Slides: Manuscript Writing Workshop 10-2-14

Part I: Principles of Effective
Writing
Kristin Sainani, PhD
Stanford University
October 2, 2014

A few examples to start…
n This was the first sentence of an article in the Journal
of Clinical Oncology (Introduction section):
n “Adoptive cell transfer (ACT) immunotherapy is based
on the ex vivo selection of tumor-reactive
lymphocytes, and their activation and numerical
expression before reinfusion to the autologous tumor-bearing
host.”
n Ask Yourself:
n Is this sentence easy to understand?
n Is this sentence enjoyable and interesting to read?

And here’s the final sentence
from the same article…
n “Current studies in our laboratory are focused on
the logistical aspects of generating autologous-cell
based patient treatments, the genetic
modification of lymphocytes with T-cell receptor
genes and cytokine genes to change their
specificity or improve their persistence, and the
administration of antigen specific vaccines to
augment the function of transferred cells.”
n This is classic academic writing: boring,
unreadable, written to obscure rather than to
inform!

A classic hallmark of academic writing:
spunky verbs become clunky nouns…
n “Adoptive cell transfer (ACT) immunotherapy is based on
the ex vivo selection of tumor-reactive lymphocytes,
and their activation and numerical expression before
reinfusion to the autologous tumor-bearing host.”
n “Current studies in our laboratory are focused on the
logistical aspects of generating autologous-cell based
patient treatments, the genetic modification of
lymphocytes with T-cell receptor genes and cytokine
genes to change their specificity or improve their
persistence, and the administration of antigen specific
vaccines to augment the function of transferred cells.”

“My professor friend told me that in his
academic world, ‘publish or perish’ is really
true. He doesn’t care if nobody reads it or
understands it as long as it’s published.”
There’s a hint of truth here, n’est-ce pas?
From: Anne Ku. “The joys and pains of writing and editing,” Le Bon Journal, 2003
http://www.bonjournal.com/volume2/issue1writing.pdf

Another example…
Dysregulation of physiologic microRNA
(miR) activity has been shown to play an
important role in tumor initiation and
progression, including gliomagenesis.
Therefore, molecular species that can
regulate miR activity on their target RNAs
without affecting the expression of relevant
mature miRs may play equally relevant
roles in cancer.
From an article in Cell

Note the use of nouns
instead of verbs.
Example
roles in cancer.

Note the use of vague
words.
Example
roles in cancer.

Note the use of
unnecessary jargon and
acronyms.
Example
roles in cancer.

Note the passive voice.
Example
roles in cancer.

Note the distance between
the subject and the main
verb of this sentence.
Example
roles in cancer.

Possible rewrite…
n Changes in microRNA expression play a
role in cancer, including glioma.
Therefore, events that disrupt
microRNAs from binding to their target
RNAs may also promote cancer.

Principles of effective writing
n “Vigorous writing is concise. A sentence should
contain no unnecessary words, a paragraph no
unnecessary sentences, for the same reason
that a drawing should have no unnecessary lines
and a machine no unnecessary parts. This
requires not that the writer make all his
sentences short, or that he avoid all detail and
treat his subjects only in outline, but that every
word tell.”
-- Strunk and White, The Elements of Style

“The secret of good writing is to strip every
sentence to its cleanest components. Every word
that serves no function, every long word that
could be a short word, every adverb that carries
the same meaning that’s already in the verb,
every passive construction that leaves the reader
unsure of who is doing what—these are the
thousand and one adulterants that weaken the
strength of a sentence. And they usually occur in
proportion to the education and rank.”
-- William Zinsser in On Writing Well, 1976

Three lessons:
• 1. Cut unnecessary words and phrases; learn to
part with your words!
• 2. Follow: subject + verb + object (active voice)
• 3. Write with verbs: use strong verbs, avoid
turning verbs into nouns, and don’t bury the
main verb!

Don’t be afraid to cut!
• 1. Cut unnecessary words and phrases

Cut unnecessary words
Example:
s
“This paper provides a review of the basic tenets of cancer
biology study design, using as examples studies that illustrate
the methodologic challenges or that demonstrate successful
solutions to the difficulties inherent in biological research.”
and
“This paper reviews cancer biology study design, using
examples that illustrate specific challenges and solutions.”

Example:
is associated with
“As it is well known, increased athletic activity has been related to a
profile of lower cardiovascular risk, lower blood pressure levels, and
improved muscular and cardio-respiratory performance.”
à
I
fitness.
“Increased athletic activity is associated with lower cardiovascular risk,
lower blood pressure, and improved fitness.”
“Increased athletic activity lowers cardiovascular risk and blood pressure,
and improves fitness.” (stronger level of evidence)

Hunt down and cast out all unneeded
words that might slow your reader.
n Dead weight words and phrases (“as it is well known”, “as it
has been shown”, “it can be regarded that”)
n Empty words and phrases (“basic tenets of”, “methodologic”)
n Long words or phrases that could be short (“muscular and
cardiorespiratory performance”)
n Unnecessary jargon (“muscular and cardiorespiratory
performance”)
n Repetitive words or phrases (illustrate/demonstrate;
challenges/difficulties)
n Adverbs (very, really, quite, basically, generally)

Long words and phrases that
could be short…
Wordy version Crisp version
n A majority of most
n A number of many
n Are of the same opinion agree
n Less frequently occurring rare
n All three of the the three
n Give rise to cause
n Due to the fact that because
n Have an effect on affect

n Be vigilant and ruthless
n After investing much effort to put words on a
page, we often find it hard to part with them.
But fight their seductive pull…
n Try the sentence without the extra words and
see how it’s better—conveys the same idea with
more power

Cutting extra words
Example:
“Brain injury incidence shows two peak
periods in almost all reports: rates are
the highest in young people and the
elderly.”
More punchà
“Brain injury incidence peaks in the young
and the elderly.”

