another. Cohort studies are not perfect, and the limitations of this particular study included difficulty with accurately quantifying the amount of coffee and tea someone drinks, and also the fact that brain tumours are rare, so a very large number of people must be followed over a long period of time to record new cancers.

 

What did the research involve?

This research involved participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, an ongoing study conducted in 10 European countries and including 521,448 men and women. The participants were mostly aged between 25 and 70, and recruited between 1991 and 2000.

At the start of the study, blood samples and body measurements were taken and the participants completed a health and lifestyle questionnaire. The questionnaire recorded information on diet during the previous 12 months, and specifically coffee and tea intake. Total consumption of coffee and tea was estimated in mL per day, with methods of assessment differing between countries. The methods used were not specifically reported in the research paper.

Over an average of 8.5 years of follow-up the researchers used population registries, health insurance records and cancer mortality registries (depending on country) to determine development of brain tumours. In their statistical analyses researchers excluded all cancers present at study start and participants who were missing data on diet or missing laboratory information on the microscopic structure (histology) of the cancers that developed. Analyses between coffee and tea consumption and brain cancer risk were adjusted for age, BMI, smoking and education.

 

What were the basic results?

After exclusions the final cohort included 410,309 men and women. During follow-up there were 343 new cases of glioma and 245 cases of meningioma. 

Daily coffee and tea intake was highly variable across European countries, with the highest coffee consumption reported in Denmark (798mL/day) and the lowest in Italy (98mL/day). For tea, the highest consumption was reported in the United Kingdom (532mL/day) and the lowest in Spain (6.2mL/day). Higher consumption of coffee and tea was generally associated with slightly older age, higher education, current smoking and lower BMI.

The researchers split the participants into five different groups (quintiles) based on their consumption levels of tea, coffee and both drinks together. From the lowest (first quintile) to highest intake (fifth quintile), no amount of coffee, tea or combined coffee and tea was associated with either type of brain cancer.

When the researchers looked at each country separately there were no significant associations between the cancers and drinking more than 100mL of coffee and tea per day compared with drinking less than 100mL per day, although there was a non-significant association between drinking less than 100mL and decreased risk. However, when the researchers combined the results for all of the countries they found that drinking more than 100mL per day was associated with 34% reduced risk of developing glioma compared with drinking less than this (hazard ratio 0.66, 95% CI 0.44 to 0.97).

 

How did the researchers interpret the results?

The researchers conclude that in this large cohort they observed an inverse association between total coffee and tea consumption and the risk of glioma. They say that this was consistent with the findings of a recent study.

 

Conclusion

This research has strengths, particularly its size and duration: it followed 410,309 men and women for 8.5 years, allowing a reasonable time for brain tumours to develop. However, while it found a trend towards an association between higher coffee and tea consumption and lower risk of glioma, careful consideration should be given to the possible shortcomings of this study:

• Brain tumours are rare cancers. As reported in the journal article, the age-adjusted incidence rates for brain and nervous system tumours in Europe range from between 4 and 6 cases per 100,000 person-years for women, and between 6 and 8 per 100,000 person-years for men. In this study, from a population of 410,309 followed for 8.5 years, there were only 343 new cases of glioma and 245 cases of meningioma.
• Dietary questionnaires varied between countries, for example, some asked participants to specify intake of caffeinated and decaffeinated drinks, while others assessed coffee only and not tea. The questions asked in each country are not reported, but asking people to quantify the volume of tea or coffee that they drink each day is likely to involve estimation. Also, the same volume of coffee is likely to cover a variable amount of caffeine depending on whether this is, for example, freshly brewed coffee, instant coffee, espresso, latte or cappuccino.
• Methods of ascertaining new cancer cases also differed by country and the accuracy of these registers may vary.
• Analyses were adjusted for age, BMI, smoking and education. However, as the authors rightly point out, risk factors for brain tumours are largely unknown, so there is the possibility that other unknown risk factors were confounding the observed association.
• Overall, there was no association between any level of coffee and tea consumption and risk of glioma or meningioma in individual countries, although there was a non-significant trend within each for consumption of more than 100mL to be associated with lower risk than consumption of less than 100mL. It was only when the results for all countries were combined that a significant decreased risk was found for higher consumption.

These findings are of scientific interest and, as they echo the results of a previous study, they are likely to lead to further research investigating the effect that caffeine may have on physiological processes in the brain. However, they currently have limited implications for health. The adverse effects of excess caffeine on general wellbeing are well established.

Links To The Headlines

Contraceptive coil raises hope of delaying womb cancer. BBC News, September 28 2010

Contraceptive coil could be used to treat womb cancer: researchers. The Daily Telegraph, September 28 2010

Links To Science

Minig L. Franchi D, Boveri S et al. Progestin intrauterine device and GnRH analogue for uterus-sparing treatment of endometrial precancers and well-differentiated early endometrial carcinoma in young women. Annals of Oncology [published online] September 28 2010

The “contraceptive coil raises hope of delaying womb cancer”, reported the BBC. A “promising early trial” has found that the coil, also known as the intrauterine device or IUD, can deliver hormones to the lining of the womb (endometrium), which can halt or reverse cancer growth, explained the website.

