First time DNA sequencing saved a patient’s life.

Rsearchers and clinicians are now exploring new tools, such as whole-genome sequencing and RNA analysis, developing better techniques to analyze sequence data, and finding ways to get patients with the same diseases connected faster. This effort is making rare disease diagnosis likely to experience another revolution in the next decade.

Exome explosion

About 15 years ago, Kliegman and his colleagues started noticing a huge unmet need at Children’s Hospital of Wisconsin. Families would end up there after years of searching for a diagnosis, and there was no system in place to settle their cases. Then chair of the pediatrics department at the Medical College of Wisconsin (MCW), Children’s Hospital’s academic partner, Kliegman began bringing together specialists to discuss undiagnosed cases in detail. But the team wasn’t galvanized until it came up against the case of Nic Volker, a young boy with severe inflammatory bowel disease. By the time Volker turned four, his intestines were dotted with holes, he’d had a colostomy, and he mainly ate through a feeding tube. The hospital’s gastrointestinal specialist couldn’t make sense of the disease, leaving Volker’s doctors with no options beyond treating his symptoms.

In 2009, at the request of Volker’s pediatrician, a team at MCW sequenced the boy’s exome. The $75,000 bill was covered by funds raised by Howard Jacob, the founding director of MCW’s genetics center, who hadn’t expected to implement exome sequencing there for at least another five years. Analysis of Volker’s genetic data picked up more than 16,000 gene variants, and four months of sifting through those variants revealed that a mutation in X-linked inhibitor of apoptosis protein (XIAP), a gene on the long arm of the X chromosome, was the likely culprit behind his illness.¹ XIAP mutations were already associated with X-linked lymphoproliferative disease, an immunodeficiency disorder that leaves boys unable to fight off Epstein-Barr virus. Because the gene only affects immune cells, a cord blood transplant to replace Volker’s immune cell progenitors was enough to essentially cure him, says Kliegman. The case became nationally renowned as the first time DNA sequencing saved a patient’s life.

That was one of those
eureka moments.

—Robert Kliegman
Children's Hospital of Wisconsin

In a paper describing the research, the Wisconsin team noted that a thorough study of the available medical literature turned up a list of more than 2,000 gene variants that could have been responsible for Volker’s condition on the basis of his symptoms alone, and XIAP wasn’t on it. The boy’s case “was profound for all of the people in the hospital,” says Kliegman. “That was one of those eureka moments.” The experience led to a shift in the mindset of the hospital’s board, and now genetic sequencing is a cornerstone of the center’s diagnostic approach. By 2014, the MCW’s Human and Molecular Genetics Center (now the Genomic Sciences and Precision Medicine Center) was sequencing more than 700 patients per year.

The primary work of a doctor is to treat pain and relieve suffering.

The primary work of a doctor is to treat pain and relieve suffering. We often speak of these two entities as if they were the same thing. Eric Cassell, a physician who writes frequently about the moral dimensions of medicine, argues, in a now classic paper, that pain and suffering are very different. Pain, according to Cassell, is an affliction of the body. Suffering is an affliction of the self. Suffering, writes Cassell, is a specific state of distress that occurs when the intactness or integrity of the person is threatened or disrupted. Thus, there are events in a life that can cause tremendous pain, and yet cause no suffering. Childbirth is perhaps the most obvious. Women often experience pain in labor but are rarely said to be suffering. And those who are suffering may have no pain at all. A diagnosis of terminal cancer, even in the absence of pain, may cause terrible suffering. The fears of death and uncontrollable loss of autonomy and self combined with the fear of a pain that is overwhelming can cause suffering well before the symptoms begin. There are no drugs to treat suffering. But, says Cassell, giving meaning to an illness through the creation of a story is one way in which physicians can relieve suffering.

What is Diagnostic error?

\
This question may look simple to answer but there are many pitfalls in reaching this conclusion
Research into diagnostic error, like research into the diagnosis process itself, is still a very new field. There is even difficulty in deciding what constitutes a diagnostic error. What a thoughtful patient may consider an error is not necessarily the same as that which his equally thoughtful doctor might consider an error.