Blaise Pascal on the elegance in
brevity:
“I have only made this letter rather long
because I have not had time to make it
shorter.” (“Je n'ai fait celle-ci plus
longue que parceque je n'ai pas eu le
loisir de la faire plus courte.”)
--Lettres provinciales, 16, Dec.14,1656
(though reference also attributed to St. Augustine, and
Cicero….)

Practice: cut the clutter!
Anti-inflammatory drugs may be protective for
the occurrence of Alzheimer’s Disease.

Possible rewrite
Anti-inflammatory drugs may protect against
Alzheimer’s Disease.

Practice
Clinical seizures have been estimated to
occur in 0.5% to 2.3% of the neonatal
population.

Possible rewrite
Clinical seizures occur in 0.5% to 2.3%
of newborns.

Practice
To control infection with Mycobacterium
tuberculosis (M. tb), a robust T cell-mediated
immune response is necessary,
and deficiency in this response predisposes
an individual towards active TB.

Possible rewrite
A deficient T-cell response predisposes an
individual to active TB.

Use active voice
• 2. Follow: subject + verb + object
(active voice!)

Use active voice
“Subject verb object”
or just…
“Subject verb”

Use active voice
The passive voice….
n Object-Verb-Subject or just Object-Verb
n Classic example: “Mistakes were made.”
n Passive verb = a form of the verb “to be” +
the past participle of the main verb
n The main verb must be a transitive verb
(that is, take an object).

Use active voice
Examples…
Object
Passive:
My first visit to Boston will always be
remembered by me.
Verb Subject
Active:
I will always remember my first visit to Boston.
From: Strunk and White

Use active voice
"Cigarette ads were designed to appeal especially to
children."
vs.
"We designed the cigarette ads to appeal especially to
children.”
Responsible party!

Use active voice
Passive:
General dysfunction of the immune system has
been suggested at the leukocyte level in both animal
and human studies.
à
Active:
Both human and animal studies suggest that
diabetics have general immune dysfunction at the
leukocyte level.

Use active voice
Passive:
Increased promoter occupancy and transcriptional
activation of p21 and other target genes were
observed.
à
Active:
We observed increased promoter occupancy and
transcriptional activation of p21 and other target
genes.

Practice: use the active voice
A recommendation was made by the
DSMB committee that the study be halted.

In the active voice…
The DSMB committee recommended that
the study be halted.

Major differences in the reaction times of
the two study subjects were found.

We found major differences in the reaction
times of the two study subjects.

The activation of Ca++ channels is
induced by the depletion of endoplasmic
reticulum Ca++ stores.

Depleting Ca++ from the endoplasmic
reticulum activates Ca++ channels.

Use strong verbs
3. Write with verbs:
• use strong verbs
• avoid turning verbs into nouns
• don’t bury the main verb

Use strong verbs
Verbs make sentences go!
Compare:
“Loud music came from speakers embedded in
the walls, and the entire arena moved as the
hungry crowd got to its feet.”
With:
“Loud music exploded from speakers
embedded in the walls, and the entire arena
shook as the hungry crowd leaped to its feet.”
Latter sentence from the novel: Bringing Down the House, Ben Mezrich

Use strong verbs
Verbs make sentences go!
Compare:
“Loud music came from speakers embedded in
the walls, and the entire arena moved as the
hungry crowd got to its feet.”
With:
“Loud music exploded from speakers
embedded in the walls, and the entire arena
shook as the hungry crowd leaped to its
feet.”
Latter sentence from the novel: Bringing Down the House, Ben Mezrich

Don’t turn verbs into nouns
Don’t kill verbs by turning them into
nouns.

Example:
During DNA damage, recognition of H3K4me3
by ING2 results in recruitment of Sin3/HDAC
and repression of cell proliferation genes.

Example:
During DNA damage, recognition of H3K4me3 by
ING2 results in recruitment of Sin3/HDAC and
repression of cell proliferation genes.
à
During DNA damage, H3K4me3 recruits ING2 and
Sin3/HDAC, which together repress cell proliferation
genes.
S ay exactly who does what to whom!

Weak verbs
Obtain estimates of
Has seen an expansion in
Provides a methodologic emphasis
Take an assessment of
Formerly
spunky verbs
transformed
into boring
nouns
estimate
has expanded
emphasizes methodology
assess

Provide a review of
Offer confirmation of
Make a decision
Shows a peak
review
confirm
decide
peaks

Don’t bury the main verb
Keep the subject and main verb
(predicate) close together at the start of
the sentence…
n Readers are waiting for the verb!

The case of the buried predicate…
One study of 930 adults with multiple
sclerosis (MS) receiving care in one of two
managed care settings or in a fee-for-service
setting found that only two-thirds of those
needing to contact a neurologist for an MS-related
problem in the prior 6 months had
done so (Vickrey et al 1999).
predicate
subject

The case of the buried predicate…
One study found that, of 930 adults with
multiple sclerosis (MS) who were receiving
care in one of two managed care settings or
in a fee-for-service setting, only two-thirds of
those needing to contact a neurologist for an
MS-related problem in the prior six months
had done so (Vickrey et al 1999).

Practice: write with verbs
“The fear expressed by some teachers that
students would not learn statistics well if they
were permitted to use canned computer
programs has not been realized in our
experience. A careful monitoring of achievement
levels before and after the introduction of
computers in the teaching of our course revealed
no appreciable change in students’
performances.”

Practice Exercises
Really long
subject!
were permitted to use canned computer programs
has not been realized in our experience. A
careful monitoring of achievement levels before
and after the introduction of computers in the
teaching of our course revealed no appreciable
change in students’ performances.”
Passive
voice

Practice Exercises
were permitted to use canned computer programs
has not been realized in our experience. A
careful monitoring of achievement levels before
and after the introduction of computers in the
teaching of our course revealed no appreciable
change in students’ performances.”
Buried predicate
+ boring verb
Really long
“hedge” word subject!

