Precision medicine early whatsapp comversations

·         Inputs can be in the form of problem statements that show and illustrate the current imprecision medicine that exists through published or unpublished common but complex case scenarios followed by our own work and imaginings to address the problem statement.

·         Can each of this writing team's members google "comparative effectiveness research, precision medicine, case experiences reasoning, decision making and after you share the review of literature here we could discuss the evolving framework for this write up? 

·         Let's first discuss precision Medicine beginning with the most popular definition?

·         https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587042/ a link to a past write up that was also a similar invited article. Again our current write up will be based primarily on what "medicine" we are currently working on especially illustrating the imprecision in current workflows and how we may overcome these utilizing available and evolving solutions to usher in the era of "precision Medicine."

·         obstacles in terms of individual patient decision making (and we need not think about fraternities, just patient problems and solutions)

·         As medicine is essentially diagnosis and treatment can we have the group's inputs on what would they consider to be "precision diagnosis" and "precision treatment?"

·         This illustrates our current imprecise medicine that is our daily bread and what we tried to highlight in Cuttack as making do with a workflow where we see an incomplete or blurred picture most of the time.

·         Vivek: Precision treatment could be reaching inside at the genomic level of the patient condition and finding a treatment that can target the genomic defect of that specific patient? A patient presenting to us recurrently with a particular disease and to prevent recurrence we may try to make a clinical prediction tool for that patient that will help us to predict future recurrence of the same disease and help early intervention for that patient. 

·         This is the current popular thought about precision Medicine but can we share why should diagnosing and treating illness with precision be limited to genomics when we are aware that it is a product of gene and environmental drivers?

·         Alright these are different ways to reach precision for a given patient but can anyone share what it would look like in terms of reaching precision toward diagnosis and treatment? In other words what image or picture comes in our mind when we think of an ideal diagnosis or treatment outcome? 

·         SC: A particular protocol to tackle various aspects of physician patient contact from first contact to reaching diagnosis using set guidelines and methods as per evidence based literature and reaching a management strategy

·         These are alright as far as an average requirement is concerned but can it make us cater to the individual patient's requirement with precision?

·         Problem with non precision current generation population based medicine is well summarized here, 

·         "Facing a rapidly growing body of medical knowledge, physicians rely on high-level aggregate-based knowledge resources, such as online knowledge bases, meta-analyses and clinical practice guidelines. However, this results, by default, in clinicians treating individual patients as if they were members of a homogeneous group." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289871/ 

·         SC: There is a lot of overlap between the terms "precision medicine" and "personalized medicine." According to the National Research Council, "personalized medicine" is an older term with a meaning similar to "precision medicine." However, there was concern that the word "personalized" could be misinterpreted to imply that treatments and preventions are being developed uniquely for each individual; in precision medicine, the focus is on identifying which approaches will be effective for which patients based on genetic, environmental, and lifestyle factors. The Council therefore preferred the term "precision medicine" to "personalized medicine." However, some people still use the two terms interchangeably.

·         Both are same. Yes Shreyas although currently the terms are used nearly interchangeably there is a lot of difference in their literal meanings. And I guess in that context I need to reframe my initial question when I asked the group's thoughts on what do we mean by "precise" diagnosis and treatment and perhaps I should ask what comes to our minds when we hear "ideal" way to diagnosis and treatment and I shall try to illustrate my own answer to this with a case (not my own)

·         Actually the answer will be anywhere but precise and perhaps the nature of Medical practice is to think diffusely with a wider net of differentials and once a large amount of data (both from the patient as well as general knowledge) is gathered we settle down into weaving a story of the where and why of the problem till we reach a stable decision point when we begin to think about what can be done about it. Again this is just system 2 thinking that would not be done in critical care emergencies when one would read whatever data is visible on the surface of the body and jump to action for example intubating a person who is gasping and collapsed with hypotension. I too am waiting to describe the other chronic case scenario which is where system 2 needs an ideal vision that can come from precision thinking and mind you often the critical ill collapsed person will recover and then you will need to deliver care for the chronic problem that made him collapse in the first place

·         Thanks for sharing this. As soon as we get into the introduction of his lecture we are shown that the medicine that is prescribed is currently not precise. What is not well highlighted to the public including scientists at large is that the process of Medicine is not often about the active principles in our medicine but more often about time and ill understood cellular events in the body that lead to healing (aka the target of precision Medicine). This point will find important mention in our paper

·         ‪+91 74095 48443: Precision medicine as per book is defined as to reaching as much as closer to a specific symptom or in better words looking for root cause of a symptom.

