DNA Sequencing: A Promising Development in Diagnosing Inherited Diseases

Genome sequencing has become cheaper and more widely available


Published:

Photo courtesy of iStock

Nic Volker spent much of his first four years in a hospital bed. Every time he ate, his immune system attacked his digestive tract, creating holes in his intestines that led to infection and extreme malnutrition. After dozens of tests and operations, his doctors remained mystified as to the cause of the illness, and many gave up hope.

The Washington Post covered this case in its April 20, 2016 issue and reported that, at the time Nic was experiencing these problems (2004-2010), DNA sequencing was costly (around $100,000), untested and unchartered technology. But with little to lose, a bold team of doctors, scientists and the boy’s parents pushed to have portions of his genome sequenced. With lots of theoretical knowledge (the key DNA researcher had worked only with rats) and a little luck, the team identified the mutation that caused the disease and were able to target it with treatment.

Dubbed by Forbes in January 2011 as “The first child saved by DNA sequencing,” Nic Volker’s story made national news and served as an inspiration to both researchers and families looking for answers — including those who parent special needs children. Since then, DNA sequencing has become cheaper and more widely available.

One private company, Illumina, claims it will soon be able to provide customers with whole genome sequencing for $100, though the National Institutes of Health has reported that the quality of genome sequencing varies greatly, and producing a high-quality sequence remains labor-intensive and expensive. Still, universities and private companies operate research and sequencing labs throughout the country, and the Triangle boasts major research labs at Duke University and the University of North Carolina, as well as numerous biotech companies with a focus on DNA sequencing.

Doctors and scientists are still trying to determine how this sudden wealth of information translates and should be used in a case-by-case basis. “There’s still a lot we don’t know,” says Dr. Laurie Smith, Ph.D., M.D., a member of the Department of Pediatric’s Division of Genetics and Metabolism Department at the UNC School of Medicine, adding that DNA sequencing technology is not “ready for prime time.”


The Science

The Human Genome Project took 11 years and required $2.7 billion dollars. It was completed in 2003 and produced the first map of all the hereditary information encoded in human DNA. This map is known as a “genome.” By reading or “sequencing” the DNA of any individual (using a blood sample or saliva), then comparing it to the map, scientists can identify differences or “mutations” that may or may not cause diseases or developmental delays.

Whole genome sequencing (WGS), which was used during the project, reveals the most complete picture of an individual’s DNA. There are about three billion nucleotides (DNA building blocks) in a complete genome, and scientists are still working to determine the significance of much of this information.

By contrast, whole exome sequencing (WES) looks only at the “exons” or protein-coding regions of genes. The exome, about 1.5 percent of the total genome, represents portions of the genome. Since much less DNA is sequenced, WES is cheaper than WGS and easier to interpret. However, WES provides less information to researchers than potentially available through WGS. Most scientists anticipate that as technology improves and more is learned about the whole genome, WES will give way to WGS.


The Research

Niko Katsanis runs what he calls an “intellectual hotel” — the Duke University Department of Cell Biology Center for Human Disease Modeling, which brings together a dream team of experts in various fields to solve genomic puzzles. As an extension of his research, he also leads the Duke Task Force on Neonatal Genomics, which is focused on faster diagnosis and improving the care and treatment of neonates (newborns less than a month old) and infants with genetic conditions.

The core challenge for Katsanis and his lab is trying to define success. “It’s different for everybody,” he says.

For the parents of an afflicted child, he hopes to offer a molecular diagnosis. While there is often no clear treatment, he says a diagnosis offers “a modicum of help” and relief from uncertainty. Determining a diagnosis allows a family to end the “diagnostic odyssey” (or search for a diagnosis) of repeated testing and searching for answers, and gain access to social services that may not otherwise be available. The whole family can benefit from the medical and emotional support of connecting with other families affected by the same condition. And there’s always the slight chance a diagnosis will lead to treatment of or, more likely, better management of symptoms. 


For Katsanis and his peers, a diagnosis is not enough.

“The intellectual goal is to move from prescription to prediction. ‘Take two and call me in the morning’ is a fantasy in these cases,” Katsanis says. “Therapeutic access for these patients is very low and will take a long time to develop for each disease. Compared with finding cures, sequencing the human genome was a walk in the park, and that took 10 to 15 years. It will take the same amount of time for each therapeutic drug.”