Possible rewrite
Many teachers feared that the use of canned
computer programs would prevent students
from learning statistics. We monitored student
achievement levels before and after the
introduction of computers in our course and
found no detriments in performance.

Take-home messages
Effective scientific writing conveys an idea clearly
and concisely.
Scientific writing should be easy and even
enjoyable to read.
Three key principles of effective writing:
• 1. Cut all unnecessary words and phrases.
• 2. Use the active voice (subject-verb-object).
• 3. Write with verbs.

Editing Exercises, in groups of
2-3

Possible Answers (1)
n H. pylori infection causes an acute increase in gastric acid
(hyperchlorhydria) followed by a decrease
(hypochlorhydria) that lasts up to eight months (1).
Hypochlorhydria increases the host’s susceptibility to
pathogens such as cholera, typhoid, and shigella (2). With
such superinfections, the host may produce copious stool
and emesis—the vehicles necessary to spread H. pylori.
This may lead to malnutrition and chronic diarrhea (3).
n Chronic H. pylori infection increases gastric pH. This
elevated pH increases the host’s susceptibility to
gastrointestinal superinfection, which may propagate H.
pylori infection via diarrhea and vomiting.

Possible Answers (2)
n There is no standard approach for assessing ulnar collateral
flow prior to harvesting the radial artery. This review examines
the benefits and drawbacks of common approaches.
n We will examine the controversy surrounding methods for
assessing ulnar collateral flow prior to harvesting the radial
artery.

Possible Answer (3)
n Breast cancer is the most common non-skin
cancer in U.S women, with 267,000
new cases in 2003. Between 1975 and
2000 breast cancer prevalence increased
by 4% in women over 40 but remained
constant in those under 40. This
suggests underlying genetic causes,
given comparable screening patterns and
lifestyle-related risk factors.

Have you ever?
Got stuck on a paragraph for several
hours?
Got stuck on one sentence for more
than an hour?

There are two kinds of stuck
in writing!
n 1. Problems with the logic/ideas
n Can only be fixed by figuring out what you are
trying to say.
n Staring at the page will not help!
n Rearranging words on the page will not help!
n 2. Problems with the prose
n May be fixed by focusing on word order and word
choice.

Steps in the writing process:
1. Prewriting
2. Writing the first draft
3. Revision

What does your writing
process look like now?
Proportionally, how much time do
you think you spend on each step?
1. Prewriting
2. Writing
3. Revision

What I think it should be
(roughly!):
1. Prewriting (70%)
2. Writing the first draft (10%)
3. Revision (20%)

1. Prewriting tips
Get organized first:
n Don’t try to write and gather information
simultaneously!
n Gather and organize information BEFORE
writing the first draft.

Develop a road-map
n Arrange key facts and citations from the
literature into a crude road map/outline
BEFORE writing the first draft.
n Think in paragraphs and sections…

Brainstorm away from the
computer
n Write on the go!
n While exercising (Turn off that ipod!)
n While driving alone (Turn off the radio!)
n While waiting in line (Put down the magazine!)
n Work out take-home messages
n Organize your paper
n Write memorable lines

2. First draft tips:
n Don’t be a perfectionist!
n The goal of the first draft is to get the ideas
down in complete sentences in order.
n Focus on logical organization more than
sentence-level details.
n Writing the first draft is the hardest step for
most people. Minimize the pain by writing
the first draft quickly and efficiently!

Example of first-draft writing:
Errors in publication occur when the
authors have typos, omissions, or such
poor writing of the methods that others
cannot figure out what they did or
reproduce their tables and figures.
Sometimes there’s just so much to write
up that errors will occur in almost every
case.

Revised version:
Published papers frequently have typos,
omissions, and otherwise poor
documentation of methods. These errors
make it impossible to figure out exactly
what was done or to reproduce the results.

The finding of these HLA alleles may have some practical
implications as well. Now we all divide up into those who carry
archaic DNA and those who don’t. A potential implication is that
people who carry archaic HLAs could be more prone to
autoimmunity. Autoimmunity is associated with HLA factors. There
could be downsides to archaic HLAs. Since we’ve evolved
separately from Neanterdals for a few hundred thousand years, we
may have evolved important differences in the proteins that
interact with HLA. The archaic HLAs may interact more poorly with
some of these proteins, potentially causing mistakes, like
autoimmunity. “This is all just speculation. But we have been apart
for all this time, so it would be very surprising if there weren’t
differences,” Parham says. “It would solve a long-standing puzzle.”

Revised version:
Neanderthal (or Denisovan) proteins continue to live on and
function inside us; and this may also have a downside, Parham
notes. Neanderthals evolved separately from us for a few
hundred thousands years, so their proteins may be somewhat
mismatched to our immune systems and could play a role in
autoimmune disease. Autoimmunity is poorly understood but
known to be related to HLA types. “This is all just speculation.
But we have been apart for all this time, so it would be very
surprising if there weren’t differences,” Parham says. “It would
solve a long-standing puzzle.”

It’s also difficult to study the biology because
the brain is so inaccessible. Cancer scientists
can take out a tumor and look directly at the
cells, but autism researchers cannot directly
study brain cells (except on autopsy), let alone
developing brain cells. Stanford is on the
cutting edge of solving this problem—in fact,
Dolmetsch’s solution is so innovative it seems
straight out of a science fiction novel.

Revised version:
It’s also difficult to access the brain.
Scientists can slice cancer cells out of a
tumor and directly study them, but they can’t
just scoop cells out of the brain, let alone the
developing brain. Stanford is on the cutting
edge of solving this problem—in fact,
Dolmetsch’s solution seems straight out of a
science fiction novel.