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·         ☆ As earlier we used to treat diseases purely based upon the symptoms but now there is much need to know about how a particular sign & symptom is arising because not only every human but every cell (out of all 50-75 trillion) are different & functioning differently and there is need to understand mechanism of symptoms.

e.g. Prescribing antipyretics just because patient have a fever will not solve our motto if we think from *precision medicine* point of view.

And definitely no doubt in this: "Precision medicine is the reinvention of human disease", as author kept title of chapter one. There is need to understand symptoms from very starting & using all our knowledge to get good results in the end. Because i am very satisfied here that every disease develops in so called *sequential process.* There is a need to understand all those steps which is responsible for occurence of a disease to effectively use available treatment in a precise manner.

·         https://www.personalizedmedicinebulletin.com/2016/02/29/capitalizing-on-collaboration-the-presidents-precision-medicine-initiative/

·         Thanks Vivek for this extensive review of the introduction to precision Medicine. Can we now begin searching for specific case reports illustrating the success or failure of precision Medicine?

·         Let's begin by searching for cases that begin with the whole patient description along with life events reflecting environmental pathways that also delves deeper into elucidating the molecular pathways in the same patient

This case report below has 2000 citations 

"A 59-year-old male patient who was originally from India but who had lived in Sweden for many years and who often returned to India had type 2 diabetes mellitus and had had multiple strokes. In November 2007, he traveled to India and on 5 December was hospitalized in Ludhiana, Punjab, with a large gluteal abscess. In December 2007, he was admitted to a hospital in New Dehli, where he was again operated on and where he developed a decubital ulcer. On 8 January 2008 he was referred to Örebro, Sweden. During his stay in New Dehli he received amoxicillin (amoxicilline)-clavulanic acid, metronidazole, amikacin, and gatifloxacin (all of them parenterally).

Clinical isolate K. pneumoniae 05-506 was derived from a urinary culture on 9 January 2008. He had no clear symptoms of urinary tract infection at that time. The amount of bacteria found in a culture of his urine was only 1,000 CFU/ml. Both ESBL-positive Escherichia coli and a carbapenem-susceptibleAcinetobacter sp. were isolated from his deep wounds. An ESBL-positive E. coli strain was also found in a culture of fluid resulting from external otitis.

On 6 March 2008, the patient was discharged to a nursing home. On 1 April a new urine sample for culture was taken, and an ESBL-producing K. pneumoniae isolate was found. The original carbapenem-resistant K. pneumoniae isolate has never been found in any other cultures of samples from the patient. As K. pneumoniae 05-506 was carbapenem resistant and positive by the MBL Etest (AB bioMerieux), it was investigated further. Moreover, fecal samples were collected from the patient during his stay at the nursing home to identify the source of 05-506; however, while 05-506 could not be recovered, an MBL-positive E. coliisolate was recovered and was designated E. coli NF-NDM-1."

·         While we are currently sharing case reports to get a hang of what we are aiming at (to begin a discussion), in the main article we shall try to only share original cases shared online by our students here. For example here 

·         Will be looking forward to it. Let's start exploring every case report from other teams shared here to find out the patient utility of the precision Medicine approach particularly in terms of how precision Medicine influenced patient outcomes. My hunch is that we will find that the molecular elucidation of disease pathways using molecular precision Medicine doesn't till now influence patient outcomes but the clinical pathway elucidation does and this is what we may try to establish through the cases shared online by our students (how many Avinash in total)? Sharing a simpler infectious disease case report that used molecular diagnostics, not to precise in terms of pathway elucidation but just take a look and discuss if it was useful in the four cases? 