For example, when a patient comes to my office with a sore throat and a fever, I might check for strep, and if it’s not present I’ll probably send him out with a diagnosis
of a viral illness. But I share with all such patients what I expect to happen over the next few days—that they should start to feel better within a day or two. And if not, I tell them to call me and let me know. Because, while the odds are overwhelming that this is simply a viral syndrome, it’s not 100 percent certain. I might be wrong. The test might be wrong. It might be mono. It might be some other kind of bacterial tonsillitis. It might be cancer. I can’t just check under the hood and see if the spark plugs need to be replaced—the way a mechanic diagnoses the funny noise your car is making. Instead, I have to listen to the engine and, based on the indirect evidence I can collect, make a thoughtful and well-informed guess as to what is probably going on. If I send that patient home with a diagnosis of a viral syndrome and he doesn’t get better and has to come back, would that be a diagnostic error? I suspect the patient would think so. And certainly it wasn’t a correct diagnosis. But did I make an error? Should I have done something different? I could have been more certain. I could have sent my patient to an Ear, Nose, and Throat specialist who could have looked down his throat with a special scope. I could have even asked for a biopsy of the red and swollen tissue to confirm my diagnosis. That would be time-consuming and painful for the patient and ridiculously expensive. But even then, the diagnosis would not have been 100 percent certain. In medicine, uncertainty is the water we swim in. The chance of being wrong is overwhelming when dealing with something more complicated than a sore throat. Doctors—far more than the patients they care for—recognize that some error is inevitable.

diagnostic errors—like this one nearly was—are often due to a multitude of missteps made along the way.
excerpt from

Every Patient Tells a Story, Medical Mysteries and the Art of Diagnosis – Lisa Sanders

Decreasing number of Autopsies

Decreasing number of Autopsies
Religious stupidity ,greed of Insurance companies and Spineless academicians of the present day.

Who pays for the Autopsy?

If it is part of a police investigation the DA or PD pick up the tab; if the insurance company requests it they pick up the tab; If the family wants one done, they pay for it. If someone died for an unknown reason in a hospital, the hospital eats the cost.


AUTOPSY — literally to see for oneself — is the
dissection and examination of a dead body to
determine the cause of death and establish the
evolution of a disease. It was coined in 1678, while
its Synonym •post-mortem examination' (or post,
mortem for short) was first used in 1850 and
'necropsy' in 1856. Although the term 'post-
mortem examination' is appropriate etymologi-
call", autopsy is more commonly used. Autopsy
forms the cornerstone of PATHOLOGY and has
made an important contribution to our current
understanding of disease. It has the ability to
recognize the mistakes made by doctors and
thereby improve their diagnostic skills. At first
limited to gross and microscopic anatomy, it may
now also make use of specialized techniques such
as microbiology, electron microscopy, radiology,
toxicology, and chromatography.


In 1410 Pope Alexander V died suddenly and
was autopsied. Towards the end of the 15th
century, Pope Sixtus permitted students to dissect
human bodies to learn anatomy. One of the ear-
liest autopsies recorded, performed by Bernard
Tornius in the 15th century, is that of a child.
Antonio Benivienni, a 15th century Florentine
physician, correlated his findings with clinical
features in 15 cases. The idea that bodies could
display clues to diseases that ravaged them began
around the 16th century. The impetus given by
Andreas VESALIUS (p 846) in 1543 to normal
human anatomy dissection led to a change.
Theophile Bonet published his Sepulchretum Sive
anatomia practica in 1679; it comprised 3000
autopsies but subscribed to the theory of HUMORS
and thus missed the opportunity to recognize the
anatomic-pathologic correlation. In 1724 Hermann
ROERHAAVE (p 121) documented the first case of