Final version (after outside
editing!):
Another impediment: access to the brain.
Scientists can slice cancer cells out of a
tumor and study them directly, but they can't
just scoop cells out of the brain. Stanford is
on the forefront of solving this problem—in
fact, Dolmetsch's solution seems straight out
of a science fiction novel.

3. Tips on revision
• Read your work out loud
• Do a verb check
• Get rid of clutter
• Do an organizational review
• Get feedback from others
• Get editing help

Do a verb check
Underline the main verb in each sentence.
Watch out for:
(1) lackluster verbs (e.g., There are many
students who struggle with chemistry.)
(2) passive verbs (e.g., The reaction was
observed by her.)
(3) buried verbs (e.g., A careful monitoring of
achievement levels before and after the
introduction of computers in the teaching of our
course revealed no appreciable change in
students’ performances.).

Do an organizational review
In the margins of your paper, tag each
paragraph with a phrase or sentence that
sums up the main point.
Then move paragraphs around to
improve logical flow and bring similar
ideas together.

Get outside feedback
Ask someone outside your department to read
your manuscript.
Without any technical background, they should
easily grasp:
-the main findings
-take-home messages
-significance of your work
Ask them to point out particularly hard-to-read
sentences and paragraphs!

Part III: The Original
Manuscript

Recommended order for
writing an original manuscript
n 1. Tables and Figures
n 2. Results
n 3. Methods
n 4. Introduction
n 5. Discussion
n 6. Abstract

What verb tense do I use?
*Use past tense for completed actions:
We found that…
Women were more likely to…
Men smoked more cigarettes than…
The average reaction time was…
*Use the present tense for assertions that continue to
be true, such as what the tables show, what you
believe, and what the data suggest:
Figure 1 shows…
The findings confirm…
The data suggest…
We believe that this shows…

1. Tables and Figures
Tables and Figures tell the story of your
manuscript.
Figures and tables should stand alone. The
reader should not need to refer back to the
main text.
Editors, reviewers, and readers may look
first (and maybe only) at titles, abstracts,
and tables and figures!

2. Results ≠ Raw Data
n T he results section should:
n Summarize what the data show
n Point out simple relationships
n Describe big-picture trends
n Cite figures or tables that present supporting
data
n Avoid simply repeating the numbers that
are already available in tables and figures.

Results section exercise, in
groups of 2-3

Possible Answer
n Results
n Table 1 shows the characteristics of the study
subjects. The groups were similar in age and
socioeconomic status. Obese sedentary men
were heavier and larger than both lean groups;
and lean exercisers had significantly lower body
fat then lean sedentary men. Lean exercisers
had higher VO2 max (l·min-1) and better
fitness than both sedentary groups.
n

3. Methods and Materials
• Give a clear overview of what was done
• Give enough information to replicate the study
(like a recipe!)
• Be complete, but make life easy for your reader!
1. Break into smaller sections with subheadings
2. Cite a reference for commonly used methods
3. Display in a flow diagram or table where possible
• You may use jargon and the passive voice more
liberally in the methods section

Who, what, when, where,
how, and why…
Reprinted, with permission, from: Annesley TM. Who, what, when, where, how, and why: The ingredients in
the recipe for a successful methods section. Clinical Chemistry. June 2010 vol. 56 no. 6, 897-901.

4. Introduction
n Good News: The introduction is easier to
write than you may realize!
n Follows a fairly standard format
n Typically 3 paragraphs long
n Recommended range: 2 to 5
n It is not an exhaustive review of your general
topic
n should focus on the specific hypothesis/aim of
your study

Introduction
Reproduced with permission from: Annesley TM. "It was a cold and rainy night." Set the scene
with a good introduction. Clinical Chemistry. May 2010 56: 708-713. (Figure 1)

Introduction
1. What’s known
2. What’s unknown
n limitations and gaps in previous studies
3. Your burning question/hypothesis/aim
4. Your experimental approach
5. Why your experimental approach is new and different
and important (fills in the gaps)
Mimi Zeiger. Essentials of Writing Biomedical Research Papers, McGraw Hill Professional, 1999

Corresponds to roughly 3 paragraphs…
1. What’s known
≈ Paragraph 1
2. What’s unknown
n limitations and gaps in previous studies
≈ Paragraph 2
3. Your burning question
4. Your experimental approach
5. Why your experimental approach is new and different
and important (fills in the gaps)
≈ Paragraph 3

Introduction, Example
The relations between excess body weight and mortality, not only from all
causes but also from cardiovascular disease, are well established.1,2,3,4,5,6
Although we have known for some time that excess weight is also an important
factor in death from cancer,7 our knowledge of the magnitude of the relation,
both for all cancers and for cancers at individual sites, and the public health
effect of excess weight in terms of total mortality from cancer is limited. Previous
studies have consistently shown associations between adiposity and increased
risk of cancers of the endometrium, kidney, gallbladder (in women), breast (in
postmenopausal women), and colon (particularly in men).8,9,10,11,12
Adenocarcinoma of the esophagus has been linked to obesity.11,13,14 Data on
cancers of the pancreas, prostate, liver, cervix, and ovary and on hematopoietic
cancers are scarce or inconsistent.7,8,9,10,11,15,16,17 The lack of consistency may be
attributable to the limited number of studies (especially those with prospective
cohorts), the limited range and variable categorization of overweight and obesity
among studies, bias introduced by reverse causality with respect to smoking-related
cancers, and possibly real differences between the effects of overweight
and obesity on the incidence of cancer and on the rates of death from some
cancers.18,19
We conducted a prospective investigation in a large cohort of U.S. men and
women to determine the relations between body-mass index (the weight in
kilograms divided by the square of the height in meters) and the risk of death
from cancer at specific sites. This cohort has been used previously to examine
the association of body-mass index and death from any cause.5
Eugenia E. Calle, Ph.D., Carmen Rodriguez, M.D., M.P.H., Kimberly Walker-Thurmond, B.A., and Michael J. Thun, M.D. Overweight, Obesity,
and Mortality from Cancer in a Prospectively Studied Cohort of U.S. Adults. N Engl J Med 2003; 348:1625-1638.