Https://www.sciencedirect.com/science/article/pii/S2405579417300347 

·         Not clinical but cellular diagnostics such as culture which was also done for this child and revealed similar findings. However we need not be anti CBNAAT and just need to find out if elucidation of clinical pathways alone is efficacious enough although again one may think more data is always better to decision making

·         Well in this case the child would have been treated for TB even with just that CSF report but again as I said above, having more precise data at all clinical, cellular, molecular levels is always welcome

·         Let's look at the pathways this way:

External: life events 

Internal: cellular and molecular events 

Instead of discriminating between clinical and molecular. Aren't glucose, creatinine, albumin also molecules that we regularly depend on?

·         See this example shared by Aadipta here 

https://mobile.nytimes.com/2018/02/14/magazine/her-various-symptoms-seemed-unrelated-then-one-doctor-put-it-all-together.html?referer=http://m.facebook.com/

·         One of our past students who had been publishing with us since his 3rd year mbbs (fever uncertainty, case based experiences)is currently at the cutting edge of elucidating internal pathways to precision Medicine as he is now a professor of hemat-onc in Milwaukee, Wisconsin. Have asked him to join this writing team and he too is keen.

·         Yes Vivek some more thinking around this question: logically external life event pathways are likely to apparently influence patient related outcomes because of the very meaning of "patient related outcomes" which are distinguished from "disease related outcomes" that are often represented by "internal pathway representatives such as hba1c, cholesterol or even PFT values. 

Better elucidation of both external life event pathways and internal cellular and molecular event pathways through precision medicine approaches may help to predict something even better than the currently pedestalled "patient related outcome?"

"In the colloquial sense, “precision” also implies a high degree of certainty of an outcome, as in “precision-guided missile” or “at what precise time will you arrive?” So will precision medicine usher in an age of diagnostic and prognostic certainty?

In fact, the opposite will probably result. The new tools for tailoring treatment will demand a greater tolerance of uncertainty and greater facility for calculating and interpreting probabilities than we have been used to as physicians and patients."

http://www.nejm.org/doi/full/10.1056/NEJMp1608282 

·         https://consciousnotebooksequel.blogspot.in/2015/12/the-story-of-glomerular-injury.html?m=1 

The story above elucidates how external life events can be correlated to internal disease pathways

·         Thanks Anamika we are also considering the link between external macro world pathways (life events) and internal metabolic pathways and trying to find case studies to illustrate them. So due to your inputs we need to also find case studies that elucidate wellness pathways (such as the story of a person who leads a normal healthy existence for most period of his her life...is there any such person or is it very common? If so what is the life path for such people?). For beginning to illustrate abnormal macro pathways and their links to internal molecular pathways we had shared an illustrative scenario just before you joined us and will share the link again here https://consciousnotebooksequel.blogspot.in/2015/12/the-story-of-glomerular-injury.html?m=1

·         Yes so from a macro multicellular organism perspective, when we talk about such "atypical serine/threonine kinase" proteins governing the lives of these single cells as their regulators or perhaps decision makers as to which path to choose when confronted with decision nodes such as challenges in the external cellular mileu, we automatically need to study those "diverse nutritional and environmental cues, including growth factors, energy levels, cellular stress, and amino acids" that make up the immediate external mileu around each of the more than trillion cells we harbor?

·         What I am driving at is that currently precision Medicine is happy to dig out one small factor (protein or nucleic acid) and immediately try to link it with an environmental factor that may have some marketable role in influencing it artificially. Perhaps precision Medicine needs more pathway elucidation to the point of linking macro world pathways with microworld pathways before we can see if artificial chemicals can influence these pathways?

·         From a multicellular macro perspective I would love to see this article as the story of another actor that creates conflict and tries to disrupt one pathway (hitherto discovered by a species of multicellular organisms aka humans) and I am sure the article could be made to represent an action thriller.

·         Let's write this article to define the right path (between single atoms, simple molecules, complex quaternary molecules aka proteins and the cells they constitute and the multicellular universe constituted by those cells? Perhaps not just one path but describe in detail it's myriad branchings so that the world is able to appreciate the entire tree?

·         And let's utilize original data gathered by us to write it?