Despite these challenges, Katsanis finds his work, which includes extensive testing of human DNA on zebrafish, thrilling. (According to the National Institutes of Health, 70 percent of human genes are found in zebrafish.)

“Every day we learn something,” he says. “Genomics is like a huge fire hose spewing out stuff, and right now we just have a little bucket.”


The Doctor’s Office

Most clinics and labs claim between a 20-30 percent rate of “positive results” with WES and WGS cases, which means they find a direct connection between a gene mutation and a child’s disease. UNC’s Smith says her positive results are closer to 70 percent.

“We are very picky with the patients we take for WES,” she says.

All of her patients are referred to her through pediatricians or genetic counselors, and she is selective about which referrals she accepts.

“By the time we’ve screened for clinical features and reviewed the child’s medical history and performed some testing, we are relatively confident that the child has a genetic disorder that might be found with sequencing. And we don’t want to just look at the patient’s DNA,” she says. “We won’t perform sequencing unless we can get both parents sequenced as well.”

Smith is quick to point out the drawbacks of genomic sequencing: A high price tag often not covered by insurance, and the likelihood that the best-case scenario is just a diagnosis. “Families need to understand the limitations,” she says.

In addition, Smith takes the ethical treatment of her patients very seriously. WGS and WES involve several unresolved moral issues, such as a patient finding out something he or she may not want to know about. While sequencing a child’s genome, for example, a doctor may find genetic mutations that are unrelated to the disorder in question. Smith says this happens in 3-5 percent of cases. These “incidental findings” include adult-onset disorders and an increased risk for certain cancers that may or may not affect the individual’s health, and may or may not have health ramifications for family members or future children.

“There is the possibility of receiving information you might not want to hear,” Smith cautions. “You have to figure out how comfortable you are with the knowledge you will gain.”

She notes that parents are asked beforehand whether they want to hear incidental findings, though the American College of Medical Genetics and Genomics recommends that doctors disclose any “actionable” incidental findings that might be alleviated or prevented with lifestyle changes or preventive medicine. (Currently, there are about 60 findings listed, which you can learn more about at ncbi.nlm.nih.gov/clinvar/docs/acmg.).


The Clinical Trial

One way for a family to avoid the high cost of WES and WGS is to participate in a clinical trial. One such trial is run by the Undiagnosed Diseases Network, which is funded by the NIH and available through seven clinic locations around the country. Dr. Vandana Shashi, M.D., is a professor of pediatrics and the principal investigator for the Undiagnosed Disease Network at Duke University.

Like Smith, Shashi and the Undiagnosed Diseases Network only see children who have been thoroughly evaluated and recommended by a pediatrician or geneticist.

“Patients (adults and children) from all over the country apply,” Shashi says. “We’ve come to recognize that we can’t help some patients with a diagnosis, so we review very carefully the workup by a patient’s physician or geneticist, and we look for signs of an undiagnosed disorder that we can help resolve.”

The Duke University location ends up taking about half of the patients who apply and, like Smith’s office, the Undiagnosed Diseases Network lab has a diagnosis rate that is higher than average — around 35 percent.

Shashi says working with the Undiagnosed Disease Network gives her access to researchers there and at research cores across the country. In addition, modern technology facilitates the comparison of DNA modification cases so that physicians and researchers around the world can determine if they can work together to diagnose previously unknown diseases.

One of Shashi’s favorite resources is GeneMatcher, a freely accessible online database of genes and associated disease characteristics. “It’s the ‘match.com’ for genes,” she says. “It allows me to compare notes on specific genes with any clinician or researcher in the world. It’s fantastic.”


The Direct-to-Consumer Option

As DNA sequencing technology becomes faster and less expensive, companies are starting to provide direct-to-consumer testing, like 23andMe, which has a strong brand name and some staying power (it won the Time Magazine “Product of the Year” award in 2008). 23andMe offers DNA reports on various topics, from ancestry to health to family planning, but it does not provide WGS or WES — rather, it is a “genotyping” service that looks only at specific points in the genome known to vary among individuals.

The company is very forthcoming about its products’ limitations.

“The 23andMe Health + Ancestry Service is not diagnostic, and should not be used to address concerns regarding a suspected genetic disorder,” says Stacey Detweiler, a licensed and certified genetics counselor for 23andMe. “It is important for families with an ill child to work with their health care providers, such as a geneticist or a genetic counselor, to determine appropriate testing options.”