WWhhaat’ts’ sk knnoowwnn WWhhaat’ts’ su unnkknnoowwnn
The relations between excess body weight and mortality, not only from all
causes but also from cardiovascular disease, are well established.1,2,3,4,5,6
Although we have known for some time that excess weight is also an important
factor in death from cancer,7 our knowledge of the magnitude of the relation,
both for all cancers and for cancers at individual sites, and the public health
effect of excess weight in terms of total mortality from cancer is limited. Previous
studies have consistently shown associations between adiposity and increased
risk of cancers of the endometrium, kidney, gallbladder (in women), breast (in
postmenopausal women), and colon (particularly in men).8,9,10,11,12
Adenocarcinoma of the esophagus has been linked to obesity.11,13,14 Data on
cancers of the pancreas, prostate, liver, cervix, and ovary and on hematopoietic
cancers are scarce or inconsistent.7,8,9,10,11,15,16,17 The lack of consistency may be
attributable to the limited number of studies (especially those with prospective
cohorts), the limited range and variable categorization of overweight and obesity
among studies, bias introduced by reverse causality with respect to smoking-related
cancers, and possibly real differences between the effects of overweight
and obesity on the incidence of cancer and on the rates of death from some
cancers.18,19
We conducted a prospective investigation in a large cohort of U.S. men and
women to determine the relations between body-mass index (the weight in
kilograms divided by the square of the height in meters) and the risk of death
from cancer at specific sites. This cohort has been used previously to examine
the association of body-mass index and death from any cause.5
Gaps/limitations of
previous studies
“This study will
answer the
question with
better methods.”

Introduction Example
Exogenous estrogens prevent or substantially retard the decrease in bone
mineral density (BMD) that accompanies menopause [1]. However, it is unclear
whether exogenous estrogens, administered as oral contraceptives (OCs), can
modify premenopausal BMD. Several studies suggest that exposure to OCs
during the premenopausal years has a favorable effect on BMD [2-10], whereas
other studies show no effect [11-18].
Past studies of the relationship between OC use and BMD have several
limitations. Studies have focused primarily on crude measures of OC use, such
as current, past and never. These categories combine diverse types of OC use
and may reduce the power to detect an effect. Many studies also failed to take
into account lifestyle characteristics of study participants. Finally, few studies
have considered an effect of OCs on BMD in women of races other than white.
The aim of this study was to evaluate the associations of OCs with spine, hip
and whole body BMD in black and white premenopausal women. Our primary
hypothesis was that there would be an association between cumulative exposure
to estrogen from OCs and BMD.
Osteoporos Int. 2002 Nov;13(11):893-900.

What’s
known
What’s
unknown/
the research
question
The lit.
review
Gaps in
previous
research
Exogenous estrogens prevent or substantially retard the decrease in bone
mineral density (BMD) that accompanies menopause [1]. However, it is unclear
whether exogenous estrogens, administered as oral contraceptives (OCs), can
modify premenopausal BMD. Several studies suggest that exposure to OCs
during the premenopausal years has a favorable effect on BMD [2-10], whereas
other studies show no effect [11-18].
Past studies of the relationship between OC use and BMD have several
limitations. Studies have focused primarily on crude measures of OC use, such
as current, past This and never. study
These categories combine diverse types of OC use
and may reduce the power to detect an effect. Many studies also failed to take
into account lifestyle characteristics of study participants. Finally, few studies
have considered an effect of OCs on BMD in women of races other than white.
The aim of this study was to evaluate the associations of OCs with spine, hip
and whole body BMD in black and white premenopausal women. Our primary
hypothesis was that there would be an association between cumulative exposure
to estrogen from OCs and BMD.

Introduction Section Exercise,
paragraph 1
n Ovarian cancer is the deadliest gynecologic cancer
with a high mortality rate that has remained
unchanged in the past four decades. The dismal
prognosis of ovarian cancer is in large part due to the
acquired resistance to chemotherapy. Epithelial
ovarian cancer, the most common type of ovarian
cancer, is initially responsive to cisplatin therapy. The
recurrent disease, however, is often refractory to
treatment and leads to mortality. New strategies to
overcome drug resistance are urgently needed in
order to reduce the mortality rate of ovarian cancer.
n

Introduction Section
paragraph 2
n The discovery of small interfering RNA (siRNA) by Fire and Mello
in 1998 has provided new avenues of combating resistant
cancers. Silencing genes that are involved in drug resistance
using RNA interference (RNAi) can allow for reversing cisplatin
resistance in ovarian cancer. Successful treatment of ovarian
cancer cells with multidrug resistance (MDR) gene-silencing
siRNAs and cisplatin requires the development of novel vehicles
that can specifically and effectively deliver cisplatin to cell nuclei
and siRNAs to cell cytoplasms, respectively. We report here the
first use of nanoscale metal-organic frameworks (NMOFs) for
the co-delivery of cisplatin and pooled siRNAs to overcome drug
re-sistance in ovarian cancer cells.
n