·         Vivek podder: I missed reading this article before and they nicely mixed external and molecular events. In our paper, when we will utilize the original data, whereever we have external pathyways aka life events, but if we don't have known precise molecular pathways of a patient, shall we then present the known generalized mechanisms as examplified in the link?

·         Yes that as well as even just demonstrate how not knowing the exact pathways (other than from similar past published data) still creates a picture of an external patient pathway that seems complete (especially with follow up data)? Can we dig into the similarities and dissimilarities between the macro clinical approach to understanding multicellular organism pathways and micro molecular approach toward elucidating micro cellular and genomic pathways?

·         But let's continue reviewing the literature. Till date Vivek you have shared a few links but not discussed any of them in detail. Let's discuss one borrowed case study review in the context of precision Medicine and one original case study documented online by our elective students

·         Let me again share that 2009 case report paper that was cited 2000 times

External pathway elucidation :

"A 59-year-old male patient who was originally from India but who had lived in Sweden for many years and who often returned to India had type 2 diabetes mellitus and had had multiple strokes. In November 2007, he traveled to India and on 5 December was hospitalized in Ludhiana, Punjab, with a large gluteal abscess. In December 2007, he was admitted to a hospital in New Dehli, where he was again operated on and where he developed a decubital ulcer. On 8 January 2008 he was referred to Örebro, Sweden. During his stay in New Dehli he received amoxicillin (amoxicilline)-clavulanic acid, metronidazole, amikacin, and gatifloxacin (all of them parenterally).

Internal pathway elucidation:

Clinical isolate K. pneumoniae 05-506 was derived from a urinary culture on 9 January 2008. He had no clear symptoms of urinary tract infection at that time. The amount of bacteria found in a culture of his urine was only 1,000 CFU/ml. Both ESBL-positive Escherichia coli and a carbapenem-susceptibleAcinetobacter sp. were isolated from his deep wounds. An ESBL-positive E. coli strain was also found in a culture of fluid resulting from external otitis.

On 6 March 2008, the patient was discharged to a nursing home. On 1 April a new urine sample for culture was taken, and an ESBL-producing K. pneumoniae isolate was found. The original carbapenem-resistant K. pneumoniae isolate has never been found in any other cultures of samples from the patient. As K. pneumoniae 05-506 was carbapenem resistant and positive by the MBL Etest (AB bioMerieux), it was investigated further. Moreover, fecal samples were collected from the patient during his stay at the nursing home to identify the source of 05-506; however, while 05-506 could not be recovered, an MBL-positive E. coliisolate was recovered and was designated E. coli NF-NDM-1."

·         Vivek meanwhile would you like to share the two ovarian tumor case studies with dramatic external pathways and see if we can elucidate a connection between their external and internal?

·         An interesting case presented to us two months ago in the month of August with Shortness of breath, abdominal distension. A CT scan showed mass in the ovary. An laparotomy was done to perform Total Abdominal Hysterectomy with Bilateral Salpingo-oophorectomy. The patient developed hypotension on the table and the surgeons were forced to stop the surgery after excision of the mass. The mass measured 6,600 grams and the specimen was sent to histopathological examination. The report came out to be clear cell carcinoma of the ovary. https://saratuppaluri.blogspot.in/2017/10/case-of-ovarian-mass-with-chronic.html?m=1 

http://bmjcaselogvivek.blogspot.in/2017/11/55f-with-post-op-hypotension-following.html 

·         Share the PPT presentation as it contains the sequence of external pathways well delineated there

·         This is the picture of the pathways that affect a human being that every doctor believing in precision Medicine strives to achieve 

https://qph.ec.quoracdn.net/main-qimg-1b1bd275db02d8432557047b33c97335

The image was shared by Mark Roseman in response to this question 

https://www.quora.com/Is-a-doctor-more-intelligent-than-an-engineer 

·         Vivek above is the presented version of the external and internal pathway data of the first patient.

·         Vivek can you share a completely deidentified version of the bronchial adenocarcinoma patient who had been planned for precision Medicine treatment based on precision bio markers from Tata memorial center?