The 23andMe services are designed for people who are curious about their ancestry, or who want to know whether they have genetic traits that could lead to a greater risk of developing certain diseases in the future. Currently, 23andMe tests for 10 diseases, including late-onset Alzheimer’s and Parkinson’s. Detweiler says the company’s DNA test could also be helpful for family planning purposes.

“Individuals planning for a pregnancy can benefit from knowing and sharing their carrier status with their health care providers,” she says.

Detweiler adds that there are factors, including “family history, lifestyle and environment, as well as a number of genetic variants, that are not covered by the test that can also play a role in one’s health.” She says clients should only use the 23andMe results as supplemental information to discuss with a genetic counselor or health care provider.

LabCorp, Inc., a private company headquartered in Burlington with an office in Research Triangle Park, provides genetic testing for doctors in hospitals and private practices across the country. LabCorp also has a long-standing relationship with 23andMe. Geraldine McDowell, senior technical director for LabCorp’s Center for Molecular Biology and Pathology, calls direct-to-consumer genetic testing “a very exciting area for LabCorp and for consumers as they look for more information about their health.”

However, like Detweiler and Smith, McDowell is thinking carefully about what constitutes too much information.

“Is it good for a child or their parent to know that he is at greater risk for developing a cancer that may not affect him until well into adulthood, or which may never develop?” she asks. “Does that create an obligation to notify potential spouses or partners, or employers, or insurers? How much to know and when to know it is a big question that we’re in the early stages of grappling with.”


The Future

Despite the ethical qualms, most scientists agree that universal WGS for newborns will be standard in the near future. Other countries are already pursuing it. Smith recently gave a talk in Estonia, a country poised to implement DNA sequencing for all newborns.

The U.S. is trying to approach DNA sequencing carefully. The NIH has sponsored Genomic Sequencing for Childhood Risk and Newborn Illness (“The BabySeq Project”) to study the effect of knowing the makeup of a child’s genome on the child’s health and health care costs.

Scientists, who can’t move forward without data, tend to be more willing to sacrifice privacy issues in order to gain access to a variety of genomes. Katsanis struggles with this at Duke University.

“There is a disagreement about who owns the data — the families or the researchers,” he says. “We try to engage families and patients as collaborators, and sometimes it’s wonderful, sometimes it’s trying. We hope the families will be forthcoming, and that they’ll understand it’s the best way for all of us to move forward.”


Caitlin Wheeler is a freelance writer living in Durham.

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November 2017

Step back in time with a 19th-century costumed interpreter and watch the millstones at work grinding corn into meal. Registration encouraged online. Tickets available at the...

Cost: $5/adult, $3 ages 7-16. Free for ages 6 and younger

Where:
Historic Yates Mill County Park
4620 Lake Wheeler Rd.
Raleigh, NC
View map »


Telephone: 919-856-6675
Website »

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Celebrate the wonderful world of exotic animals and reptiles. Enjoy live specimens, presentations, raffles, vendors and much more. Purchase tickets online.  

Cost: $12 ages 13 and older, $5 ages 5-12.

Where:
N.C. State Fairgrounds, Kerr Scott Building
1025 Blue Ridge Rd.
Raleigh, NC
View map »


Website »

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Take part in a class that teaches individualized ways to foster motor development for your child. Learn about tummy time alternatives, best positions for your baby, how to help your child learn to...

Cost: $18

Where:
Open Arts
1222 Copeland Oaks Dr.
Morrisville, NC  27560
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Sponsor: Babies On The MOVE
Contact Name: Rebecca Quinones
Website »

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Join Mindful Families of Durham, a Buddhist-inspired spiritual community that supports area parents, caregivers, and their children in the practice of mindfulness and the understanding of the...

Cost: Free

Where:
Erwin Road
Durham, NC  27705
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Sponsor: Mindful Families of Durham
Contact Name: Adam, Laura, Josh, Sumi
Website »

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Take part in a class that teaches individualized ways to foster motor development for your child. Learn about carry positions, best positions for your baby, how to help your child learn to crawl,...

Cost: $18

Where:
Open Arts
1222 Copeland Oaks Dr.
Morrisville, NC  27560
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Sponsor: Babies On The MOVE
Contact Name: Rebecca Quinones
Website »

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Kicks off the holiday season with local art, music, food, and family activities at various locations in Durham’s historic downtown district. Presented by the Durham Arts Council with support...