Introduction Section
paragraph 3
n MOFs are an emerging class of self-assembled, porous materials whose
properties can be readily tuned by varying the molecular building blocks. When
scaled down to the nano-regime, NMOFs serve as efficient nanocarriers for the
delivery of imaging contrast agents and chemotherapeutics. We surmised that
NMOFs represent a unique nanocarrier platform by virtue of their high porosity
and controllable surface functionalities: the large pores of NMOFs can be used to
load chemotherapeutics while the metal ions on the NMOF surfaces can be used
to bind siRNAs. The simultaneous and efficient delivery of cisplatin and pooled
siRNAs to ovarian cancer cells can allow for enhanced anticancer efficacy by
blocking multiple drug resistance pathways. In this work, cisplatin and siRNA
were sequentially loaded into UiO NMOFs by covalent attachment to bridging
ligands inside the NMOFs and coordinating to metal sites on the NMOF surfaces,
respectively. UiO NMOFs protect siRNAs from nuclease degradation, enhance
siRNA cellular uptake, and promote siRNA escape from endosomes to silence
MDR genes in cisplatin-resistant ovarian cancer cells. As a result, co-delivery of
cisplatin and siRNAs with NMOFs led to an order of magnitude enhancement in
chemotherapeutic efficacy in vitro, as indicated by cell viability assay, DNA
laddering, and Annexin V staining.
n

5. The Discussion section…
• Gives you the most freedom
• Gives you the most chance to put good
writing on display
• Is the most challenging to write

The Discussion
Follow your rules for good writing!

Invert the cone!
Answer the question asked.
Support your conclusion (your data, others’ data)
Defend your conclusion (anticipate criticisms)
Give the “big-picture” take-home message
I.e., what do my results mean
and why should anyone care?

• Start with: “WE FOUND THAT…” (or something similar)
• Explain what the data mean (big-picture!)
• State if the findings are novel
Key finding (answer to the
question(s) asked in Intro.)
Key secondary findings
• Give possible mechanisms or pathways
• Compare your results with other people’s results
• Discuss how your findings support or challenge the
paradigm
Context
• Anticipate readers’ questions/criticisms
• Explain why your Strengths and limitations results are robust
• Recommended confirmatory studies (“needs to be
confirmed”)
• Point out unanswered questions and future directions
What’s next
• Give the big-picture (human) implications of basic science
findings
• Tell readers why they should care
The “so what?”: implicate,
speculate, recommend
• Restate your main finding.
Strong conclusion • Give a final take-home message.

Discussion, example
LAST PARAGRAPH OF INTRODUCTION:
The differences in health benefits between a carbohydrate-restricted
diet and a calorie- and fat-restricted diet are of considerable public
interest. However, there is concern that a carbohydrate-restricted diet
will adversely affect serum lipid concentrations.1 Previous studies
demonstrating that healthy volunteers following a low-carbohydrate diet
can lose weight have involved few subjects, and few used a comparison
group that followed consensus guidelines for weight loss.2,3 The
reported effects of a carbohydrate-restricted diet on risk factors for
atherosclerosis have varied.2,3,4 We performed a study designed to
test the hypothesis that severely obese subjects with a high
prevalence of diabetes or the metabolic syndrome [a] would
have a greater weight loss, [b] without detrimental effects on
risk factors for atherosclerosis, while on a carbohydrate-restricted
(low-carbohydrate) diet than on a calorie- and fat-restricted
(low-fat) diet.
Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med 2003;348:2074-2081

The Discussion
1. We found that severely obese subjects with a high
prevalence of diabetes and the metabolic syndrome lost
more weight in a six-month period on a carbohydrate-restricted
diet than on a fat- and calorie-restricted diet.
[answer to a] The greater weight loss in the low-carbohydrate
group suggests a greater reduction in
overall caloric intake, rather than a direct effect of
macronutrient composition. [mechanisms] However, the
explanation for this difference is not clear. Subjects in this
group may have experienced greater satiety on a diet
with liberal proportions of protein and fat. However, other
potential explanations include the simplicity of the diet
and improved compliance related to the novelty of the
diet. [possible mechanisms/unanswered questions]

2. Subjects in the low-carbohydrate group had greater decreases in triglyceride
levels than did subjects in the low-fat group; nondiabetic subjects on the low-carbohydrate
diet had greater increases in insulin sensitivity, and subjects with
diabetes on this diet had a greater improvement in glycemic control. No adverse
effects on other serum lipid levels were observed. [answer to b] Most
studies suggest that lowering triglyceride levels has an overall cardiovascular
benefit.14,15,16 Insulin resistance promotes such atherosclerotic processes as
inflammation,17 decreased size of low-density lipoprotein particles,18 and
endothelial dysfunction.19 Impaired glycemic control in subjects with other
features of the metabolic syndrome markedly increases the risk of coronary
artery disease.20 As expected, we found that the amount of weight lost had a
significant effect on the degree of improvement in these metabolic factors.
[comparison to previous studies and paradigms] However,
even after adjustment for the differences in weight loss between the groups,
assignment to the low-carbohydrate diet predicted greater improvements in
triglyceride levels and insulin sensitivity. [unexpected] Subjects who lost
more than 5 percent of their base-line weight on a carbohydrate-restricted diet
had greater decreases in triglyceride levels than those who lost a similar
amount of weight while following a calorie- and fat-restricted diet.
[supporting details]

3. There was a consistent trend across weight-loss strata toward
a greater increase in insulin sensitivity in the low-carbohydrate
group, although these changes were small and were not
significant within each stratum. [supporting details: dose/
response] Although greater weight loss could not entirely
account for the greater decrease in triglyceride levels and
increase in insulin sensitivity in the low-carbohydrate group, we
cannot definitively conclude that carbohydrate restriction alone
accounted for this independent effect. [mechanisms] Other
uncontrolled variables, such as the types of carbohydrates
selected (e.g., the proportion of complex carbohydrates or the
ratio of carbohydrate to fiber), or other unknown variables may
have contributed to this effect. In addition, more precise
measurements of insulin sensitivity than we used would be
needed to confirm this effect of a carbohydrate-restricted diet.
[limitations/future studies]