·         http://bmjcaselogvivek.blogspot.com/2018/03/62-years-old-man-with-non-small-cell.html 

·         Yes "traditionally, whole-brain radiation therapy (WBRT) has been the standard treatment for brain metastases with multiple intracranial lesions although studies have shown no overall survival benefit and no improvement in quality of life.

It's one of the reasons why oncologists currently have shifted to what are termed as precision Medicine approaches and one sees case reports where "small-molecule inhibitor of EGFR-TKI is used in lung adenocarcinoma with brain metastases showing EGFR mutation-positive with reasonable quality of life outcomes. This is perhaps what has also been planned for our patient in Tata memorial. Shreyas do you have his current update?

·         Sir how would you like to illustrate our original cases? Any set of basic questions that we will try to answerwith every illustration?

·         What are the external life event pathways elucidated for that case? What are the internal macro-micro-molecular event pathways elucidated (or planned as in your current bronchogenic carcinoma) for that case? What is the precise diagnosis and therapy that can be arrived at given whatever data we have on hand?

·         Some food for thought on the introduction to our write up 

"Today, the three classical biological explanations of the individual self––the immune system, the brain, the genome––are being challenged by the new field of microbiome research. Evidence shows that our resident microbes orchestrate the adaptive immune system, influence the brain, and contribute more gene functions than our own genome. The realization that humans are not individual, discrete entities but rather the outcome of ever-changing interactions with microorganisms has consequences beyond the biological disciplines. In particular, it calls into question the assumption that distinctive human traits set us apart from all other animals––and therefore also the traditional disciplinary divisions between the arts and the sciences."

http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2005358 

·         Thanks Vivek let's rewrite the abstract in the imrad format and let's all begin sharing our case based experiences to weave together the write up using a case-study design. More here to enable you to write the methods section. Please share your first draft using your experiences of macro life events that you have encountered in diverse patients ranging from infective, immune mediated and neoplastic some of which already discussed using others published experiences above. Currently we need to weave this thread using our own unpublished similar experiences. The diversity of the experiences shared by this group here may help to weave a perfect cover

More here to enable you to write the methods section 

https://explorable.com/case-study-research-design

·         Very interesting Anamika so we did talk about external and internal pathways to disease here before as exemplified by the tree image contributed by Dr Modali and you suggest that external macro life pathways may have an influence on internal micro genomic life events. While we shall be sharing a case study of two patients recorded by our students (online record shared earlier), one of them is still currently admitted it would be great if you could share similar case based experiences from your end

·         So while we elucidate molecular internal micro pathway data from normal humans can we discuss what are the macro external event pathways in normal humans that help to classify their lived lives as normal?

Sharing two patients with internal cancer where their external lives also appear to be abnormally lived here 

http://bmjcaselogvivek.blogspot.com/2018/02/51-year-old-women-with-psychosis.html

https://saratuppaluri.blogspot.in/2017/10/case-of-ovarian-mass-with-chronic.html?m=1

·         Thanks Vivek for collating some of the previous discussion here in the form of a draft. Please share it also with Amy so that she can begin editing it as we move forward in terms of collecting original primary data in the form of case based experiences shared already by yourself and Kaushik. Avinash and Madhava please share your case based experiences too that can be woven together to cover all organ systems toward a grand unifying theory. 🙂

·         Yes let's see the critical mass of different cases building up here to finally weave our grand unifying theory (a qualitative meta analysis) toward our aim of demonstrating how we may leapfrog solutions to current precision Medicine internal pathway roadblocks using external pathway indicators

·         Yes this is a very interesting dilemma that we have to deal with. When we adopt a precision approach we are trying to focus on to the internal disease pathways with razor sharp precision that can often make us ignore the external life events, a patient's journey, pre and post morbidity may otherwise help to illustrate. So in a way it appears to be a choice between the forest and the trees? The question is how do we reconcile both effortlessly in to our workflow? 🙂

·         While the above paper was based on how we are doing it at the warm bedside this paper will be not only about how to go about it with a deeper understanding of the cold bench but also how to use our insights from macro events to guide understanding of micro molecular events (aka targets in the language fostered by the bench)