Cost: Free and open to the public.

Where:
Downtown Durham
120 Morris St.
Durham, NC  27701
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Sponsor: Durham Arts Council
Telephone: 919-560-2719
Contact Name: Susan Tierney
Website »

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Participants develop their naturalist skills and understanding of local nature. Ages 5-8 with parent. Register online.

Cost: $8/resident, $10/nonresident

Where:
Stevens Nature Center/Hemlock Bluffs
2616 Kildaire Farm Rd.
Cary, NC
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Telephone: 919-387-5980
Website »

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Celebrate the natural world and where favorite Thanksgiving foods come from. Make a craft. All ages with adult. Register online.

Cost: $1/person

Where:
Crowder District Park
4709 Ten-Ten Rd.
Apex, NC
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Telephone: 919-662-2850
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Search the preserve for hidden holiday-themed clues and learn about native wild turkeys. Make a turkey decoration. Ages 5 and older with parent. Register online. Choose course code...

Cost: $1/person

Where:
Horseshoe Farm Nature Preserve
2900 Horse Shoe Farm Rd.
Wake Forest, NC
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Website »

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Search for salamanders, owls and more. Ages 10-13. Register online.

Cost: $12/resident, $16/nonresident

Where:
Stevens Nature Center/Hemlock Bluffs
2616 Kildaire Farm Rd.
Raleigh, NC
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Telephone: 919-387-5980
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Park West Village hosts Winter Wonderland in the District. This year’s event will take place the weekend of November 17th. Take the family to enjoy train rides, magical winter lights, live...

Cost: Free; $5 donation for sledding

Where:
Park West Village
3400 Village Market Place
Morrisville, NC  27560
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Telephone: 919-234-6710
Contact Name: Conner Dixon
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See ponies, hunters and jumpers compete in an event that benefits Duke Children's Hospital. Visit the website for hours and fees.

Cost: See website for fees

Where:
Gov. James B. Hunt Horse Complex
4601 Trinity Rd.
Raleigh, NC
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Website »

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Children ages 18 months-4 years and their parents enjoy free creative movement and music classes. The creative movement class focuses on the development of gross motor skills and...

Cost: Free

Where:
Saint Raphael Preschool
5801 Falls of Neuse Rd.
Raleigh, NC  27615
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Sponsor: St. Raphael Preschool
Telephone: 919-865-5725
Contact Name: Sarah Rapp
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Make crafts celebrating turkeys. All ages with adult. Meet at the Cardinal Shelter. Registration not required. 

Cost: Free

Where:
Crowder District Park
4709 Ten-Ten Rd.
Apex, NC
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Telephone: 919-662-2850
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Children ages 18 months-4 years and their parents enjoy free creative movement and music classes. The creative movement class focuses on the development of gross motor skills and...

Cost: Free

Where:
Saint Raphael Preschool
5801 Falls of Neuse Rd.
Raleigh, NC  27615
View map »


Sponsor: St. Raphael Preschool
Telephone: 919-865-5725
Contact Name: Sarah Rapp
Website »

More information

Kids ages 6 and younger enjoy stories. Take part in an optional arts and crafts session after storytime for $5.

Cost: Free

Where:
Read With Me Book Shop
111 E. Hargett St., $110
Raleigh, NC  27601
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Website »

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Learn what it was like to be a kid at the first Thanksgiving. Play games and make a food collage. Choose either the 10:30-noon and 2-3:30 p.m. session. Ages 7 and older. Register online.

Cost: $6/child

Where:
Historic Yates Mill County Park
4620 Lake Wheeler Rd.
Raleigh, AL
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Telephone: 919-856-6675
Website »

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Toddler Time is a special time for ages 5 and younger to bounce under the supervision of their parents, and without interference from the big kids. Purchase tickets online.

Cost: $7-$10

Where:
Sky Zone Durham
1720 Guess Rd., Ste. 90
Durham, NC  27701
View map »


Website »

More information

Children ages 18 months-4 years and their parents enjoy free creative movement and music classes. The creative movement class focuses on the development of gross motor skills and...