4. Many of our subjects were taking lipid-lowering
medications and hypoglycemic agents. Although
enrolling these subjects introduced confounding
variables, it allowed the inclusion of subjects with
the obesity-related medical disorders typically
encountered in clinical practice. Analyses from which
these subjects were excluded still revealed greater
improvements in insulin sensitivity and triglyceride
levels on a carbohydrate-restricted diet than on a
fat- and calorie-restricted diet. [limitations and how
they were addressed]

5. Our study included a high proportion of black subjects,
a group previously underrepresented in lifestyle-modification
studies. [strength] As compared with the
white subjects, the black subjects had a smaller
overall weight loss. Future studies should explore
whether greater weight loss in this population can be
achieved by more effective incorporation of culturally
sensitive dietary counseling. [future directions]
6. The high dropout rate in our study occurred very early
and affected our findings. The very early dropout of
these subjects may indicate that attrition most closely
reflected base-line motivation to lose weight, rather
than a response to the dietary intervention itself.
[limitation]

7. Taken together, our findings demonstrate that severely obese subjects with
a high prevalence of diabetes and the metabolic syndrome lost more weight
during six months on a carbohydrate-restricted diet than on a calorie- and
fat-restricted diet. The carbohydrate-restricted diet led to greater
improvements in insulin sensitivity that were independent of weight loss and
a greater reduction in triglyceride levels in subjects who lost more than 5
percent of their base-line weight. [conclusion; restate answers to a and
b] These findings must be interpreted with caution, however, since the
magnitude of the overall weight loss relative to our subjects' severe obesity
was small, and it is unclear whether these benefits of a carbohydrate-restricted
diet extend beyond six months. Furthermore, the high dropout rate
and the small overall weight loss demonstrate that dietary adherence was
relatively low in both diet groups. [big picture] This study proves a
principle and does not provide clinical guidance; given the known
benefits of fat restriction, future studies evaluating long-term
cardiovascular outcomes are needed before a carbohydrate-restricted
diet can be endorsed. [take-home message]

EXAMPLE 2: Low-Fat Dietary Pattern and Colorectal
Cancer in The Women's Health Initiative Dietary
Modification Trial.
INTRODUCTION
The Women's Health Initiative (WHI) Dietary Modification Trial is a randomized
controlled trial designed in 1991-1992 to test whether a low-fat eating pattern with
increased fruits, vegetables, and grains reduces the risk of breast cancer, colorectal
cancer, or, secondarily, coronary heart disease in postmenopausal women. At that
time, international comparisons suggested that countries with 50% lower fat intake
than the US population had approximately one third the risk of colorectal cancer.1-2
Migration studies supported this hypothesis. Women migrating from countries with
low fat consumption to countries with high fat consumption experienced the higher
colorectal cancer rates of their new country.3-4 Fairly consistent evidence existed
for an effect of dietary fat, vegetables and fruits, and grains on colorectal cancer
risk from within-country observational studies,2, 5-8 although the protective effect
of lower fat intake was no longer clear after adjusting for energy intake.2, 9 The
WHI Dietary Modification Trial is the first randomized trial to
directly address the health effects of a low-fat eating pattern in
predominantly healthy postmenopausal women from diverse
racial/ethnic, geographic, and socioeconomic backgrounds. This
article reports the principal results for colorectal cancer. [the
question
JAMA. 2006;295:643-654

Discussion:
1. An intervention aimed toward a low-fat eating
pattern did not reduce colorectal cancer risk in
postmenopausal women. [answer to the question
asked] Despite a significant change in fat intake and
increases in vegetable, fruit, and grain consumption,
the intervention hazard ratio is in the direction of an
increased risk. [supporting evidence from this trial]
There were no substantial differences in tumor
characteristics or in rates of bowel screening between
groups. [supporting evidence] Although self-reported
incidence of colorectal polyps or adenomas was lower in
the intervention group, no evidence of a trend toward
lower colorectal cancer risk with time in the intervention
group was observed over the mean 8.1-year study
period.

2. These findings are consistent with the findings from the
Polyp Prevention Trial,31 a secondary prevention trial of
polyp recurrence, which had a similar goal for fat, fruit,
and vegetable intake but also included a goal of 18 g/1000
kcal of dietary fiber.32 The Polyp Prevention Trial observed
no effect on polyp recurrence in the 2079 participants
followed up for 4 years.32 A small trial in Toronto, Ontario,
of high fiber and low fat showed no effect on recurrence of
neoplastic polyps, but, within an intensive counseling
subgroup, concentrations of fecal bile acids appeared to be
reduced.33 A small factorial trial in Australia of a low-fat
intervention, -carotene supplementation, or wheat bran
supplementation found no reduction in recurrence rates of
adenomas but suggested that the combination of low fat
and wheat bran reduced the transition from smaller to
larger adenomas.34 [supporting evidence: other
TRIALS]

3. Since the WHI Dietary Modification Trial was designed,
the hypothesized relationship between dietary fat and risk
of colorectal cancer has been questioned.35 More recently,
higher red meat consumption has been associated with
increased colorectal cancer risk,23, 36-39 particularly in the
distal colon.23 The putative mechanism may be related to
heme, the iron carrier of red meat, rather than to its fat
content.23 In the WHI, the dietary intervention reduced
red meat consumption (Table 2), with no apparent overall
benefit on colorectal cancer risk but, perhaps, some shift
in risk in distal vs proximal colon cancers.
[consistency with the latest paradigm]
[mechanisms: is red meat more important than
fat?]