This study did not involve the conventional coil (IUD) as this does not release hormones. This was a study of the levonorgestrel-releasing intrauterine system (LNG-IUS or Mirena coil). It was used alongside monthly injections of a hormone called GnRH (gonadotropin-releasing hormone) for the treatment of women in a specialist cancer centre. Twenty of the women had abnormal overgrowth of the womb lining and 14 had early-stage cancer of the womb lining (endometrial cancer). The combined coil and hormone injection was shown to reduce their risk of the disease progressing or recurring.

This is important early research of a potential new treatment combination. Women should not interpret the news reports as meaning that using the coil (either conventional or Mirena) will reduce their risk of developing endometrial cancer, or that it can be used as a treatment for cancer. The Mirena coil is currently licensed in the UK as a long-term contraceptive, particularly in women who have heavy periods.

 

Where did the story come from?

The study was carried out by researchers from the European Institute of Oncology in Milan and the Centro Integral Oncologico Clara Campal (CIOCC) in Madrid. No sources of external funding were reported. The study was published in the peer-reviewed medical journal Annals of Oncology.

The headlines in both The Daily Telegraph and BBC News are likely to confuse the reader into thinking that the conventional coil (IUD) was studied. However, the research looked at the commonly used Mirena coil, in combination with GnRH hormone treatment. This is not currently a conventional treatment method, and it was being trialled here in a very specific population of women who wanted to avoid surgical treatment of their cancer or pre-cancer.

 

What kind of research was this?

This case series reported the experiences of gynaecologists who used the Mirena coil plus gonadotropin-releasing hormone (GnRH) to treat women aged under 40. These women had abnormal overgrowth (hyperplasia) of the lining of the womb (endometrium) or early-stage endometrial cancer. The sample of women all wished to preserve their fertility, which ruled out conventional treatments for these conditions, including hysterectomy, radiotherapy or chemotherapy.

 

What did the research involve?

The study involved 34 women, including 20 women with endometrial hyperplasia and 14 women with early-stage cancer. The women had been referred to the European Institute of Oncology in Milan between January 1996 and June 2009 to investigate conservative (non-surgical) treatment of their condition. The average age of the women was 34 years. All women underwent full assessment, examination and staging of their condition before treatment. The treatment involved insertion of the Mirena coil for one year, as well as monthly GnRH injections for six months.

Pelvic ultrasound examination and a biopsy of the lining of the womb were carried out at six months and one year to assess the results. On average, the women were followed up for about two-and-half years, though the highest length of follow-up was over eight years. The researchers determined the response to treatment according to whether there was any difference from pre-treatment measurements. The results were classed as:

• complete response if the latest biopsy showed normal womb lining
• stable disease if the latest biopsy had the same appearance under the microscope as the first sample
• progressed disease if early cancer appeared in those who had initial hyperplasia only
• recurrence if new hyperplasia or early cancer appeared in the latest biopsy compared with a previously negative biopsy

Complete response at one year was the researchers’ primary outcome of interest. Adverse effects, treatment failure rates, pregnancy rates, recurrence and survival were all secondary outcomes.

 

What were the basic results?

The complete response rate to treatment was 95% in patients with hyperplasia (19 out of 20 women) and 57.1% in women with early-stage cancer (8 out of 14 women) at the first six-month follow-up. Disease progression was observed in 1 out of the 20 women with hyperplasia and 4 out of 14 women with early-stage cancer. Two patients with early-stage cancer remained stable.

Recurrence occurred in 4 out of 20 women with hyperplasia and 2 out of 14 women with early-stage cancer. The average time to recurrence was 36 months (range between 16 and 62 months). These women were all treated appropriately in line with current guidance.

All women, including those who responded and those who had progression or recurrence and then received conventional treatment, were alive without evidence of disease at the last follow-up (average of 29 months). Nine women achieved 11 spontaneous pregnancies.

 

How did the researchers interpret the results?

The researchers concluded that the combined treatment showed effectiveness in “a substantial proportion” of patients with endometrial hyperplasia and early-stage endometrial cancer. They say that close follow-up during and after treatment is crucial.

 

Conclusion

This study reported the experiences of treating 34 young women with early-stage endometrial cancer or pre-cancerous endometrial hyperplasia. The women wished to preserve their fertility, which ruled out conventional surgical treatments. They were treated with a combination of the Mirena coil, which was inserted for one year, and gonadotropin-releasing hormone (GnRH) injections for six months.

The results of this small sample of women were generally positive, with high complete response rates. Those who did not respond to treatment or who had recurrent disease were treated in line with current recommendations, and all the women were alive at the final follow-up. The results are encouraging and will require replication in larger population samples.

These are early results for a combined treatment, used in a specialist hospital setting, for women with a specific type of disease. Women should not misinterpret from the news reports that the coil (either the conventional [IUD] or Mirena coil) can reduce their risk of developing endometrial cancer or can be used as a treatment for cancer. The Mirena coil is currently licensed in the UK as a long-term contraceptive, particularly in women who have heavy periods. This study investigated insertion of the Mirena coil for one year along with monthly GnRH injections for six months.

Links To The Headlines

Contraceptive coil raises hope of delaying womb cancer. BBC News, September 28 2010

Contraceptive coil could be used to treat womb cancer: researchers. The Daily Telegraph, September 28 2010

Links To Science

Minig L. Franchi D, Boveri S et al. Progestin intrauterine device and GnRH analogue for uterus-sparing treatment of endometrial precancers and well-differentiated early endometrial carcinoma in young women. Annals of Oncology [published online] September 28 2010