Cost: Free

Where:
Saint Raphael Preschool
5801 Falls of Neuse Rd.
Raleigh, NC  27615
View map »


Sponsor: St. Raphael Preschool
Telephone: 919-865-5725
Contact Name: Sarah Rapp
Website »

More information

Explore the woods and shoreline for signs of nature and collect treasures to make a craft. Take a full water bottle, snack and a bag lunch. Ages 6-11. Meet at the Cypress Shelter. Advance...

Cost: $16/child

Where:
Harris Lake County Park
2112 County Park Dr.
New Hill, NC  27562
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Sponsor: Harris Lake County Park
Telephone: 919-387-4342
Contact Name: Jackie Trickel
Website »

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Kids ages 6 and younger enjoy stories. Take part in an optional arts and crafts session after storytime for $5.

Cost: Free

Where:
Read With Me Book Shop
111 E. Hargett St., $110
Raleigh, NC  27601
View map »


Website »

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Listen for the sound of silver bells and climb aboard in your pajamas for a first-class journey on the Polar Express. Come early to meet Santa and enjoy kid-friendly activities and a traditional...

Cost: $14-$29

Where:
Meymandi Concert Hall
2 E. South St.
Raleigh, NC  27601
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Website »

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Athletes improve their flexibility, balance, joint mobility, as well as body and breath awareness. Special attention will be paid to core strength and posture and its importance in performance and...

Cost: Call for fees

Where:
Little Guru Kids Yoga and Creative Arts
215 Glenwood Avenue, Suite A
Raleigh, NC  27603
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Sponsor: Little Guru Kids Yoga
Telephone: 919-345-5873
Contact Name: Jen Bluestone
Website »

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Children ages 18 months-4 years and their parents enjoy free creative movement and music classes. The creative movement class focuses on the development of gross motor skills and...

Cost: Free

Where:
Saint Raphael Preschool
5801 Falls of Neuse Rd.
Raleigh, NC  27615
View map »


Sponsor: St. Raphael Preschool
Telephone: 919-865-5725
Contact Name: Sarah Rapp
Website »

More information

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Celebrate what you're thankful for. Play a game and make a pine cone turkey craft. All ages with adult. Drop-in program. Registration not required.

Cost: Free

Where:
Historic Yates Mill County Park
4620 Lake Wheeler Rd.
Raleigh, NC
View map »


Telephone: 919-856-6675
Website »

More information

Shop more than 20 local vendors offering amazing gifts this holiday season. Enjoy daily raffles with proceeds benefiting local animal rescue Paws in the City. Kids can enjoy crafts...

Cost: Free

Where:
Cary Crossroads
333 Crossroads Blvd
Cary, NC  27518
View map »


Website »

More information

Children ages 18 months-4 years and their parents enjoy free creative movement and music classes. The creative movement class focuses on the development of gross motor skills and...

Cost: Free

Where:
Saint Raphael Preschool
5801 Falls of Neuse Rd.
Raleigh, NC  27615
View map »


Sponsor: St. Raphael Preschool
Telephone: 919-865-5725
Contact Name: Sarah Rapp
Website »

More information

A wonderfully kid-paced hour featuring music, play and dancing with toddler stars singing on the mic at Cotton's gently amplified & participatory music show. Children delight in...

Cost: Free with admission

Where:
Pump It Up Raleigh
10700 World Trade Blvd, #112
Raleigh, NC  27617
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Sponsor: Pump it Up
Telephone: 919-828-3344
Contact Name: Owner/manager Kellie Paterson McHugh
Website »

More information

Read the story by Karma Wilson and make a Thanksgiving-themed craft. All ages. Registration not required.

Cost: Free

Where:
Historic Yates Mill County Park
4620 Lake Wheeler Rd.
Raleigh, AL
View map »


Telephone: 919-856-6675
Website »

More information

See a contemporary re-imagination of Tchaikovky's timeless music. Purchase tickets online.

Cost: $35-$55

Where:
Durham Performing Arts Center
123 Vivian St.
Durham, NC  27701
View map »


Website »

More information

See the classic holiday story brought to life onstage featuring favorite characters Santa and Mrs. Claus, Hermey the Elf, Bumble the Abominable Snow Monster, Clarice, Yukon Cornelius and...