4. Mixed support exists for an influence of vegetables and fruits on
colorectal cancer risk.37, 40-42 Some of the antioxidants they contain
have not proved efficacious in reducing colorectal adenomas or
preventing incident colorectal cancer in randomized trials.43-45 Regular
consumption of alcohol has been associated with elevated risk of
colorectal cancer in some prospective studies, particularly among
persons with low folate status.46 This pattern was not found in the
comparison group of this study. Observations in East Africa by
Burkitt47 led to the hypothesis that very high fiber reduces colorectal
cancer risk. This has mixed support from observational studies48-50
and polyp and adenoma recurrence trials.31, 33-34,51-52 A European trial
found an adverse effect of soluble fiber on colorectal adenoma
recurrence,51 while an Arizona trial found no effect of wheat bran
supplement on colorectal adenoma recurrence.52 Our study is
consistent with lack of association in that women in the intervention
group modestly increased their fiber (Table 2) with no apparent
benefit over 8.1 years of follow-up.
[existing paradigms: does fiber matter?]

5. The observed interactions between the
intervention and baseline aspirin use, and
between intervention and use of combined
hormone therapy, are consistent with
synergistic effects of a low-fat dietary pattern
and these potentially protective agents.
However, given the large number of
interactions tested, these findings could also
have occurred by chance.
[Could the null finding be wrong? Maybe low-fat
diet matters for some groups]

6. From National Health and Nutrition Examination Survey (NHANES)
data, in 1977, women reported consuming 40.5% of their energy
from fat, while in 1987, the average was only 35.9%,54 and in 2000,
the average was 33% (NHANES 1999-2000). Organizations including
the National Cancer Institute, American Cancer Society, and Institute
for Cancer Prevention have recommended both lower fat intake and
increased vegetable and fruit use.55-56
7. One explanation for a lack of intervention effect on colorectal
cancer could be that the intervention did not achieve a large enough
difference between the intervention and comparison groups. Although
the changes achieved were substantial, and likely as large as could be
achieved in a trial of free-living individuals, they fell short of the
original design assumptions based on the Women's Health Trial
studies.27 Using food frequency data, the WHI intervention on
average achieved only about 70% of the designed reduction in fat. If
design assumptions are revised to take into account this departure
from goal, the predicted HR would have been 0.86, an effect size
excluded by these results. The power to detect this effect size under
the observed comparison group incidence rate and the achieved
adherence is approximately 40%. [Could the null finding be
wrong? Alternative explanations to no association]

8. Whether greater adherence, intervention of longer
duration, or initiation of change at an earlier age would
influence colorectal cancer risk remain unanswered
questions. The self-reported first occurrence of polyps or
adenomas was lower in dietary intervention women,
suggesting that longer follow-up (currently planned) may
reveal delayed benefit in favor of the intervention. Yet no
time trends regarding colorectal cancer risk over 8 years
of follow-up have been seen. To the extent that the WHI
Dietary Modification Trial intervention addressed the
recommendations from national organizations, the current
results suggest that changing dietary patterns to meet
these recommendations in mid to late life will have limited
or no benefit in preventing colorectal cancers in
postmenopausal women. [Defending their results]

9. The strengths of this study are its randomized design,
long-term follow-up, large numbers of participants,
diversity of race/ethnicity and socioeconomic status, and
high retention rate. The limitations of this study include
not attaining intervention goals as designed for reducing
fat intake or achieving large separation from the
comparison group in increased fruit, vegetable, or grain
intake. Thus the potential intervention effect of the WHI
low-fat dietary pattern may be underestimated.
Furthermore, there was no study-specified colonoscopy,
nor was there systematic screening for adenomatous
polyps; hence, the incidence of both colorectal cancer and
polyps or adenomas would be underestimated.
[Strengths and limitations]

10. In conclusion, there is no evidence
that a low-fat dietary pattern intervention
reduces colorectal cancer risk over an
average of 8.1 years of follow-up.
[Restatement of findings] Evidence from
this study, along with that from polyp
prevention trials, strongly suggests that
lowering dietary fat intake and increasing
fruit, vegetable, and fiber intake in mid to
late life cannot be expected to reduce the
risk of colorectal cancer in this length of
time. [Take-home message]

What NOT to do…
Don’t start your discussion like this!
Discussion
n This meta-analysis is subject to a number of
limitations. The estimates of risk for
melanoma subsequent to using sunlamps/
sunbeds are based on published data in a
series of 10 articles over a period of 20 years.
A pooled analysis of original observations
taken in the 10 studies would have provided a
more powerful approach …

The Discussion: verb tense
Past, when referring to study details, results, analyses,
and background research:
• We found that
• Subjects may have experienced
• Miller et al. found
Present, when talking about what the data suggest:
The greater weight loss suggests
The explanation for this difference is not clear.
Potential explanations include

6. Abstract
Abstracts (ab=out, trahere=pull; “to pull out”)
n Overview of the main story
n Gives highlights from each section of the paper
n Limited length (100-300 words, typically)
n Stands on its own
n Used, with title, for electronic search engines
n Most often, the only part people read

Abstract
1. Background
2. Question/aim/hypothesis
n “We asked whether,” “We hypothesized that,”…etc.
3. Experiment(s)
n Quick summary of key materials and methods
4. Results
n Key results found
n Minimal raw data (prefer summaries)
5. Conclusion: The answer to the question asked/take-home
message
6. Implication, speculation, or recommendation
Mimi Zeiger. Essentials of Writing Biomedical Research Papers, McGraw Hill Professional, 1999

Good references
n Clinical Chemistry Guide to Scientific
Writing:
http://www.aacc.org/publications/
clin_chem/ccgsw/Pages/default.aspx#
n Mimi Zeiger. Essentials of Writing
Biomedical Research Papers, McGraw Hill
Professional

For more training:
Writing in the Sciences MOOC:
https://class.stanford.edu/courses/Medicine/Sci-
Write/Fall2014/about

Slides: Manuscript Writing Workshop 10-2-14

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