At the birth of medicine, millennia ago, diagnosis (the identification of the patient’sdisease) and prognosis (the understanding of the disease’s likely course and outcome) were the most effective tools a doctor brought to the patient’s bedside. But beyond that, little could be done to either confirm a diagnosis or alter the course of the disease. Because of this impotence in the face of illness, the consequences of an incorrect diagnosis were minimal. The true cause of the illness was often buried with the patient. In more recent history, medicine has developed technologies that have transformed our ability to identify and then treat disease. The physical exam—invented primarily in the nineteenth century—was the starting point. The indirect evidence provided by touching, listening to, and seeing the body hinted at the disease hidden under the skin. Then the X-ray, developed at the start of the twentieth century, gave doctors the power to see what they had previously only imagined. That first look through the skin, into the inner structures of the living body, laid the groundwork for the computerized axial tomography (CT) scan in the 1970s and magnetic resonance imaging (MRI) in the 1990s. Blood tests have exploded in number and accuracy, providing doctors with tools to help make a definitive diagnosis in an entire alphabet of diseases
starting point. The indirect evidence provided by touching, listening to, and seeing the body hinted at the disease hidden under the skin. Then the X-ray, developed at the start of the twentieth century, gave doctors the power to see what they had previously only imagined. That first look through the skin, into the inner structures of the living body, laid the groundwork for the computerized axial tomography (CT) scan in the 1970s and magnetic resonance imaging (MRI) in the 1990s. Blood tests have exploded in number and accuracy, providing doctors with tools to help make a definitive diagnosis in an entire alphabet of diseases

It is very important forPatients to call the clinic and find out about the results.The ball can be dropped !

The recent Netflix series about "Diagnosis from New York times"  showing various rare disorders is really interesting.

it is just a coincidence that I was reading  the preview of her book

Every Patient Tells a Story: Medical Mysteries and the Art of Diagnosis

By Lisa Sanders

I was right away able to guess the description of a patient with intractable vomiting as chronic cannabis use syndrome. I did have one such patient who used to go to the ER almost every week for IV fluids.

I still do not know the mechanism by which standing in a hot showerhelps the nausea and vomiting . is it sensory oveload? interference with emesis pathways and heatsensing pathways ?

Here are some comments I have about this Netflix series.

The girl with the CPT 2 disease in the first few minutes I thought she had McArdle syndrome. I was surprised that none of her local doctors sent her to have a muscle biopsy.

Is it possible that only part of the history is given.

Anyway even without diagnosis if she were to follow the same diet for McArdle's and avoid excessive physical activity which she seems to be doing and enjoying and suffering from it even if she did not have a gene sequencing and the label of CPT 2 disease she could have some symptomatic relief.

Diet considerations/ treatment CPT 2 disease

• Low-fat diet with limited long-chain triglycerides for neonatal and infantile form

• MCT oil

• Portagen/Monogen

• High MCT formula

o Need essential FA (safflower, walnut,canola)

• Carnitine

• Consider cornstarch (> 1 y) if symptomatic

• Avoid fasting

• If severe, continuous feeds at night

 As for the goof up by NIH in the case of the child suffering from paroxysmal dyskinesia

All I can say is in medicine no news is no news is neither good news are bad news.

How many times did the mother of the child suffering from paroxysmal dyskinesia contact NIH in those two years?

I always tell my patients that it is very important for them to call the clinic and find out about the results because the ball can be dropped by anyone. No one is more interested in their own results than the patient.

How can video compression algorithms help genome sequencing

How can we learn from video compression algorithms to help us make use of this information to improve gene detection algorithms of the genome sequencing information.

A video compression algorithm detect the difference between one for frame to another similarly we can detect the difference between one gene sequence to another using the similar techniques.

(PDF) A Systematic Review on Real Time Video Compression

Video compression algorithms look for spatial and temporal redundancies

Compared to this gene sequencing needs only spatial redundancy detection.

Much more dedicated hardware is available for video compression than available for gene sequencing.

By adopting the same kind of algorithms bioinformatic researchers can improve their ability to detect mutations in genes.

 

IGSR: The International Genome Sample Resourcehttps://www.internationalgenome.org/wiki/Analysis/vcf4.0/

 

VCF (Variant Call Format) version 4.0

 

 

The first first four Gifts almost everyone gets

 Within moments of being born, most babies find themselves receiving the first four gifts of
life
Eye contact
A smile
A hug
Some food.

We receive many other gifts in a lifetime, but few can ever surpass those first four. That first time may be the purest"hospitality transaction" we'll ever have, and it's not much of a surprise that we'll
crave those gifts for the rest of our lives. I know I do.

From

Setting the Table: The Transforming Power of Hospitality in Business.

By Danny Meyer