Cost: $15 and up

Where:
Fletcher Theater
2 E. South St.
Raleigh, NC  27601
View map »


Website »

More information

See the classic holiday story brought to life onstage featuring favorite characters Santa and Mrs. Claus, Hermey the Elf, Bumble the Abominable Snow Monster, Clarice, Yukon Cornelius and...

Cost: $15 and up

Where:
Fletcher Theater
2 E. South St.
Raleigh, NC  27601
View map »


Website »

More information

See a contemporary re-imagination of Tchaikovky's timeless music. Purchase tickets online.

Cost: $35-$55

Where:
Durham Performing Arts Center
123 Vivian St.
Durham, NC  27701
View map »


Website »

More information

Catch this comedy classic on the big screen—as the symphony plays the charming and delightful score by John Williams live. Purchase tickets online.

Cost: $14-$29

Where:
Meymandi Concert Hall
2 E. South St.
Raleigh, NC  27601
View map »


Website »

More information

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Fit & Able Productions presents the Turkey Chase trail festival at Umstead Park. Take part in a 5K, 10K or 20K. After the race, enjoy fruit, brownies and other...

Cost: $25-$45

Where:
Umstead Park
8801 Glenwood Ave.
Raleigh, NC  27617
View map »


Sponsor: Fit and Able Productions
Telephone: 919-673-4689
Contact Name: Travis
Website »

More information

Celebrate what you're thankful for. Play a game and make a pine cone turkey craft. All ages with adult. Drop-in program. Registration not required.

Cost: Free

Where:
Historic Yates Mill County Park
4620 Lake Wheeler Rd.
Raleigh, NC
View map »


Telephone: 919-856-6675
Website »

More information

Toddler Time is a special time for ages 5 and younger to bounce under the supervision of their parents, and without interference from the big kids. Purchase tickets online.

Cost: $7-$10

Where:
Sky Zone Durham
1720 Guess Rd., Ste. 90
Durham, NC  27701
View map »


Website »

More information

Shop more than 20 local vendors offering amazing gifts this holiday season. Enjoy daily raffles with proceeds benefiting local animal rescue Paws in the City. Kids can enjoy crafts...

Cost: Free

Where:
Cary Crossroads
333 Crossroads Blvd
Cary, NC  27518
View map »


Website »

More information

The Raleigh Boychoir makes an appearance before its big Christmas concert.

Cost: Free

Where:
Quail Ridge Books
4209-100 Lassiter Mill Rd.
Raleigh, NC  27609
View map »


Website »

More information

Kids ages 6 and younger enjoy stories. Take part in an optional arts and crafts session after storytime for $5.

Cost: Free

Where:
Read With Me Book Shop
111 E. Hargett St., $110
Raleigh, NC  27601
View map »


Website »

More information

See the classic holiday story brought to life onstage featuring favorite characters Santa and Mrs. Claus, Hermey the Elf, Bumble the Abominable Snow Monster, Clarice, Yukon Cornelius and...

Cost: $15 and up

Where:
Fletcher Theater
2 E. South St.
Raleigh, NC  27601
View map »


Website »

More information

Take a 30-minute tour to view the main power drive and milling machinery. Tickets available inside the park's visitor center. Online registration encouraged.

Cost: $5/adult, $3 ages 7-16. Free for ages 6 and younger

Where:
Historic Yates Mill County Park
4620 Lake Wheeler Rd.
Raleigh, NC
View map »


Telephone: 919-856-6675
Website »

More information

Explore the historic nature of Leigh Farm Park with a friendly guide. Venture inside the historic farmhouse while being captivated by tales about life at Leigh Farm throughout the years.

Cost: Free

Where:
Leigh Farm Park
370 Leigh Farm Rd.
Durham, NC  27707
View map »


Sponsor: Durham Parks and Recreation
Telephone: 919-560-1116
Contact Name: Natalya Buckel
Website »

More information

See the classic holiday story brought to life onstage featuring favorite characters Santa and Mrs. Claus, Hermey the Elf, Bumble the Abominable Snow Monster, Clarice, Yukon Cornelius and...

Cost: $15 and up

Where:
Fletcher Theater
2 E. South St.
Raleigh, NC  27601
View map »


Website »

More information

Catch this comedy classic on the big screen—as the symphony plays the charming and delightful score by John Williams live. Purchase tickets online.

Cost: $14-$29

Where:
Meymandi Concert Hall
2 E. South St.
Raleigh, NC  27601
View map »


Website »

More information

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